Radiolabeled complexes and pharmaceutical compositions including the same

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

[0001] RADIOLABELED COMPLEXES AND PHARMACEUTICAL COMPOSITIONS INCLUDING THE SAME

[0002] The present invention relates to the field of radiolabeled complexes, in particular to novel radiopeptides targeting the urokinase-type plasminogen activator receptor (uPAR), and pharmaceutical compositions including the same.

[0003] Radiopharmaceuticals are drugs, which contain radioactive isotopes (radionuclides). Radiopharmaceuticals can be used to treat various conditions, including cancers, blood disorders and hyperthyroidism. In radionuclide therapy of cancer, a molecule labeled with a radionuclide is used to deliver a toxic level of radiation to disease sites. Accordingly, the molecule is used to "target" the disease site, e.g. specific cancer cells. Accordingly, the radionuclide complex combines the specificity of cancer cell targeting with the known antitumor effects of ionizing radiation. Thereby, not only the primary tumor site, but also its metastases can be targeted. The choice of the molecule that carries the radiation to the tumor is usually determined by its selectivity and affinity to the tumor's target structures, such as antigens or receptors. Even if a target structure is not selective for a certain kind of cancer, overexpressed target structures are of interest, because they allow the delivery of the radionuclide complex after its systemic administration in high concentration to those (overexpressing) target cells while leaving other cells (with no or minor expression only) essentially unaffected. Radionuclides are usually linked to the targeting molecule through chelating agents. Thereby, strong complexes with the metal ion of the radionuclide can be formed. The radioactive decay of the radionuclides can cause significant damage to cancer cells by releasing high energy electrons, positrons or alpha particles as well as gamma rays at the target site. The human urokinase-type plasminogen activator receptor (uPAR) is a glycosyl- phosphatidyl-inositol (GPI) membrane-anchored protein (Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F, Dano K. Cellular receptor for urokinase plasminogen activator. Carboxyl- terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991 ;266:1926-33.) It is not expressed at detectable levels in most quiescent cells of adult humans, but transiently present in normal tissue during wound healing (Mazar AP, Ahn RW, O'Halloran TV. Development of novel therapeutics targeting the urokinase plasminogen activator receptor (uPAR) and their translation toward the clinic. Curr Pharm Des. 2011 ;17:1970-8. doi : 10.2174 / 13816121 1796718152). uPAR expression has been found in solid tumors including breast, gastric, pancreatic, colorectal, prostate, ovarian, oral and esophageal cancer, where it has been associated with tumorigenesis, metastasis, angiogenesis, tumor proliferation and invasion (Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des. 2004;10:39- 49. doi:10.2174 / 1381612043453559; Alpizar-Alpizar W, Christensen IJ, Santoni-Rugiu E, Skarstein A, Ovrebo K, lllemann M, et al. Urokinase plasminogen activator receptor on invasive cancer cells: a prognostic factor in distal gastric adenocarcinoma. Int J Cancer. 2012;131 :E329-36. doi:10.1002 / ijc.26417; Christensen A, Kiss K, Lelkaitis G, Juhl K, Persson M, Charabi BW, et al. Urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and epidermal growth factor receptor (EGFR): tumor expression patterns and prognostic value in oral cancer. BMC Cancer. 2017;17:572. doi:10.1 186 / s12885-017- 3563-3; Mekkawy AH, Pourgholami MH, Morris DL. Involvement of urokinase-type plasminogen activator system in cancer: an overview. Med Res Rev. 2014;34:918-56. doi:10.1002 / med.21308; Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar EH. Evolving role of uPA / uPAR system in human cancers. Cancer Treat Rev. 2008;34:122-36. doi:10.1016 / j.ctrv.2007.10.005). It was also found expressed in several hematologic malignancies including multiple myeloma and acute leukemias (Mazar AP et al., 2011 , supra). Importantly, uPAR is present not only in tumors, but also in a number of tumor- associated cells, including angiogenic endothelial cells and macrophages (Mazar AP et al., 2011, supra). Cleaved uPAR present in the blood plasma was proposed as a biomarker for the diagnosis and therapy of cancer (Rasch MG, Lund IK, Almasi CE, Hoyer-Hansen G. Intact and cleaved uPAR forms: diagnostic and prognostic value in cancer. Front Biosci. 2008;13:6752-62. doi : 10.2741 / 3186). Increased blood plasma levels of uPAR have been associated with poor prognosis of patients with colon cancer (lllemann M, Bird N, Majeed A, Laerum OD, Lund LR, Dano K, et al. Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor-1 in colon cancer liver metastases. Int J Cancer. 2009;124:1860-70. doi:10.1002 / ijc.24166).

[0004] Based on its expression pattern, uPAR may be a relevant tumor-associated target for diagnostic and therapeutic radiopharmaceuticals. uPAR-targeting agents were identified using phage display and affinity maturation techniques to develop synthetic uPAR-binding peptides (Ploug M, Ostergaard S, Gardsvoll H, Kovalski K, Holst-Hansen C, Holm A, et al. Peptide-derived antagonists of the urokinase receptor. Affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation. Biochem. 2001 ;40:12157-68. doi:10.1021 / bi010662g; Ploug M. Structure- driven design of radionuclide tracers for non-invasive imaging of uPAR and targeted radiotherapy. The tale of a synthetic peptide antagonist. Theranostics. 2013;3:467-76. doi:10.7150 / thno.3791 ).

[0005] The nonapeptide AE105 has been reported to bind to human uPAR with high binding affinity (KD= 0.4 nM) (Ploug M et al., 2001 , supra). This peptide was, therefore, used as a uPAR-targeting agent for the development of nuclear imaging agents and radiotherapeutics (Ploug M et aL, 2001 , supra; Li D, Liu S, Shan H, Conti P, Li Z. Urokinase plasminogen activator receptor (uPAR) targeted nuclear imaging and radionuclide therapy. Theranostics. 2013;3:507-15. doi:10.7150 / thno.5557). AE105 was modified with various chelators including NOTA, NODAGA and DOTA, to enable the complexation of a variety of radiometals such as copper-64, gallium-68 and lutetium-177. The resultant radiopeptides were investigated in preclinical studies using various tumor mouse models; for example, [64Cu]Cu-DOTA-AE105 was used successfully to visualize small foci in a model of disseminated prostate cancer in mice (Li ZB, Niu G, Wang H, He L, Yang L, Ploug M, et al. Imaging of urokinase-type plasminogen activator receptor expression using a54Cu-labeled linear peptide antagonist by microPET. Clin Cancer Res. 2008;14:4758-66. doi:10.1 158 / 1078-0432. CCR-07-4434; Persson M, Juhl K, Rasmussen P, Brandt-Larsen M, Madsen J, Ploug M, et al. uPAR targeted radionuclide therapy with177Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer. Mol Pharm. 2014;1 1 :2796-806. doi:10.1021 / mp500177c). Moreover,68Ga-labeled DOTA-AE105 and NODAGA-AE105 were also investigated regarding their applicability for small animal PET imaging of U78MG tumor-bearing mice (Persson M, Madsen J, Ostergaard S, Ploug M, Kjaer A.68Ga-labeling and in vivo evaluation of a uPAR binding DOTA- and NODAGA-conjugated peptide for PET imaging of invasive cancers. Nucl Med Biol. 2012;39:560-9. doi : 10.1016 / j.nucmedbio.2011.10.011 ).

[0006] Clinical trials were initiated to demonstrate the potential of AE105-based radiopeptides to be used for nuclear imaging purposes. In 2014, a clinical trial was performed at Rigshospitalet, Denmark, to investigate [64Cu]Cu-DOTA-AE105 as a PET agent for the imaging of breast, urinary bladder and prostate cancer ("https: / / clinicaltrials.gov / show / NCT0213937T1\o "Current version of study NCT02139371 on ClinicalTrials.gov") (Persson M, Madsen J, Ostergaard S, Jensen MM, Jorgensen JT, Juhl K, et al. Quantitative PET of human urokinase-type plasminogen activator receptor with64Cu- DOTA-AE105: implications for visualizing cancer invasion. J Nucl Med. 2012;53:138-45. doi:10.2967 / jnumed.1 10.083386). The data of this study demonstrated a high and specific uptake of [64Cu]Cu-DOTA-AE105 in tumor lesions, resulting in images that outperformed those performed with [18F]fluoro-deoxyglucose. Another similar trial was performed using [68Ga]Ga-NOTA-AE105 for PET imaging of patients with neuroendocrine tumors (NCT03278275) (Skovgaard D, Persson M, Brandt-Larsen M, Christensen C, Madsen J, Klausen TL, et al. Safety, dosimetry, and tumor detection ability of68Ga-NOTA-AE105: First- in-human study of a novel radioligand for uPAR PET imaging. J Nucl Med. 2017;58:379-86. doi:10.2967 / jnumed.1 16.178970; Carlsen EA, Loft M, Loft A, Berthelsen AK, Langer SW, Knigge U, et al. Prospective phase II trial of prognostication by68Ga-NOTA-AE105 uPAR PET in patients with neuroendocrine neoplasms: implications for uPAR-targeted therapy. J Nucl Med. 2022;63:1371 -7. doi:10.2967 / jnumed.121 .263177).

[0007] The suitability of AE105-based radiopeptides for therapeutic applications has been scarcely investigated. Recent literature reported on the limited effectiveness of [177Lu]Lu-DOTA- AE105 in therapy experiments performed in tumor-bearing mice, likely due to its fast blood clearance and low accumulation in tumors (Persson M, Rasmussen P, Madsen J, Ploug M, Kjaer A. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts. Nucl Med Biol. 2012;39:962-9. doi:10.1016 / j.nucmedbio.2012.05.007). Moreover, the relatively high retention of [177Lu]Lu-DOTA-AE105 in the kidneys relative to the tumor uptake was also unfavorable for a therapeutic application.

[0008] Fast blood clearance is a common feature of small molecule- and peptide-based radiopharmaceuticals as it limits the maximum tumor accumulation. To address this concern, the strategy of introducing an albumin-binding moiety in the radioligands' chemical structure has been exploited in view of the optimization of their pharmacokinetic profiles. Numerous examples reported in the literature demonstrated the successful prolongation of the blood circulation time of radiopharmaceuticals as a result of the structural modification with albumin-binding entities (Lau J, Jacobson O, Niu G, Lin KS, Benard F, Chen X. Bench to bedside: Albumin binders for improved cancer radioligand therapies. Bioconjug Chem. 2019;30:487-502. doi:10.1021 / acs.bioconjchem.8b00919). This concept was initially demonstrated with folate radioconjugates (Muller C, Struthers H, Winiger C, Zhernosekov K, Schibli R. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted177Lu-radionuclide tumor therapy in mice. J Nucl Med. 2013;54:124-31 . doi:10.2967 / jnumed.112.107235; Siwowska K, Haller S, Bortoli F, Benesova M, Groehn V, Bernhardt P, et al. Preclinical comparison of albumin-binding radiofolates: impact of linker entities on the in vitro and in vivo properties. Mol Pharm. 2017;14:523-32. doi:10.1021 / acs.molpharmaceut.6b01010; Benesova M, Guzik P, Deberle LM, Busslinger SD, Landolt T, Schibli R, et al. Design and evaluation of novel albumin- binding folate radioconjugates: systematic approach of varying the linker entities. Mol Pharm. 2022; 19:963-73. doi:10.1021 / acs.molpharmaceut.1 c00932) and adopted later for other tumor-targeting agents, including prostate-specific membrane antigen (PSMA)- targeting radioligands (Benesova M, Umbricht CA, Schibli R, Muller C. Albumin-binding PSMA ligands: optimization of the tissue distribution profile. Mol Pharm. 2018;15:934-46. doi:10.1021 / acs.molpharmaceut.7b00877; Umbricht CA, Benesova M, Schibli R, Muller C. Preclinical development of novel PSMA-targeting radioligands: modulation of albumin- binding properties to improve prostate cancer therapy. Mol Pharm. 2018;15:2297-306. doi:10.1021 / acs.molpharmaceut.8b00152; Kelly J, Amor-Coarasa A, Ponnala S, Nikolopoulou A, Williams C, Jr., Schlyer D, et al. Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors. Eur J Nucl Med Mol Imaging. 2018. doi:10.1007 / s00259-018-4004-5; Kelly JM, Amor-Coarasa A, Pon Nikolopoulou A, Williams C, Jr., DiMagno SG, et al. Albumin-binding PSMA l implications for expanding the therapeutic window. J Nucl Med. 2019;60: doi:10.2967 / jnumed.1 18.221 150; Kuo HT, Merkens H, Zhang Z, Uribe CF, Lau J, Z et al. Enhancing treatment efficacy of177Lu-PSMA-61 7 with the conjugation of an al binding motif: preclinical dosimetry and endoradiotherapy studies. Mol 2018;15:5183-91. doi:10.1021 / acs.molpharmaceut.8b00720; Kuo HT, Lin KS, Zh Uribe CF, Merkens H, Zhang C, et al. Novel177Lu-labeled albumin-binder-conj PSMA-targeting agents with extremely high tumor uptake and enhanced tumor-to absorbed dose ratio. J Nucl Med. 2020. doi:10.2967 / jnumed.120.250738; Kuo HT, Zhang Z, Uribe CF, Merkens H, Zhang C, et al.177Lu-labeled albumin-binder-conj PSMA-targeting agents with extremely high tumor uptake and enhanced tumor-to absorbed dose ratio. J Nucl Med. 2021 ;62:521 -7. doi:10.2967 / jnumed.120.25073 achieved high tumor uptake resulted in an increased absorbed radiation dose improved the therapeutic outcome in preclinical studies (Umbricht CA et al, 2018, s was found that the y?ara-substituted 4-phenylbutanoate-based albumin binders (Dum Trussel S, Buller F, Trachsel E, Bootz F, Zhang V, et a! A portable albumin binder DNA-encoded chemical library. Angew Chem Int Ed Engl. 2008;47:31 doi:10.1002 / anie.200704936) were promising to be combined with small molecul peptides (Umbricht CA et al, 2018, supra; Kramer V, Fernandez R, Lehnert W, Ji Franco LD, Soza-Ried C, Eppard E, et al. Biodistribution and dosimetry of a single albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC. Eur J Nu Mo! Imaging. 2021 ;48:893-903. doi:10.1007 / s00259-020-05022-3), however, truncated version of Evans blue effectively enhanced the blood residence time modified radioligands (Wang Z, Jacobson O, Tian R, Mease RC, Kiesewetter DO, Ni al. Radioligand therapy of prostate cancer with a long-lasting prostate-specific me antigen targeting agent90Y-DOTA-EB-MCG. Bioconjug Chem. 2018;29:2 doi:10.1021 / acs.bioconjchem.8b00292; Zang J, Fan X, Wang H, Liu Q, Wang J, Li First-in-human study of177Lu-EB-PSMA-61 7 in patients with metastatic castration-r prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46:148-58. doi:10.1007 / s002 4096-y). Lessons learnt from a plethora of preclinical studies reported in the literature refer to the fact that the experience from one targeting agent cannot be translated to another targeting agent. The use of a strong albumin binder such as the p-iodophenyl entity improved the tissue distribution of folate radioconjugates (Muller C et al., 2013, supra). The same albumin binder was, however, not ideal for PSMA ligands (Umbricht CA et al., 2018, supra; Kramer V. etal., 2021 , supra) for which albumin binders with moderate affinity revealed to be more useful (Deberle LM, Benesova M, Umbricht CA, Borgna F, Buehler M, Zhernosekov K, et al. Development of a new class of PSMA radioligands comprising ibuprofen as an albumin- binding entity. Theranostics. 2020;10:1678-93. doi:10.7150 / thno.40482; Borgna F, Deberle LM, Busslinger SD, Tschan VJ, Walde LM, Becker AE, et al. Preclinical investigations to explore the difference between the diastereomers [177Lu]Lu-SibuDAB and [177Lu]Lu- RibuDAB toward prostate cancer therapy. Mol Pharm. 2022;19:2105-14. doi:10.1021 / acs.molpharmaceut.1 c00994). The optimum albumin binder and spacer entity to obtain the desired distribution profile must, thus, be identified for each specific tumor- targeting agent separately in systematic investigations.

[0009] In view of the above, it is the object of the present invention to overcome the drawbacks outlined above and to provide a novel radiolabeled complex targeting the urokinase-type plasminogen activator receptor (uPAR) having increased blood circulation time and, therewith, enhanced accumulation of activity at a target site, e.g. a tumor site.

[0010] This object is achieved by means of the subject-matter set out below and in the appended claims.

[0011] Although the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodologies, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0012] In the following, the elements of the present invention will be described. These elements are listed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

[0013] Throughout this specification and the claims which follow, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step but not the exclusion of any other non-stated member, integer or step. The term "consist of" is a particular embodiment of the term "comprise", wherein any other non-stated member, integer or step is excluded. In the context of the present invention, the term "comprise" encompasses the term "consist of". The term "comprising" thus encompasses "including" as well as "consisting" e.g., a composition "comprising" X may consist exclusively of X or may include something additional e.g., X + Y.

[0014] The terms "a" and "an" and "the" and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0015] The word "substantially" does not exclude "completely" e.g., a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention. The term "about" in relation to a numerical value x means x + 20%, preferably x + 10%, more preferably x ± 5%, even more preferably x ± 2% and still more preferably x ± 1 %.

[0016] Radiolabeled Complexes

[0017] In a first aspect, the present invention provides a radiolabeled complex targeting the urokinase-type plasminogen activator receptor as defined in the appended claims.

[0018] The radiolabeled complex of the present invention comprises:

[0019] (a) a targeting peptide moiety binding the urokinase-type plasminogen activator receptor (uPAR),

[0020] (b) a chelating moiety,

[0021] (c) a radionuclide, and

[0022] (d) an albumin-binding moiety, wherein the targeting peptide moiety, the chelating moiety and the albumin-binding moiety are linked via a common trifunctional linker moiety L1 .

[0023] Thus, the radiolabeled complex comprises a conjugate comprising a targeting moiety, a chelating moiety and an albumin-binding moiety (linked via a common trifunctional linker), wherein a radionuclide as defined herein is complexed by the chelating moiety.

[0024] Targeting Peptide

[0025] As used herein, the term "targeting peptide" (also referred to as "targeting moiety") refers to a peptide or polypeptide, which is able to bind (specifically) to the urokinase-type plasminogen activator receptor (uPAR). Peptides binding uPAR are known in the art. In some embodiments, the amino acids of the targeting peptide or polypeptide may be modified, for example by phosphorylation, acetylation, hydroxylation and / or methylation. The binding of the targeting peptide to the urokinase-type plasminogen activator receptor (uPAR) may be reversible or irreversible. Typically, the targeting peptide moiety comprises at least 5 amino acids, preferably at least 6 amino acids, more preferably at least 7 amino acids, still more preferably at least 8 amino acids and most preferably at least 9 amino acids. In a preferred embodiment, the targeting peptide may e.g. comprise 7 to 20 amino acids, i.e. the targeting peptide may comprise 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19 or 20 amino acids. In a more preferred embodiment, the targeting peptide comprises 8 to 15 amino acids, in a still more preferred embodiment, the targeting comprises 9 to 13 amino acids.

[0026] In a particular embodiment, the targeting peptide moiety comprises the amino acid sequence:

[0027] (Xaai)-([beta]-cyclohexyl-L-alanine)-(Phe)-(Xaa4)-(Xaa5)-(Xaa6)-(Xaa7)-(Xaa8)-(Xaa9), wherein

[0028] (Xaai) is preferably selected from the group consisting of (D-Asp), (Asp), (Leu), (D-Glu), and (D-Thr), and is more preferably selected from (D-Asp) and (Asp);

[0029] (Xaa4) is preferably selected from the group consisting of (D-Ser) and (Ser);

[0030] (Xaa5) is preferably selected from the group consisting of (D-Arg), (Arg), (Tyr), (D-Tyr), and (Gin), and is more preferably (D-Arg);

[0031] (Xaa6) is preferably selected from the group consisting of (Tyr), ([beta]-cyclohexyl-L-alanine), N-(2,3-dimethoxybenzyl)glycine, and is more preferably (Tyr);

[0032] (Xaa7) is preferably selected from the group consisting of (Leu) and (D-Phe);

[0033] (Xaa8) is preferably selected from the group consisting of (Trp), ([beta]-1 -naphthyl-L-alanine), ([beta]-2-naphthyl-L-alanine), (N-(3-indolylethyl)glycine), (N-benzylglycine), (N- (methylnaphthalyl)glycine) and (N-(2,3-dimethoxybenzyl)glycine), and is more preferably (Trp); and

[0034] (Xaa9) is preferably selected from the group consisting of (Ser), (D-His), (lie), (N-(2- methoxyethyOglycine), and (N-(2[beta]methoxyethyl)glycine), and is more preferably (Ser).

[0035] Thus, in a particular embodiment, the targeting peptide moiety may comprise an amino acid sequence selected from the group consisting of (D-Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 1 ), (Leu)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Gln)-(Tyr)-(Leu)-(Trp)-(Ser) ((SEQ ID NO: 2),

[0036] (D-Glu)-([beta]-cydohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Tyr)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID

[0037] NO: 3),

[0038] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 4),

[0039] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 5), (D-Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 6),

[0040] (D-Thr)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 7),

[0041] (D-Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-([beta]-2-naphthyl-L- alanine)-(Ser) (SEQ ID NO: 8),

[0042] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 9), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-([beta]-1 -naphthyl-L- alanine)-(Ser) (SEQ ID NO: 10), (D-Glu)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Tyr)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO:

[0043] 11 ),

[0044] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Leu)-(Leu)-(Trp)-(D-His) (SEQ ID NO: 12),

[0045] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-([beta]-cyclohexyl-L-alanine)- (Leu)-(Trp)-(lle) (SEQ ID NO: 13),

[0046] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-([beta]-1 -naphthyl-L- alanine)-(D-His) (SEQ ID NO: 14),

[0047] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N-(2,3-dimethoxybenzyl)glycine)- (D-Phe)-(N-(3-indolylethyl)glycine)-(N-(2-methoxyethyl)glycine) (SEQ ID NO: 15),

[0048] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N-(2,3-dimethoxybenzyl)glycine)- (D-Phe)-(N-benzylglycine)-(N-(2[beta]methoxyethyl)glycine) (SEQ ID NO: 16), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N-(2,3-dimethoxybenzyl)glycine)- (D-Phe)-(N-(methylnaphthalyl)glycine)-(N-(2-methoxyethyl)glycine) (SEQ ID NO: 17), and

[0049] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(N-(2,3-dimethoxybenzyl)glycine)- (D-Phe)-(N-(2,3-dimethoxybenzyl)glycine)-(lle) (SEQ ID NO: 18). In a preferred embodiment, the targeting peptide moiety may comprise the amino acid sequence:

[0050] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Xaa5)-(Xaa6)-(Leu)-(Trp)-(Xaa9) (SEQ ID NO: 19), wherein

[0051] (Xaa5) is selected from (D-Arg), (D-Lys), (D-Cys), and (D-Ser);

[0052] (Xaa6)is selected from (Tyr) and (Pro); and

[0053] (Xaa9) is selected from (Cys) and (Ser). Thus, in a preferred embodiment, the targeting peptide moiety may comprise an amino acid sequence selected from the group consisting of

[0054] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO: 4),

[0055] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Lys)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO:

[0056] 20),

[0057] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Cys)-(Tyr)-(Leu)-(Trp)-(Cys) (SEQ ID NO:

[0058] 21 ),

[0059] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Ser)-(Tyr)-(Leu)-(Trp)-(Ser) (SEQ ID NO:

[0060] 22), and

[0061] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Cys)-(Pro)-(Leu)-(Trp)-(Cys) (SEQ ID NO: 23).

[0062] In a particular preferred embodiment, the targeting peptide moiety comprises the amino acid sequence (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)- (Ser) (SEQ ID NO: 4).

[0063] This uPAR-binding nonapeptide is also referred to as AE105:

[0064]

[0065] The targeting peptide moiety may also comprise a mutated form of the AE105 nonapeptide, such as (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Glu)-(Ser) (SEQ ID NO: 24), for example.

[0066] In another embodiment, the targeting peptide moiety may comprise a derivative of AE105 e.g. having the amino acid sequence [((Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D- Arg)-(Tyr)-(Leu)-(Trp)-(Ser))2-(βAIa)-(Lys)] (SEQ ID NO: 25), referred to as AE120, or having the amino acid sequence (Lys)-(Ser)-(Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D- Lys)-(cyclohexyl-D-Gly)-(Leu)-(Trp)-(Ser)-(Ser)-(Lys) (SEQ ID NO: 26), referred to as AE170.

[0067] In still another embodiment, the targeting peptide moiety may comprise a cyclized variant of AE105, e.g. having the amino acid sequence (Lys)-(Ser)-(Asp)-([beta]-cyclohexyl-L- alanine)-(Phe)-(D-Ser)-(D-Lys)-(Tyr)-(Leu)-(Trp)-(Ser)-(Ser)-(Lys) (SEQ ID NO: 27) referred to as AE147.

[0068] Thus, the targeting peptide moiety of the inventive conjugate / radiolabeled complex preferably comprises or consist of a AE105 nonapeptide, or a derivative or mutated form thereof, or a (cyclized) variant thereof.

[0069] Radionuclide Various radionuclides (radioisotopes) are known to be useful in the field of radionuclide therapy. In particular, the term "radionuclide" (or "radioisotope") refers to isotopes of natural or artificial origin with an unstable neutron to proton ratio that disintegrates with the emission of corpuscular (i.e. positrons (beta plus-radiation); helium nuclei (alpha-radiation) or electrons (beta minus-radiation, Auger and conversion electron radiation) or electromagnetic radiation (gamma-radiation). In other words, radionuclides undergo radioactive decay. Said radionuclide may preferably be useful for cancer imaging or therapy.

[0070] Non-limiting examples of suitable radionuclides include99mTc,1 l lln,67Ga,68Ga,86Y,90Y,177Lu,161Tb,149Tb,155Tb,152Tb,186Re,188Re,61Cu,64Cu,67Cu,55Co,57Co,43Sc,44Sc,47Sc,225Ac,213Bi,212Bi,212Pb,227Th,153Sm,166Ho,166Dy,169Er,16SEr,103Pd,109Pd,103mRh,18F,123l,124l,131l, and2l 1At. Accordingly, the radionuclide of the inventive radiolabeled complex may be any one of the before-mentioned examples. The choice of suitable radionuclides may depend inter alia on the chemical structure and chelating capability of the chelating agent, and the intended application of the resulting (complexed) conjugate (e.g. diagnostic vs. therapeutic). For instance, the beta-minus emitters such as90Y,l31l,161Tb and177Lu may be used for systemic radionuclide therapy. For example, DOTA, as chelating agent, may advantageously enable the use of177Lu,161,155, 152, 149Tb,43,44,47Sc,225Ac,213, 212Bi, or212Pb as radionuclides, while NODAGA is more favorably used for chelation of68,67Ga, and61'64,67Cu.

[0071] Preferably, the radionuclide is selected from the group consisting of111ln,67Ga,68Ga,86Y,90Y,177Lu,161Tb,152Tb,155Tb,149Tb,61Cu,64Cu,67Cu,55Co,57Co,43Sc,44Sc,47Sc,225Ac,213Bi,212Bi,212Pb,1S3Sm,166Ho,225Ac,21 lAt and166Dy. In particular embodiments, for imaging purposes, the radionuclide may be44Sc. In further embodiments, the radionuclide may be64Cu. In some embodiments, the radionuclide may be68Ga.

[0072] Preferably, for therapeutic purposes, the electron-emitting radionuclide may be selected from177Lu and161Tb, and alpha-emitting radionuclides may be selected from149Tb and212Pb whereof the latter decays via a beta minus emission to the alpha-particle emitting212Bi.

[0073] Chelating Moiety In the radiolabeled complex, the radionuclide metal ion usually forms a non-covalent bond with functional groups of the chelating moiety, e.g. amines or carboxylic acids. Typically, the chelating moiety has at least two such complexing functional groups to be able to form a chelate complex.

[0074] As used herein, the term "chelating moiety" (also referred to as "chelator") refers to polydentate (multiple bonded) ligands capable of forming two or more separate coordinate bonds with (coordinating") a central (metal) ion, in particular the radionuclide metal ion. Specifically, such molecules or molecules sharing one electron pair may also be referred to as „Lewis bases". The central (metal) ion is usually coordinated by two or more electron pairs to the chelating agent. The terms, „bidentate chelating agent", „tridentate chelating agent", and „tetradentate chelating agent" are known in the art and refer to chelating agents having two, three, and four electron pairs, respectively, which are readily available for simultaneous donation to a metal ion coordinated by the chelating agent. Usually, the electron pairs of a chelating moiety forms coordinate bonds with a single central (metal) ion; however, in certain examples, a chelating moiety may form coordinate bonds with more than one metal ion, with a variety of binding modes being possible.

[0075] The terms "Coordinating" and "Coordination" refer to an interaction in which one multi- electron pair donor coordi natively bonds (is "Coordinated") to, i.e. shares two or more unshared pairs of electrons with, one central (metal) ion.

[0076] The chelator or chelating moiety is preferably a macrocyclic bifunctional chelator having a metal chelating group at one end and a reactive functional group at the other end, which is capable to bind to other moieties, e.g. peptides. Preferably, the chelator may be selected such that the chelator forms a square bi-pyramidal complex for complexing the radionuclide. In another embodiment, the chelator does not form a planar or a square planar complex.

[0077] The chelating moiety may be selected based on its ability to coordinate the desired central (metal) ion, usually the radionuclide as described herein.

[0078] Accordingly, the chelating moiety may be a macrocyclic or linear chelator characterized by one of the following Formulae (1 a) to (Iff):

[0079]

[0080]

[0081]

[0082] Preferably, the chelating moiety is selected from 1 ,4,7,10-tetraazacyclododecane-1 , 4, 7,10- tetraacetic acid (DOTA), 1 ,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7- bis(carboxymethyl)-1 ,4,7-triazonan-1 -yl)pentanedioic acid (NODAGA), N,N'-bis[2- hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine- / V / / V'-diacetic acid (HBED-CC), 2- (4,7,10-tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecan-1 -yl)-pentanedioic acid

[0083] (DOTAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), l,4,7-triazacydononane-1 - [methyl(2-carboxyethyl)-phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9, 15-tetraazabicyclo[9,3,1]pentadeca-1 (15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), Diethylenetriaminepentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1 ,4,7,10-Tetraazacyclododecane- 1,4,7-triacetic acid (DO3A) and derivatives thereof (cf. formulae 1 d, 1 e, 1f), hydrazinonicotinic acid (HYNIC), 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid (AAZTA), and 1 ,4,7,10-Tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane

[0084] (DOTAM).

[0085] In a preferred embodiment, the chelating moiety is selected from DOTA (which may be characterized by Formula (1 a)), NOTA (which may be characterized by Formula (1g)), NODAGA (which may be characterized by Formula (1 h)) and DOTAGA (which may be characterized by Formula (1 b)).

[0086] More preferably, the chelating moiety is selected from DOTA (1 ,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic aacciidd,, and DOTAGA (2-(4,7,10- tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecan-1 -yl)-pentanedioic acid) or derivatives thereof.

[0087] Particularly preferably, the chelating agent is DOTA. Advantageously, DOTA effectively forms complexes with diagnostic (e.g.68Ga) and therapeutic (e.g.161Tb or177lu) radionuclides and thus enables the use of the same conjugate (targeting molecule linked to the chelating agent) for both imaging and therapeutic purposes, i.e. as a theragnostic agent. DOTA derivatives capable of complexing Scandium radionuclides (43Sc,44Sc,47Sc), including DO3AP, DO3APPrA, or DO3APABn(which may be characterized by Formulae (I d), (1 e) and (If)) may also be preferred and are described in Kerdjoudj et al. Dalton Trans., 2016, 45, 1398-1409.

[0088] The chelating agent, for example DOTA, may be complexed with any appropriate radionuclide (in particular with the radionuclide as described above) as a central (metal) ion. It is within the skill and knowledge of the skilled person in the art to select suitable combinations of conjugates and radionuclides. In some embodiments, the chelator may be DOTA and the radionuclide may be68Ga. In other embodiments, the chelator may be NODAGA and the radionuclide may be68Ga. In other embodiments, the chelator may be DOTA and the radionuclide may be44Sc. In yet further embodiments, the chelator may be DOTA and the radionuclide may be64Cu. In other embodiments, the chelator may be NODAGA and the radionuclide may be61Cu,64Cu or67Cu. In other embodiments, the chelator may be DOTAM and the radionuclide may be212Pb. In a preferred embodiment, the chelator may be DOTA and the radionuclide may be161Tb. In another preferred embodiment, the chelator may be DOTAGA and the radionuclide may be177Lu. In another preferred embodiment, the chelator may be DOTA and the radionuclide may be, 77Lu.

[0089] Albumin-binding Moiety

[0090] The inventive radiolabeled complex comprises an albumin-binding moiety which is preferably capable of selectively binding to serum albumin, e.g. to mouse serum albumin or human serum albumin (HSA). The term "selectively binding" means that a compound binds with a greater affinity to its intended target than it binds to another, non-target entity. "Binding affinity" is the strength of the binding interaction between a ligand (e.g. a small organic molecule, protein or nucleic acid) to its target / binding partner. Binding affinity is typically measured and reported by the equilibrium dissociation constant (KD), a ratio of the "off-rate" (koff) and the "on-rate" (kon), which is used to evaluate and rank order strengths of bimolecular interactions. The "on-rate" (Kon) characterizes how quickly a ligand binds to its target, the "off-rate" (koff) characterizes how quickly a ligand dissociates from its target. KD(koff / Kon) and binding affinity are inversely related. Thus, the term "selectively binding" preferably means that a ligand binds to its intended target with a KDthat is lower than the KDof its binding to another, non-target entity. There are many ways to measure binding affinity and dissociation constants, such as ELISA, gel-shift assays, pull-down assays, equilibrium dialysis, analytical ultracentrifugation, surface plasmon resonance, and spectroscopic assays.

[0091] The albumin-binding moiety may be any known or newly developed albumin-binding moiety. Particularly preferred albumin-binding moieties are described herein below. The albumin-binding moiety may preferably bind non-covalently to serum albumin, preferably HSA, typically with a binding affinity of less than about 100 μm (micromolar), e.g. of about 3 μm (micromolar) to 50 μm (micromolar).

[0092] Human Serum Albumin (HSA) is the most abundant protein in human blood plasma and constitutes about half of serum protein. The term "Human Serum Albumin" or "HSA" as used herein preferably refers to the serum albumin protein encoded by the human ALB gene. More preferably, the term refers to the protein as characterized under UniProt Acc. No. P02768 (entry version 240, last modified May 10, 2017, or functional variants, isoforms, fragments or (post-translational ly or otherwise modified) derivatives thereof.

[0093] Without wishing to be bound by specific theory, it is hypothesized that the albumin-binding moiety of the inventive radiolabeled complex preferably extends circulation half-life of the conjugates, and effects compartmentalization of the inventive complexes in the blood and improved delivery to the uPAR-expressing (tumor) target cells or tissues. The albumin- binding moiety is thus envisaged to confer improved pharmacokinetic properties to the inventive complex, preferably without interfering with (reducing or abolishing) the desired function of the chelating moiety and the uPAR binding moiety.

[0094] The albumin-binding moiety may be any albumin-binding moiety known in the art. Particularly preferred albumin-binding entities are described herein below. The albumin- binding moiety may preferably bind non-covalently to HSA, typically with a binding affinity less than about 100 μm. In terms of structure, typical albumin-binding moieties in accordance with the present invention comprise linear and branched lipophilic groups comprising 1 -40 carbon atoms and a distal acidic group. Suitable albumin-binding entities are inter alia described in US 2010 / 172844 A1 , WO 2013 / 024035 A1 and WO 2008 / 053360 A2, which are incorporated by reference in their entirety herein.

[0095] In the conjugates / radiolabel complexes of the present invention, the albumin-binding moiety is preferably characterized by General Formula (2): wherein

[0096] R1and R2are each independently selected from H, F, Cl, Br, I, branched, unbranched or cyclic C1-C12 hydrocarbyl, C2-C12alkenyl, C2-C12 alkylnyl, OR6, OCOR6, CHO, COR6, CH2OR6NR6R7, CONR6R7, COOR6, CH2NR6R7, SR6, =O, =S or =NH, or R1and R2are joined to form a cyclic structure comprising a branched, unbranched or cyclic C1-C10 hydrocarbyl group, wherein said hydrocarbyl group is optionally interrupted by up to 2 heteroatoms and optionally substituted by up to 3 groups independently selected from F, Cl, Br, I, OR6, OCOR6, COOR6, CHO, COR6, CH2OR6, NR6R7, CH2NR6R7, and SR7, =O, =S and =NH,

[0097] Y is selected from a single bond or a linear, branched or cyclic, optionally substituted C1-C12 alkyl, optionally interrupted by up to two heteroatoms, OR6, OCOR6, CHO, COR6, CH2OR6NR6R7, COOR6, CH2NR6R7, SR6, =O, =S or =NH, wherein one or more of the non-adjacent CH2-groups may independently be replaced by -O-, -CO- -CO- O-, -O-CO-, -NR6-, -NR5-CO~, -CO-NR6-, -NR6-COO-, -O-CO-NR6-, -NR6-CO- NR6— , -CH=CH- , -O-CO-O-, SR6-, SO3R6-,

[0098] R6and R7are each independently selected from H or branched, unbranched or cyclic C1-12hydrocarbyl, and X is selected from O, N, P or S.

[0099] R1and R2may be in ortho-, meta or para-position.

[0100] When R1and R2are joined in order to, together, form a cyclic structure, said cyclic structure is preferably a linear or branched hydrocarbyl chain of 3-12, more preferably 3-10, even more preferably 3-9, 3-8, 3-7, 3-6, 3-5, 3-4 or 4 carbon atoms bonded at two positions to the phenyl ring, i.e. forming two bonds to said phenyl ring, such as to form a ring structure fused to said phenyl ring. Specifically, said cyclic structure may be selected from (substituted or unsubstituted) adamantyl. Preferably, said two bonds are preferably situated at the meta (3-) and para (4-) positions, at the ortho (2-) and meta positions or at the ortho and para positions of said phenyl ring. Said cyclic structure is optionally interrupted by up to 2, preferably 1 or no heteroatoms. Preferably, said cyclic structure may be a C4chain fragment (1 ,4-diradical) linked by its 1 - and 4- atoms to said phenyl ring to form a six- membered ring fused to said phenyl ring, preferably at the meta and para positions of said phenyl ring, i.e., preferably forming a meta- and para-fused six-membered ring.

[0101] Preferably, R1and R2may each be independently selected from H, halogen, preferably iodine or bromine, and C1-6alkyl, preferably C1-3alkyl, even more preferably methyl. More preferably, R1is H and R2is selected from halogen, preferably iodine or bromine, and C1-6alkyl, preferably C1.3 alkyl, even more preferably methyl. Even more preferably, R1is H and R2is H or is in the para position and selected from iodine, bromine and methyl.

[0102] Preferably, Y may be a linear or branched, optionally substituted, C1-C12hydrocarbyl, more preferably a linear or branched, optionally substituted, C1-C10hydrocarbyl, even more preferably a linear or branched, optionally substituted, C1-C6hydrocarbyl, even more preferably a a linear or branched, optionally substituted, C1-C3hydrocarbyl.

[0103] Most preferably, Y may be -(CH2)3-.

[0104] Preferably, X may be O.

[0105] Accordingly, the albumin-binding moiety according to Formula (2) may preferably comprise any one of Formulae (2a)-(21):

[0106] Preferably, the albumin-binding moiety comprises a group, which may be characterized by Formula (2c) or (2e). Thus, preferably, the albumin-binding moiety comprises a group selected from an iodophenyl moiety, and a tolyl moiety.

[0107] In another preferred embodiment, the albumin-binding moiety may comprise an ibuprofen moiety, which is shown in Formula (21). A conjugate according to the present invention, in which ibuprofen is used as an albumin-binding moiety is shown in Formula (9) below.

[0108] Alternatively, Evans Blue or derivatives thereof (e. g. truncated Evans Blue), which has been shown to bind to albumin with high affinity (Orit Jacobson, Dale O Kiesewetter, Xiaoyuan Chen (Albumin-Binding Evans Blue Derivatives for Diagnostic Imaging and Production of Long-Acting Therapeutics, Bioconjug Chem. 2016 Oct 19;27(10):2239-2247. doi: 10.1021 / acs.bioconjchem.6b00487. Epub 2016 Oct 6) may also be contemplated as albumin-binding moiety in the inventive conjugates / radiolabeled complexes.

[0109] Linker Moi eties

[0110] The present invention provides novel uPAR-binding conjugates / radiolabeled complexes with improved tumor-targeting properties and favorable pharmacokinetic profiles. As used herein, the term „pharmacokinetics" refers to the stability, bioavailability, absorption; biodistribution, biological half-life and / or clearance of a therapeutic or diagnostic agent in a subject. The present invention provides novel conjugates by covalently coupling a human serum albumin (HSA) binding moiety to an uPAR-binding peptide moiety on the one hand and a chelating moiety capable of complexing therapeutic / diagnostic radionuclides on the other hand, via suitable linkers and spacers, respectively. The linker and spacer moieties connecting the binding entities and chelator were found to be crucial for the targeting and pharmacokinetic properties of the resulting conjugates / radiolabeled complexes. The novel conjugates / radiolabeled complexes preferably exhibit superior and specific cellular uptake and internalization characteristics. Introduction of a HSA binding entity thereby advantageously improves biodistribution and, eventually, therapeutic efficacy of the inventive compounds.

[0111] Trifunctional linker moiety L 7

[0112] In the inventive conjugate / radiolabeled complex, the (uPAR binding) targeting peptide moiety, the chelating moiety and the albumin-binding moiety are linked via a common trifunctional linker moiety L1.

[0113] Accordingly, the present invention provides a conjugate represented by the general structure (I): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety.

[0114] Accordingly, the linker moiety L1 constitutes a "branching point" in the inventive conjugate / radiolabeled complex.

[0115] The linking bonds between the targeting peptide moiety and the linker moiety L1 , the chelating moiety and the linker moiety L1 , and the albumin-binding moiety and the linker moiety L1 , respectively, are covalent or non-covalent bonds. Preferably the bonds are covalent. The term "linker" is used herein to specifically refer to the group connecting or linking and thus spanning the distance between the moieties of the inventive conjugate / radiolabeled complex, i.e. the targeting peptide moiety (i.e. uPAR-binding moiety), the chelating moiety and the albumin-binding moiety, respectively.

[0116] The linker may preferably avoid sterical hindrance between the targeting peptide moiety (i.e. uPAR-binding moiety), the chelating moiety and the albumin-binding moiety and ensure sufficient mobility and flexibility. Further, the linker may preferably be designed so as to confer, support and / or allow sufficient HSA binding, high affinity uPAR binding, and rapid and optionally selective penetration of uPAR positive cells through internalization of the inventive radiolabeled complex.

[0117] Preferably, the trifunctional linker moiety L1 comprises an amino acid residue or a derivative thereof. Thus, the targeting peptide moiety (i.e. uPAR-binding moiety), the chelating moiety and the albumin-binding moiety are linked, preferably covalently linked, by an amino acid residue or a derivative thereof, wherein preferably one of the moieties may be bound to the amino group of the amino acid, one moiety may be bound to the carboxy group of the amino acid, and one moiety may be bound to a side-chain functional group, e.g. a further amino (NH2-) group, a further carboxy (COOH-) group, a hydroxyl (OH-) group, or a thio (SH-) group of the amino acid's side chain.

[0118] Preferably, the trifunctional linker moiety L1 is an amino acid selected from the group consisting of a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, an aspartic acid residue, glutamic acid residue, serine residue, threonine residue, cysteine residue, or a derivative of said amino acid residues, more preferably selected from a lysine residue, an arginine residue, a glutamine residue, an asparagine residue or a derivative of said amino acid residues, most preferably a lysine residue or a derivative thereof.

[0119] In this respect, a derivative of an amino acid residue may e.g. be an amino acid having a shortened or extended hydrocarbon chain. A derivative of an amino acid may also be a substituted amino acid, e.g. a methylated amino acid, such as e.g. methyllysine, methylarginine etc. An example of a conjugate comprising, as a trifunctional linker moiety L1 , a lysine derivative having a shortened side chain (diaminopropanoic acid) will be shown below (Formula (8)).

[0120] In a preferred embodiment, the trifunctional linker moiety L1 is a lysine residue or a derivative thereof. A conjugate according to the present invention (referred to as DOTA- uPAR-ALB-01 ), which comprises the nonapeptide AE105 as a (uPAR-binding) targeting peptide moiety, DOTA as a chelating moiety, iodophenyl as an albumin-binding moiety, and lysine as a trifunctional linker moiety is represented by formula (3):

[0121] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (3) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts, in particular when compared to prior art radiopeptide ([177Lu]Lu-DOTA-AE105) lacking the albumin- binding entity.

[0122] Linker moiety L2

[0123] In a preferred embodiment of the inventive radiolabeled complex, an (additional) linker moiety L2 is located between the trifunctional linker moiety L1 and the albumin-binding moiety providing a greater distance between the albumin-binding moiety to the chelating moiety and the targeting peptide moiety, respectively. Accordingly, in a preferred embodiment, the present invention provides a conjugate represented by the following general structure (II): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 is a linker moiety as defined above.

[0124] The linker moiety L2 which provides further distance between the albumin-binding moiety and the chelating and uPAR-binding targeting peptide moieties, respectively, may be selected from any suitable and pharmaceutical acceptable linker moieties known in the art. Preferably, the linker moiety L2 is selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly(N / -vinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, more preferably from the group consisting of amino acids, polyethyleneglycols (PEGs), and alkyl groups.

[0125] Thus, in a particular embodiment, the linker moiety L2 may comprise at least one amino acid which is preferably selected from the group consisting of lysine, arginine, glutamine, asparagine, aspartic acid, glutamic acid, serine, tyrosine, threonine, phenylalanine, cysteine, proline, leucine, isoleucine, valine, histidine, alanine, and diaminobutyric acid, or a derivative of said amino acids, or a combination of said amino acid residues. For example, the linker moiety L2 comprises at least one lysine residue or a derivative thereof.

[0126] In a preferred embodiment, the linker moiety L2 comprises a PEG moiety. The PEG based linker may comprise about 1 to 30 PEG units, and preferably comprises 1 to 10 PEG units, more preferably 2 to 7 PEG units, most preferably 3 to 5 PEG units. In a preferred embodiment, the trifunctional linker moiety L1 is a lysine residue or a derivative thereof, and the linker moiety L2 is a PEG moiety, preferably a PEG3to PEG5moiety, e.g. a PEG4moiety.

[0127] An exemplary conjugate according to the present invention (referred to as DOTA-uPAR-Alb- 02), which comprises the nonapeptide AE105 as a (uPAR-binding) targeting peptide moiety, DOTA as a chelating moiety, iodophenyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG4linker as a linker moiety L2, is represented by formula (4):

[0128] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (4) has particularly advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts.

[0129] Another exemplary conjugate according to the present invention (referred to as DOTA- uPAR-Alb-1 1 ), which comprises the nonapeptide AE105 as a (uPAR-binding) targeting peptide moiety, DOTA as a chelating moiety, p-tolyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG4linker as a linker moiety L2, is represented by formula (5):

[0130]

[0131] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (5) has particularly advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts.

[0132] Another exemplary conjugate according to the present invention (referred to as DOTA- uPAR-Alb-15), which comprises the nonapeptide AE105 as a targeting peptide (uPAR- binding) moiety, DOTA as a chelating moiety, a p-tolyl moiety as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG3linker as a linker moiety L2, is represented by formula (6):

[0133] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (6) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts. Another exemplary conjugate according to the present invention (referred to as DOTA- uPAR-Alb-18), which comprises the nonapeptide AE105 as a targeting peptide (uPAR- binding) moiety, DOTA as a chelating moiety, a p-tolyl moiety as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG5linker moiety as a linker

[0134] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (7) has particularly advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts.

[0135] Another exemplary conjugate according to the present invention (referred to as DOTA- uPAR-Alb-14), which comprises the nonapeptide AE105 as a targeting peptide (uPAR- binding) moiety, DOTA as a chelating moiety, p-tolyl as an albumin-binding moiety, diaminopropanoic acid (instead of a lysine residue) as a trifunctional linker moiety L1 , and a PEG4linker as a linker moiety L2, is represented by formula (8):

[0136]

[0137] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (8) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts.

[0138] Another exemplary conjugate according to the present invention, which comprises the nonapeptide AE105 as a targeting peptide (uPAR-binding) moiety, DOTA as a chelating moiety, ibuprofen as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG4 linker moiety as a linker moiety L2, is represented by formula (9):

[0139] Another exemplary conjugate according to the present invention (referred to as DOTAGA- uPAR-Alb-17), which comprises the nonapeptide AE105 as a targeting peptide (uPAR- binding) moiety, DOTAGA as a chelating moiety, tolyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG4linker moiety as a linker moiety L2, is represented by formula (10):

[0140] As shown in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (10) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts. In another embodiment, the linker moiety L2 may comprise an alkyl group. The alkyl linker may e.g. comprise about 1 to 30 C atoms. Preferably, the alkyl linker comprises about 5 to 20 C atoms, more preferably about 7 to 14 C atoms.

[0141] An exemplary conjugate according to the present invention, which comprises the nonapeptide AE105 as a targeting peptide (uPAR-binding) moiety, DOTA as a chelating moiety, tolyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a C7 alkyl group as a linker moiety L2, is represented by formula (1 1 ):

[0142]

[0143] Another exemplary conjugate according to the present invention, which comprises the nonapeptide AE105 as a targeting peptide (uPAR-binding) moiety, DOTA as a chelating moiety, tolyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and two C7 alkyl groups as a linker moiety L2, is represented by formula (12):

[0144] Linker moiety L3 In another preferred embodiment of the inventive radiolabeled complex, a linker moiety L3 is located between the trifunctional linker moiety L1 and the chelating moiety thereby extending the distance between the chelating moiety with respect to the uPAR-binding targeting peptide moiety and the albumin-binding moiety, respectively.

[0145] Accordingly, in a further preferred embodiment, the present invention provides a conjugate represented by the general structure (III): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 is a linker moiety as defined above.

[0146] The linker moiety L3 which provides further distance between the chelating moiety and the albumin-binding and uPAR-binding targeting peptide moieties, respectively, may be selected from any suitable and pharmaceutical acceptable linker moiety known in the art. Preferably, the linker moiety L3 is selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly(AZ-vinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, more preferably from the group consisting of amino acids, polyethyleneglycols (PEGs), and alkyl groups.

[0147] Thus, in a particular embodiment, the linker moiety L3 located between the trifunctional linker moiety Ll and the chelating moiety may comprise a PEG moiety. The PEG based linker may comprise about 1 to 30 PEG units, and preferably comprises 1 to 10 PEG units, more preferably 2 to 7 PEG units, most preferably 3 to 5 PEG units.

[0148] In a preferred embodiment, the linker moiety L3 located between the trifunctional linker moiety L1 and the chelating moiety comprises at least one amino acid which is preferably selected from the group consisting of a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, an aspartic acid residue, a glutamic acid residue, a serine residue, a threonine residue, a cysteine residue, or a derivative of said amino acid residues, or a combination of said amino acid residues, more preferably selected from a lysine residue, an arginine residue, a glutamine residue, an asparagine residue or a derivative thereof, or a combination of said amino acid residues or derivatives thereof. In a preferred embodiment, L3 is a lysine residue or a derivative thereof.

[0149] In a more preferred embodiment, the trifunctional linker moiety L1 is a lysine residue or a derivative thereof, and the linker moiety L3 located between the trifunctional linker moiety L1 and the chelating moiety is a further lysine residue or a derivative thereof.

[0150] An exemplary conjugate according to the present invention (referred to as DOTA-uPAR-Alb- 04), which comprises the nonapeptide AE105 as a targeting peptide (uPAR-binding) moiety, DOTA as a chelating moiety, iodophenyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and another lysine residue as a linker moiety L3 located between the trifunctional linker moiety L1 and the chelating moiety, is represented by formula (13):

[0151] As demonstrated in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (13) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts, respectively.

[0152] In another preferred embodiment of the inventive radiolabeled complex, a linker moiety L3 is located between the trifunctional linker moiety L1 and the (uPAR binding) peptide moiety thereby extending the distance between the targeting peptide moiety with respect to the chelating moiety and the albumin-binding moiety, respectively. Accordingly, in a further preferred embodiment, the present invention provides a conjugate represented by the general structure (IV): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 is a linker moiety as defined above.

[0153] The linker moiety L3 which provides further distance between the uPAR-binding targeting peptide moiety and the albumin-binding and chelating moieties, respectively, may be selected from any suitable and pharmaceutical acceptable linker moiety known in the art. Preferably, the linker moiety L3 is selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly(Mvinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, more preferably from the group consisting of amino acids, polyethyleneglycols (PEGs), and alkyl groups.

[0154] Thus, in a particular embodiment, the linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR binding) peptide moiety may comprise at least one amino acid which is preferably selected from the group consisting of a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, an aspartic acid residue, a glutamic acid residue, a serine residue, a threonine residue, a cysteine residue, or a derivative of said amino acid residues, or a combination of said amino acid residues, more preferably selected from a lysine residue, an arginine residue, a glutamine residue, an asparagine residue or a derivative thereof, or a combination of said amino acid residues or derivatives thereof. In a particular embodiment, L3 is a lysine residue or a derivative thereof.

[0155] In a preferred embodiment, the linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR binding) peptide moiety comprises a PEG moiety. The PEG based linker may comprise about 1 to 30 PEG units, and preferably comprises 1 to 10 PEG units, more preferably 2 to 7 PEG units, most preferably 3 to 5 PEG units. Accordingly, in a preferred embodiment, the trifunctional linker moiety L1 is a lysine residue or a derivative thereof, and the linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR binding) peptide moiety is a PEG moiety, preferably a PEG3to PEGs moiety.

[0156] An exemplary conjugate according to the present invention (referred to as DOTA-uPAR-Alb- 05), which comprises the nonapeptide AE105 as a targeting peptide (uPAR-binding) moiety, DOTA as a chelating moiety, p-iodophenyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , and a PEG4linker moiety as a linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR binding) peptide moiety, is represented by formula (14):

[0157] As demonstrated in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (14) has advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts, respectively.

[0158] In a particular embodiment, the inventive conjugate / radiolabeled complex of the present invention may comprise both, a linker moiety L3 located between the trifunctional linker moiety L1 and the chelating moiety, and a linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR-binding) targeting peptide moiety, thus providing additional distance between the chelating moiety and the albumin-binding moiety as well as the (uPAR-binding) targeting peptide moiety.

[0159] Thus, in a particular embodiment, the present invention provides a conjugate represented by the general structure (V): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 and L3 are as defined above.

[0160] In another particular embodiment, the inventive conjugate / radiolabeled complex of the present invention comprises a linker moiety L2 located between the trifunctional linker moiety L1 and the albumin-binding moiety, as well as a linker moiety L3 located between the trifunctional linker moiety L1 and the chelating moiety and / or a linker moiety L3 located between the trifunctional linker moiety L1 and the (uPAR-binding) targeting peptide moiety, thus providing additional distance between the albumin-binding moiety and the chelating moiety as well as the (uPAR-binding) targeting peptide moiety.

[0161] Thus, in a particular embodiment, the present invention provides a conjugate represented by the genera! structure (VI): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 , L2 and L3 are linker moieties as defined above.

[0162] Spacer moiety S 1

[0163] The inventive conjugate / radiolabeled complex may also comprise a spacer moiety S1 . In the following, the term "spacer" is used herein to specifically refer to a group connecting and spanning the distance between several moieties of the inventive conjugate / radiolabeled complex, i.e. "spacing" a distinct group apart from the remaining groups / entities of the conjugate / radiolabeled complex.

[0164] The spacer may preferably avoid sterical hindrance between the moieties of the inventive conjugate / radiolabeled complex and ensure sufficient mobility and flexibility. Further, the spacer may preferably be designed so as to confer, support and / or allow sufficient HSA binding, high affinity uPAR binding, and rapid and optionally selective penetration of uPAR positive cells through internalization of the compound of the invention.

[0165] In the inventive conjugate / radiolabeled complex, a spacer moiety S1 may be located between the trifunctional linker moiety L1 and the albumin-binding moiety to further enlarge the distance between the albumin-binding moiety and the chelating moiety, and the uPAR-binding targeting peptide moiety, respectively. Thus, in the inventive conjugate / radiolabeled complex, an albumin-binding entity, e.g. an iodophenyl moiety, a tolyl moiety, or an ibuprofen moiety, may be conjugated (i.e. covalently linked or attached to) to the trifunctional linker L1 via a spacer S1 . In case that a linker moiety L2 is located between the trifunctional linker L1 and the albumin-binding moiety, the spacer S1 may be located between linker moieties L1 and L2.

[0166] In a preferred embodiment, the spacer moiety S1 is located between the linker moiety L2 and the albumin-binding moiety. Thus, in a preferred embodiment, the present invention provides a conjugate represented by the general structure (VII): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 and L2 are linker moieties as defined above. In a particular embodiment, a linker moiety L3 may be located between the trifunctional linker moiety L1 and the targeting peptide moiety and / or between the trifunctional linker moiety L1 and the chelating moiety. Thus, in a particular embodiment, the present invention also provides a conjugate represented by the general structure (VIII): wherein Abm is an albumin-binding moiety, Cm is a chelating moiety, and Tpm is an uPAR- binding targeting peptide moiety, each as defined above, and L1 , L2 and L3 are linker moieties as defined above.

[0167] Any spacer moiety known in the art can suitably be used as a spacer moiety S1 . Preferably, the spacer moiety S1 is an aromatic spacer. Example of aromatic spacer moieties S1 which may be used in the inventive conjugates / radiolabeled complexes are amino- and carboxy- substituted aromatic structures, such as 2-, 3-, and 4-aminobenzoic acids, 2-, 3-, and 4- (aminomethyl)benzoic acids, 2-, 3-, and 4-(aminophenyl)acetic acids, 2-, 3-, and 4- (aminomethylphenyl)acetic acid (AMPA), (aminomethyl)pyrrole carboxylic acids, (aminomethyl)thiophene carboxylic acids, (aminomethyl)furan carboxylic acids, (aminomethyl)pyrrole acetic acids, (aminomethyl)thienyl acetic acids, and aminobiphenylcarboxylic acids. Further examples of the spacer moiety S1 are more hydrophilic moieties, such e.g. a glutamic acid moiety. Those more hydrophilic moieties may reduce the affinity to serum albumin, which may be desirable in some cases.

[0168] In a preferred embodiment, a 4-(aminomethyl)benzoic acid (AMBA) moiety is used as a spacer moiety S1 . An exemplary conjugate according to the present invention (referred to as DOTA-uPAR-Alb- 03), which comprises the nonapeptide AE105 as a (uPAR-binding) targeting peptide moiety, DOTA as a chelating moiety, p-iodophenyl as an albumin-binding moiety, lysine as a trifunctional linker moiety L1 , a PEG4linker moiety as a linker moiety L2, and a 4- (aminomethyl)benzoic acid (AMBA) moiety as a spacer moiety S1 is represented by formula (15):

[0169] As demonstrated in in vivo studies described below, a radiolabeled complex obtained from the above conjugate according to Formula (15) has particularly advantageous properties with respect to an enhanced blood circulation time and an increased uptake into xenografts, respectively.

[0170] Pharmaceutical composition

[0171] In a second aspect the present invention provides a pharmaceutical composition comprising a radiolabeled complex according to the present invention.

[0172] The details outlined above including the details regarding the radiolabeled complex of the present invention, in particular regarding the targeting peptide moiety, the chelating moiety, the albumin-binding moiety and the radionuclide as well as the linker and spacer moieties of the inventive conjugate / radiolabeled complex, apply accordingly to the pharmaceutical compositions of the invention. Thus, also in the pharmaceutical composition of the present invention, the uPAR-binding targeting peptide moiety may comprise a peptide as described above, in particular a peptide comprising 7 to 20, preferably 8 to 15, more preferably 9 to 13 amino acids.

[0173] For example, also in the pharmaceutical composition of the invention, the uPAR-binding targeting peptide moiety may comprise the amino acid sequence:

[0174] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Xaa5)-(Xaa6)-(Leu)-(Trp)-(Xaa9), wherein

[0175] (Xaa5) is selected from (D-Arg), (D-Lys), (D-Cys), and (D-Ser);

[0176] (Xaa6) is selected from (Tyr) and (Pro); and

[0177] (Xaa9) is selected from (Cys) and (Ser). Thus, also in the pharmaceutical composition of the invention the uPAR-binding targeting peptide moiety may comprise an amino acid sequence selected from the group consisting of

[0178] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Lys)-(Tyr)-(Leu)-(Trp)-(Ser), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Cys)-(Tyr)-(Leu)-(Trp)-(Cys), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser), (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Ser)-(Tyr)-(Leu)-(Trp)-(Ser), and (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Cys)-(Pro)-(Leu)-(Trp)-(Cys), and preferably comprises the nonapeptide AE105:

[0179] (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser).

[0180] Moreover, also in the pharmaceutical composition of the invention the uPAR-binding targeting peptide moiety may comprise a mutated form of the AE105 nonapeptide, such as (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Glu)-(Ser), for example.

[0181] Furthermore, also in the pharmaceutical composition of the invention the uPAR-binding targeting peptide moiety may comprise a derivative of AE105, such as AE120 having the amino acid sequence [((Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)- (Trp)-(Ser))2- (pAla)-(Lys)], or AE1 70 having the amino acid sequence (Lys)-(Ser)-(Asp)-([beta]- cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Lys)- (cyclohexyl-D-Gly)-(Leu)-(Trp)-(Ser)-(Ser)-(Lys).

[0182] Also in the pharmaceutical composition of the invention the uPAR-binding targeting peptide moiety may comprise a cyclized variant of AE105, such as AE147 having the amino acid sequence (Lys)-(Ser)-(Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(D-Lys)-(Tyr)-(Leu)- (Trp)-(Ser)-(Ser)-(Lys).

[0183] Thus, in the pharmaceutical composition of the invention, the uPAR-binding targeting peptide moiety preferably comprises or consists of an AE105 nonapeptide, or a derivative or mutated form thereof, or a (cyclized) variant thereof.

[0184] Also in the pharmaceutical composition of the present invention the chelator may be a macrocyclic chelator or a linear chelator characterized by any one of the above Formulae (1 a) to (I ff).

[0185] For example, also in the pharmaceutical composition of the invention the chelating agent may be a macrocyclic chelator selected from the group consisting of DOT A, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, AAZTA, DO3AP, DO3APPrA, and DO3APABn, or derivatives thereof, as described above, more preferably, selected from DOTA or DOTAGA, as described above.

[0186] Also in the pharmaceutical composition of the invention the radionuclide of the radiolabeled complex may be selected from a radionuclide described above, and may be for example selected from the group consisting of99mTc, ,67Ga,68Ga,86Y,90Y,177Lu,

[0187] 161Tb,161Tb,149Tb,155Tb,152Tb,186Re,188Re,61Cu64Cu,67Cu,55Co,57Co,43Sc,44Sc,47Sc,225Ac,

[0188] 213Bi,212Bi,212Pb,227Th,153Sm,166Ho,166Dy,169Er,165Er,103Pd,109Pd103mRh,18F and123l,124l

[0189] 131l and211At, preferably selected from the group consisting ofl ! 1ln,67Ga,68Ga,86Y,90Y,177Lu,161Tb,64Cu,67Cu,55Co,57Co,43Sc,44Sc,47Sc,225Ac,213Bi,212Bi,212Pb,153Sm,166Ho,225Ac,211At and166Dy. Preferably, for therapeutic applications, the radionuclide may be selected from177Lu and151Tb. Particularly preferably, the radionuclide may be177Lu, as described above. For imaging purposes, the radionuclide may be selected from67Ga and 68Ga.

[0190] Also in the pharmaceutical composition of the invention the albumin-binding moiety is preferably a compound represented by General Formula (2), as described above, and is preferably selected from an iodophenyl moiety, a tolyl moiety, and an ibuprofen moiety, more preferably from an iodophenyl moiety and a tolyl moiety, most preferably a tolyl moiety.

[0191] Also in the pharmaceutical composition of the present invention the chelating moiety, the albumin-binding moiety and the uPAR-binding targeting peptide moiety are linked via a common trifunctional linker L1 . Moreover, also in the pharmaceutical composition of the present invention the conjugate / radiolabeled complex may comprise linker (L2, L3) and spacer (SI ) moieties, as described above.

[0192] For example, also in the pharmaceutical composition of the invention the conjugate / radiolabeled complex may be represented by any one of the following general structures (I) to (VIII):

[0193] wherein

[0194] Abm is an albumin-binding moiety, Cm is a chelating moiety, Tpm is an uPAR- binding targeting peptide moiety, each as defined above;

[0195] L1 is a trifunctional linker moiety, as defined above, which preferably comprises an amino acid residue or a derivative thereof, preferably selected from the group consisting of a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, or a derivative of said amino acid residues, most preferably a lysine residue or a derivative thereof;

[0196] L2 is a linker moiety as defined above, which is preferably selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly( / V- vinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, and is more preferably selected from a PEG based linker, preferably comprising 1 to 30 PEG units, more preferably comprising 1 to 10 PEG units, still more preferably comprising 1 to 5 PEG units, most preferably comprising 3 to 5 PEG units, and an alkyl group, preferably a C1-C20 alkyl group, more preferably a C7-C14 alkyl group;

[0197] L3 is a linker moiety as defined above, which is preferably selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly( / V- vinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, and is more preferably selected from a PEG based linker, preferably comprising 1 to 30 PEG units, more preferably comprising 1 to 10 PEG units, still more preferably comprising 1 to 5 PEG units, most preferably comprising 3 to 5 PEG units, and an amino acid residue, preferably a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, or a derivative of said amino acid residues, most preferably a lysine residue or a derivative thereof; and

[0198] S1 is a spacer moiety, as defined above, preferably comprising an amino- and carboxy-substituted aromatic structure, more preferably selected from 2-, 3-, and 4- aminobenzoic acids, 2-, 3-, and 4-(aminomethyl)benzoic acids, 2-, 3-, and 4- (aminophenyl)acetic acids, 2-, 3-, and 4-(aminomethylphenyl)acetic acid (AMPA), (aminomethyl)pyrrole carboxylic acids, (aminomethyl)thiophene carboxylic acids, (aminomethyl)furan carboxylic acids, (aminomethyl)pyrrole acetic acids, (aminomethyl)thienyl acetic acids, and aminobiphenylcarboxylic acids, most preferably a 4- (aminomethyl)benzoic acid moiety.

[0199] Thus, also in the pharmaceutical composition of the invention the conjugate may e.g. be represented by any one of the above formulae (3) to (15) which forms a radiolabeled complex with a radionuclide as defined above, for example with177Lu or161Tb, preferably with177Lu, or with67Ga or68Ga. Stabilizer

[0200] The pharmaceutical composition according to the present invention comprises a radiolabeled complex, as described above, and preferably also comprises a stabilizer to provide stability against radiolytic degradation.

[0201] As used herein, the term "stabilizer" (against radiolytic degradation) refers to an agent which protects organic molecules against radiolytic degradation.

[0202] In particular, the stabilizer may be able to scavenge radicals, which may be generated, for example, when the radionuclide emits a gamma ray and the gamma ray cleaves a bond between the atoms of organic molecules, thereby forming radicals. Therefore, the stabilizer can avoid or reduce that radicals undergo other chemical reactions, which might lead to undesired, potentially ineffective or even toxic molecules.

[0203] The pharmaceutical composition of the present invention may comprise any stabilizer against radiolytic degradation known in the art. Stabilizing agents have been evaluated by Larenkov et al. (Larenkov, A., Mitrofanov, I., Pavlenko, E., Rakhimov, M.: Radiolysis- Associated Decrease in Radiochemical Purity of 177Lu-Radiopharmaceuticals and Comparison of the Effectiveness of Selected Quenchers against this Process. Molecules 2023, 28, 1884. https: / / doi.org / 10.3390 / molecules28041884), which is hereby incorporated by reference. Examples of stabilizers include, without being limited thereto, ascorbic acid or a salt thereof (e.g. sodium ascorbate), methionine, histidine, melatonine, ethanol, gentisic acid (2,5-dihydroxybenzoic acid), or a salt thereof, para-amino benzoic acid, Se-methionine, DMSA, cysteine, vanillin, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol, or a combination of said stabilizers.

[0204] In a preferred embodiment of the inventive pharmaceutical composition the stabilizer comprises ascorbic acid (L-ascorbic acid, vitamin C) and / or a salt thereof (e.g. sodium ascorbate). As shown in the appended examples, such a formulation not only decreases the complexity of the composition (and its preparation), but also provides higher stability of the radiolabeled complex. In a preferred embodiment, the pharmaceutical composition does not comprise further stabilizers in addition to ascorbic acid and / or a salt thereof. Accordingly, ascorbic acid and / or a salt thereof may be the only stabilizers present in the pharmaceutical composition. In other words, the stabilizer comprised in the pharmaceutical composition may (exclusively) consist of ascorbic acid and / or a salt thereof.

[0205] Various salts of ascorbic acid are known in the art and readily available. In general, the term "salt" refers to an ionic assembly of cations and anions, which is composed of related numbers of cations and anions, so that the product (the salt) is electrically neutral (without net charge). In salts of ascorbic acid, the salts are typically formed with the ascorbate anion. Preferred salts of ascorbic acid include the alkali salts of ascorbic acid. The term "alkali salt" refers to salts that produce hydroxide ions when dissolved in water. Non-limiting examples of preferred salts of ascorbic acid include sodium, potassium, calcium, magnesium and lithium salts of ascorbic acid; such as sodium ascorbate, sodium ascorbyl phosphate, potassium ascorbate, calcium ascorbate, magnesium ascorbate, magnesium ascorbyl phosphate and lithium ascorbate. Most preferably, the salt of ascorbic acid is a sodium salt of ascorbic acid, in particular sodium ascorbate.

[0206] The pharmaceutical composition according to the present invention is preferably an aqueous solution, in particular a radiopharmaceutical aqueous solution. As used herein, an "aqueous solution" is usually a solution of one or more solute(s) in water. The pharmaceutical composition may be for intravenous (i.v.) use / application / administration. The pharmaceutical composition is typically stable, concentrated, and ready-to-use.

[0207] In some embodiments, the pharmaceutical composition may comprise a buffer, e.g. an acetate buffer, a citrate buffer or a phosphate buffer. However, it has been found that ascorbic acid and / or a salt thereof not only provides increased stability to the radiolabeled complex, but also may function as a buffer (i) during radiolabeling of the complex and (ii) in the formulation of the pharmaceutical composition (to maintain a suitable pH for parenteral injection). Therefore, additional buffers may not be required. Thus, the composition may not contain any of an acetate buffer, a citrate buffer, and a phosphate buffer. Preferably, the pharmaceutical composition does not contain any additional buffer (in addition to ascorbic acid and / or the salt thereof, which are present as stabilizer(s) and also provide buffering functionality).

[0208] Thus, the only excipients (i.e., components of the pharmaceutical composition, which are not active ingredients, such as the radiolabeled complex) comprised in the pharmaceutical composition may be ascorbic acid and / or a salt thereof, and water (e.g., (sterile) water for injection and / or highly purified water). Accordingly, the pharmaceutical composition may consist (essentially) of

[0209] (a) the radiolabeled complex and, optionally, one or more precursors thereof;

[0210] (b) ascorbic acid and / or a salt thereof; and

[0211] (c) water (ad injectabilia).

[0212] However, in some cases, the addition of a further buffer, e.g. as described herein, may be necessary in order not to leave the range of permitted osmolarity.

[0213] In some embodiments, the pharmaceutical composition may comprise both, ascorbic acid as well as a salt thereof (as described above). For example, the pharmaceutical composition may comprise ascorbic acid and sodium ascorbate (and no further stabilizer as described above).

[0214] The weight ratio of the salt of ascorbic acid to ascorbic acid in the pharmaceutical composition, in particular the weight ratio of sodium ascorbate : ascorbic acid, may be between 30 : 1 and 70 : 1 , preferably between 40 : 1 and 60 : 1 , more preferably between 45 : 1 and 55 : 1 , even more preferably between 45 : 1 and 50 : 1. Accordingly the amount (by weight) of the salt of ascorbic acid (in particular of sodium ascorbate) preferably exceeds the amount (by weight) of ascorbic acid considerably, as described above.

[0215] Accordingly, in particular if both, ascorbic acid as well as a salt thereof (in particular sodium ascorbate), are present in the pharmaceutical composition, the concentration of ascorbic acid in the composition is preferably well below the concentration of the salt of ascorbic acid (in particular sodium ascorbate). Preferably, the concentration of ascorbic acid in the pharmaceutical composition is in the range from 0.5 to 5.0 mg / ml, preferably in the range from 0.7 to 3.0 mg / ml, more preferably in the range from 0.8 to 2.0 mg / ml, even more preferably in the range from 0.9 to 1.5 mg / ml, and still more preferably in the range from 1 .0 to 1.25 mg / ml. For example, the concentration of ascorbic acid in the pharmaceutical composition may be about 1 .1 1 mg / ml.

[0216] With regard to the concentration of the salt of ascorbic acid, it is preferred that the concentration of the salt of ascorbic acid, in particular sodium ascorbate, in the pharmaceutical composition is in the range from 10 mg / ml to 100 mg / ml, preferably in the range from 20 mg / ml to 90 mg / ml, more preferably in the range from 30 mg / ml to 80 mg / ml, even more preferably in the range from 40 mg / ml to 70 mg / ml, and still more preferably in the range from 50 mg / ml to 60 mg / ml. For example, the concentration of the salt of ascorbic acid, in particular sodium ascorbate, in the pharmaceutical composition may be about 51 mg / ml.

[0217] In some embodiments, the pharmaceutical composition is substantially free of ethanol. Higher concentrations of ethanol may be associated with tolerability issues, such that ethanol may be restricted or avoided. In some embodiments, the amount of ethanol in the pharmaceutical composition is no more than 5%, preferably no more than 2%, more preferably no more than 1 % in the final pharmaceutical composition (to be injected / infused). Even more preferably, the solution is free of ethanol.

[0218] In some embodiments, the pharmaceutical composition may comprise a sequestering agent, such as diethylentriaminepentaacetic acid (DTPA) or a salt thereof. As used herein, the term "sequestering agent" refers to an agent suitable to complex / chelate traces of unreacted radionuclide metal ions, which then can be excreted quickly via kidneys (Eur J Nucl Med Mol Imaging 2003 Feb;30(2):312-5. doi: 10.1007 / s00259-002-1054-4. Epub 2002 Nov 29).

[0219] As shown in the appended examples, the pharmaceutical composition according to the present invention can provide a stability of > 93% over at least 24 h, in particular when stored at room temperature (RT). Thus, the use of the specific stabilizer(s) as described herein ensures high radiolytic stability, in particular at least 93%, 94%, 95%, 96%, 97%, 98% or 99% intact radiopeptides, even after 24 hours, with respect to the value obtained immediately after labeling.

[0220] For example, for177Lu-DOTA-uPAR-ALB11 (cf. formula (5)) according to the present invention, at least 99% radiolytic stability was found after 24 hours when stored at room temperature. To this end, radiochemical purity may be determined by HPLC as known in the art; for example utilizing reversed phase chromatography (e.g., column: Acclaim 120, C18, 3 gm, 3 x 150 mm), e.g. at gradient conditions, with UV and radio-chemical detection.

[0221] The pharmaceutical composition according to the present invention may be provided as single-dose product, e.g. in a vial containing a single dose of the radiolabeled complex. To this end, the vial may contain about 10 to 25 ml of the pharmaceutical composition, preferably 15 to 20 ml of the pharmaceutical composition, more preferably 16 to 19 ml of the pharmaceutical composition, and even more preferably about 18 ml of the pharmaceutical composition. A single dose may allow delivery of 7.5 GBq + 10% of radioactivity at injection time.

[0222] Preferably, each of the one or more the stabilizer(s) present in the (final) pharmaceutical composition is / are already present during complex formation (radiolabeling).

[0223] As used herein, the expression "present during complex formation" is intended to refer to such agents / compounds, which are present in the reaction mixture (also referred to as "radiolabeling composition") for the complex formation (radiolabeling). To obtain the radiolabeling reaction mixture (radiolabeling composition), the radionuclide solution is added to the solution containing the conjugate comprising the chelating moiety linked to the targeting molecule and the albumin-binding entity (or vice versa). Accordingly, any agent / compound present during complex formation (radiolabeling), such as a stabilizer, may be contained in either the radionuclide solution, in the solution containing the conjugate comprising the chelating moiety linked to the targeting molecule and the albumin-binding entity, or in a separate solution to be added. After obtaining the radiolabeling composition, elevated temperatures may be applied to the radiolabeling composition (including the agents / compounds comprised therein) for a defined time window to facilitate the complex formation (radiolabeling).

[0224] As described above, it is preferred that each of the one or more the stabilizer(s) present in the (final) pharmaceutical composition is / are already present during complex formation (radiolabeling). However, the concentrations and / or weight ratios of the stabilizer(s) in the radiolabeling composition (reaction mix) during complex formation (radiolabeling) are preferably distinct from the concentrations and / or weight ratios of the stabilizer(s) in the (final) pharmaceutical composition. For example, one or more of the stabilizers present during complex formation (radiolabeling) may be additionally added after the complex formation (radiolabeling).

[0225] As used herein, the expression "after the complex formation (radiolabeling)" refers to the time when the complex forming (radiolabeling) reaction is completed. For example, when elevated temperatures were applied for radiolabeling, "after the complex formation (radiolabeling)" may refer to a time when the radiolabeling composition (radiolabeling reaction mixture) is no longer exposed to an elevated temperature (for example, when ambient temperature is reached again, e.g. by cooling down the radiolabeling composition). In particular, "after the complex formation (radiolabeling)" may refer to the formulation of the (final) pharmaceutical composition, e.g. by dilution of the radiolabeling mix with water.

[0226] Accordingly, it is preferred that ascorbic acid and / or a salt thereof is / are present during complex formation (radiolabeling). It is also preferred that ascorbic acid and / or a salt thereof is / are added after complex formation (radiolabeling). More preferably, ascorbic acid and / or sodium ascorbate is / are present during complex formation (radiolabeling) and ascorbic acid and / or sodium ascorbate is / are added after complex formation (radiolabeling).

[0227] Thereby, it is preferred that ascorbic acid and a salt thereof, in particular sodium ascorbate, are present during complex formation (i.e., in the radiolabeling composition) at a weight ratio (sodium ascorbate : ascorbic acid) of about 2 : 1 to 6 : 1 , preferably about 3 : 1 to 5 : 1 , more preferably about 3.5 : 1 to 4.5 : 1 , even more preferably about 3.75 : 1 to 4.25 : 1 , still more preferably about 4 : 1 . Preferably, ascorbic acid is present during complex formation (i.e., in the radiolabeling composition) at a concentration of 1 - 50 mg / ml, preferably 5 - 40 mg / ml, more preferably 7 - 30 mg / ml, even more preferably 10 - 20 mg / ml, still more preferably 10 - 15 mg / ml, such as about 13.3 mg / ml.

[0228] It is also preferred that the salt of ascorbic acid, in particular sodium ascorbate, is present during complex formation (i.e., in the radiolabeling composition) at a concentration of 10 - 100 mg / ml, preferably 20 - 80 mg / ml, more preferably 30 - 70 mg / ml, even more preferably 45 - 60 mg / ml, still more preferably 50 - 55 mg / ml, such as about 53.3 mg / ml.

[0229] Preferably, the salt of ascorbic acid, in particular sodium ascorbate, (but preferably not ascorbic acid) is added after complex formation (during formulation of the pharmaceutical composition).

[0230] Even more preferably, ascorbic acid and a salt thereof, in particular sodium ascorbate, are present during complex formation (radiolabeling); and the salt of ascorbic acid, in particular sodium ascorbate, (but preferably not ascorbic acid) is added after complex formation (during formulation of the pharmaceutical composition).

[0231] It is also preferred that ascorbic acid and / or a salt thereof, in particular sodium ascorbate, are the only stabilizers present during complex formation (radiolabeling) and after complex formation (e.g., during formulation of the pharmaceutical composition).

[0232] In some embodiments, the radionuclide, in particular177Lu, is present in the pharmaceutical composition at a concentration providing volumetric radioactivity of from 0.25 to 0.6 GBq / ml, preferably 0.3 to 0.55 GBq / ml, more preferably 0.35 to 0.5 GBq / ml.

[0233] Effective doses of the inventive conjugates may be determined by routine experiments, e.g. by using animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog, pig and non-human primate models. Therapeutic efficacy and toxicity of inventive conjugates or radiolabeled complexes can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50. The data obtained from the cell culture assays and animal studies can be used in determining a dose range for use in humans. The dose of said conjugates lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.

[0234] For instance, therapeutically or diagnostically effective doses of the inventive conjugates may range from about 0.001 mg to 10 mg, preferably from about 0.01 mg to 5 mg, more preferably from about 0.1 mg to 2 mg per dosage unit or from about 0.01 nmol to 1 mmol per dosage unit, in particular from 1 nmol to 1 mmol per dosage unit, preferably from 1 micromol to 1 mmol per dosage unit. It is also envisaged that therapeutically or diagnostically effective doses of the inventive conjugates (compounds) may range (per kg body weight) from about 0.01 mg / kg to 10 g / kg, preferably from about 0.05 mg / kg to 5 g / kg, more preferably from about 0.1 mg / kg to 2.5 g / kg.

[0235] According to preferred embodiments, the pharmaceutical composition is administered parenterally, in particular via intravenous or intratumoral injection, and is accordingly formulated in liquid or lyophilized form for parenteral administration. Parenteral formulations may be stored in vials, IV bags, ampoules, cartridges, or prefilled syringes and can be administered as injections, inhalants, or aerosols, with injections being preferred.

[0236] Liquid pharmaceutical compositions administered via injection and in particular via intravasal, more preferably intravenous (i.v.) injection should preferably be sterile and stable under the conditions of manufacture and storage. Such compositions are typically formulated as parenterally acceptable aqueous solutions that are pyrogen-free, have suitable pH, are isotonic and maintain stability of the active ingredient(s).

[0237] The pharmaceutical composition may comprise a pharmaceutically acceptable excipient, diluent or carrier. The term "pharmaceutically acceptable", as used herein, refers to a compound or agent that is compatible with the components of the pharmaceutical composition, in particular the active (anti-cancer) compounds, and does not interfere with and / or substantially reduce its therapeutic activities. Pharmaceutically acceptable carriers preferably have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a subject to be treated.

[0238] For liquid pharmaceutical compositions, suitable pharmaceutically acceptable excipients and carriers include water, typically pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. Particularly for injection of the (pharmaceutical) compositions, water or preferably a buffer, more preferably an aqueous buffer, may be used, which may contain a sodium salt, e.g. at least 50 mM of a sodium salt, a calcium salt, e.g. at least 0,01 mM of a calcium salt, and optionally a potassium salt, e.g. at least 3 mM of a potassium salt.

[0239] The sodium, calcium and, optionally, potassium salts may occur in the form of their halogenides, e.g. chlorides, iodides, or bromides, in the form of their hydroxides, carbonates, hydrogen carbonates, or sulfates, etc. Without being limited thereto, examples of sodium salts include e.g. NaCI, Nal, NaBr, Na2CO3, NaHCO3, Na2SO4, examples of the optional potassium salts include e.g. KCI, KI, KBr, K2CO3, KHCO3, K2SO4, and examples of calcium salts include e.g. CaCI2, Cal2, CaBr2, CaCO3, CaSO4, Ca(OH)2. Furthermore, organic anions of the aforementioned cations may be contained in the buffer.

[0240] Buffers suitable for injection purposes as defined above, may contain salts selected from sodium chloride (NaCI), calcium chloride (CaCl2) and optionally potassium chloride (KCI), wherein further anions may be present additional to the chlorides. CaCI2can also be replaced by another salt like KCI. Typically, the salts in the injection buffer are present in a concentration of at least 50 mM sodium chloride (NaCI), at least 3 mM potassium chloride (KCI) and at least 0,01 mM calcium chloride (CaCI2). The injection buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects.

[0241] The pharmaceutical composition may be provided in lyophilized form. Lyophilized pharmaceutical compositions are preferably reconstituted in a suitable buffer, advantageously based on an aqueous carrier, prior to administration. The pharmaceutical compositions are also provided for use in the preparation of a medicament for the treatment of cancer.

[0242] Medical treatment and uses

[0243] In a further aspect, the present invention also provides the use of the pharmaceutical composition as described above in medicine. For example, the pharmaceutical composition as described above may be preferably used in the treatment or in the (in vitro) diagnosis of cancer (e.g., by using an isolated sample, for example a blood sample or tumor tissue). Accordingly, the present invention also provides a method for treating cancer or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject the pharmaceutical composition as described above.

[0244] It is understood that for medical purposes, the pharmaceutical composition usually comprises an effective amount of the radiolabeled complex. As used herein, "an effective amount" means an amount of the agent(s) that is sufficient to allow for diagnosis and / or significantly induce a positive modification of the disease to be treated. At the same time, however, an "effective amount" may be small enough to avoid serious side-effects, that is to say to permit a sensible relationship between advantage and risk. An „effective amount" may vary depending on the particular condition to be diagnosed or treated and also with the age and physical condition of the patient to be treated, the severity of the condition, the duration of the treatment, the nature of the accompanying therapy, of the particular pharmaceutically acceptable excipient or carrier used, and similar factors. Accordingly, an "effective amount" may be readily determined in a specific situation by the physician. In general, effective doses may be determined by routine experiments, e.g. by using animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog, pig and non-human primate models. Therapeutic efficacy and toxicity of radiolabeled complexes can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD5O / ED5O. The data obtained from the cell culture assays and animal studies can be used in determining a dose range for use in humans. The dose of said conjugates lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.

[0245] As used herein, the term "diagnosis" or "diagnosing" refers to act of identifying a disease from its signs and symptoms and / or as in the present case the analysis of biological markers (such as genes or proteins) indicative of the disease.

[0246] As used herein, the term "treatment" or "treating" of a disease includes preventing or protecting against the disease (that is, causing the clinical symptoms not to develop); inhibiting the disease (i.e., arresting or suppressing the development of clinical symptoms; and / or relieving the disease (i.e., causing the regression of clinical symptoms). As will be appreciated, it is not always possible to distinguish between "preventing" and "suppressing" a disease or disorder since the ultimate inductive event or events may be unknown or latent. Accordingly, the term "prophylaxis" will be understood to constitute a type of "treatment" that encompasses both "preventing" and "suppressing." The term "treatment" thus includes "prophylaxis". Accordingly, the term "treatment" includes prophylactic treatment (before onset of the disease) as well as therapeutic treatment (after onset of the disease).

[0247] The pharmaceutical compositions as described herein are typically administered parenterally. Administration may preferably be accomplished systemically, for instance by intravenous (i.v.), subcutaneous, intramuscular or intradermal injection. Alternatively, administration may be accomplished locally, for instance by intra-tumoral injection. The pharmaceutical compositions as described above may be administered to a subject in need thereof several times a day, daily, every other day, weekly, or monthly.

[0248] Pharmaceutical compositions of the invention, in particular pharmaceutical compositions comprising a radiolabeled complex comprising a uPAR-binding targeting peptide moiety linked to an albumin-binding moiety and a chelating moiety complexing a radionuclide, may be used in the treatment or diagnosis of any cancer expressing an urokinase-type plasminogen activator receptor (uPAR). In particular, the presence of uPAR-expressing cells or tissues may be indicative of a solid tumor, neuroendocrine tumor and / or a hematologic malignancy. Accordingly, the cancer is preferably selected from breast, brain (e.g. glioblastoma), gastric, pancreatic, colorectal, prostate, ovarian, oral and esophageal cancer. Hematologic malignancies may be selected from multiple myeloma and acute leukemias.

[0249] Pharmaceutical compositions of the invention, in particular pharmaceutical compositions comprising a radiolabeled complex comprising an uPAR-binding targeting peptide moiety linked to an albumin-binding moiety and a chelating moiety complexing a radionuclide, may be used in the treatment or diagnosis of any cancer or hematologic malignancy expressing an urokinase-type plasminogen activator receptor (uPAR).

[0250] The pharmaceutical composition as described above may be used for both imaging and therapeutic purposes, i.e. as a "theragnostic" agent. As used herein, the term "theragnostic" includes "therapeutic-only", "diagnostic-only" and "therapeutic and diagnostic" applications. Accordingly, in a further aspect, the present invention also provides an (in vitro) method of detecting the presence of cancerous cells and / or tissues comprising (a) contacting said cancerous cells and / or tissues with the pharmaceutical composition of the invention and (b) applying detection means, optionally radiographic imaging, to detect said cells and / or tissues.

[0251] In the in vivo and in vitro uses and methods of the present invention, radiographic imaging may be accomplished using any means and methods known in the art. Preferably, radiographic imaging may involve positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0252] BRIEF DESCRIPTION OF THE FIGURES

[0253] In the following a brief description of the appended figures will be given. The figures are intended to illustrate the present invention in more detail. However, they are not intended to limit the subject matter of the invention in any way.

[0254] Figure 1 represents a schematic overview of the design of AE105-based uPAR targeting radiopeptides using distinct albumin-binding and linker / spacer entities.

[0255] Figure 2 shows for Example 6 albumin-binding curves of the radiopeptides synthesized in Example 1 using mouse (panels A and B) and human (panels C and D) blood plasma dilutions.

[0256] Figure 3 shows for Example 7 cell uptake (Panels A and D), internalization (panels B and E) and blocking studies (panels C and F) of distinct uPAR-targeting radiopeptides performed in HEK-uPAR cells after 2 h and 4 h incubation at 37 °C. The data are represented as average ± SD of three independent experiments.

[0257] Figure 4 shows for Example 9 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenograft-bearing mice acquired 1 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=l iver, Bl = urinary bladder).

[0258] Figure 5 shows for Example 9 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenograft-bearing mice acquired 4 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=l iver, Bl = urinary bladder).

[0259] Figure 6 shows for Example 9 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenogaft-bearing mice acquired 24 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=liver, Bl = urinary bladder).

[0260] Figure 7 shows for Example 10 decay-corrected blood retention of the radiopeptides in HEK-uPAR xenograft-bearing mice.

[0261] Figure 8 shows for Example 10 decay-corrected uptake of the radiopeptides in HEK- uPAR xenografts of mice.

[0262] Figure 9 shows for Example 10 decay-corrected uptake of the radiopeptides in the kidneys of HEK-uPAR-xenografted mice.

[0263] Figure 10 shows for Example 10 decay-corrected uptake of the radiopeptides in the liver of HEK-uPAR-xenografted mice.

[0264] Figure 11 shows for Example 10 xenograft-to-blood ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h injection of respective radiopeptides.

[0265] Figure 12 shows for Example 10 xenograft-to-kidney ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h after injection of respective radiopeptides.

[0266] Figure 13 shows for Example 10 xenograft-to-liver ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h after injection of respective radiopeptides.

[0267] Figure 14 represents a schematic overview of the design of 2ndgeneration AE105-based uPAR targeting peptides using variable chelators and linker entities. (PEG = polyethylene glycol; Lys = lysine; DAP = diaminopropanoic acid) Figure 15 shows for Example 16 albumin-binding curves of the radiopeptides synthesized in Example 1 1 using human (panels A and B) and mouse (panels C and D) blood plasma dilutions.

[0268] Figure 16 shows for Example 17 cell uptake (panels A and D), internalization (panels B and E) and blocking studies (panels C and F) of distinct uPAR-targeting radiopeptides performed in HEK-uPAR cells after 2 h and 4 h incubation at 37 °C. The data are represented as average ± SD of three independent experiments.

[0269] Figure 17 shows for Example 19 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenogaft-bearing mice acquired 1 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=liver, Bl = urinary bladder).

[0270] Figure 18 shows for Example 19 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenogaft-bearing mice acquired 4 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=liver, Bl = urinary bladder).

[0271] Figure 19 shows for Example 19 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenogaft-bearing mice acquired 24 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=liver, Bl = urinary bladder).

[0272] Figure 20 shows for Example 19 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenogaft-bearing mice acquired 48 h after injection of the radiopeptide [177Lu]Lu-DOTA-AE105 or177Lu-DOTA-uPAR- ALB radiopeptides (25 MBq; 0.5 nmol per mouse). (Xgrft = HEK-uPAR xenograft, Ki = kidney, H = heart, Li=liver, Bl = urinary bladder). Figure 21 shows for Example 20 decay-corrected blood retention of the radiopeptides in HEK-uPAR xenograft-bearing mice.

[0273] Figure 22 shows for Example 20 decay-corrected uptake of the radiopeptides in HEK- uPAR xenografts of mice.

[0274] Figure 23 shows for Example 20 decay-corrected uptake of the radiopeptides in the kidneys of HEK-uPAR-xenografted mice.

[0275] Figure 24 shows for Example 20 decay-corrected uptake of the radiopeptides in the liver of HEK-uPAR-xenografted mice

[0276] Figure 25 shows for Example 20 decay-corrected xenograft-to-blood ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h injection of respective radiopeptides.

[0277] Figure 26 shows for Example 20 xenograft-to-kidney ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h after injection of respective radiopeptides.

[0278] Figure 27 shows for Example 20 xenograft-to-liver ratios determined based on biodistribution data obtained at 4 h, 24 h and 48 h after injection of respective radiopeptides.

[0279] Figure 28 shows for Example 21 cell uptake and internalization of the radiopeptides in HEK-uPAR cells after 2-h and 4-h incubation period at 37 °C. (A) Uptake and internalization of [67Ga]Ga-DOTA-uPAR-ALB-1 1 ; (B) Uptake and internalization of [67Ga]Ga-DOTA-uPAR-ALB-18. (C) The radiopeptides in the presence of excess AE105 to block uPAR. The data are represented as average ± SD of two independent experiments. Figure 29 shows for Example 21 SPECT / CT images shown as maximum intensity projections (MIPs) of HEK-uPAR xenograft-bearing mice acquired 1 h and 4 h after injection of67Ga-labeled uPAR-targeting radiopeptides (10 MBq; 0.5 nmol per mouse). (A) [67Ga]Ga-DOTA-uPAR-ALB-1 1 ; (B) [67Ga]Ga-DOTA- uPAR-ALB-18 (Xgft = HEK-uPAR xenograft, Ki = kidney, Bl = urinary bladder).

[0280] EXAMPLES

[0281] In the following, particular examples illustrating various embodiments and aspects of the invention are presented. However, the present invention shall not to be limited in scope by the specific embodiments described herein. The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. The present invention, however, is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the invention only, and methods which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those described herein will become readily apparent to those skilled in the art from the foregoing description, accompanying figures and the examples below. All such modifications fall within the scope of the appended claims.

[0282] Example 1 : Synthesis and Characterization of the 1stGeneration uPAR-Targeting Peptides

[0283] DOTA-AE105, the reference compound known from the literature (Persson M et al., 2012, supra), was purchased as a custom synthesis from piCHEM (Grambach, Austria). The syntheses of the new uPAR-targeting peptides (DOTA-uPAR-ALB peptides) were performed using the technique of solid-phase peptide synthesis. All commercially available solvents and chemicals were used without further purification. Synthesis of AE105 and RI-AE105

[0284] AE105 and the resin-immobilized (Rl), fully protected version thereof (RI-AE105) were synthesized according to a reported procedure with slight modifications (Scheme 1 ). Rink amide methylbenzhydrylamine resin (0.1 mmol) was weighed into a 5 ml filter-containing syringe and swelled in 3 ml dry dichloromethane (DCM) for 45 min. Afterwards, the resin was conditioned with dimethylformamide (DMF) followed by Fmoc deprotection using a 1 :1 (v / v) DMF / piperidine solution and agitation twice for 10 minutes. The resultant deprotected resin-immobilized compound was added to a DMF solution containing Fmoc- Ser(‘Bu)-OH (0.4 mmol, 4 equiv), O-(benzotriazol-1 -yl)-N, N, N', N'-tetramethyluronium- hexafluorophosphate (HBTU, 0.396 mmol, 3.96 equiv) and N,N-diisopropylethylamine (DIPEA, 0.8 mmol, 8.0 equiv) and stirred for 1 h. Conjugation and Fmoc deprotection of the following amino acid building blocks was performed the same way using Fmoc-Trp(Boc)- OH, Fmoc-Leu-OH, Fmoc-Tyr(‘Bu)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-D-Ser(tBu)-OH, Fmoc- Phe-OH and Fmoc-Cha-OH in this sequence. Conjugation of the last amino acid residue Fmoc-Asp(C)'Bu)-OH, as well as the following coupling steps reported for the preparation of the new DOTA-uPAR-ALB peptides, was performed in analogy to the methodology described above, however, in this case, 1 -hydroxybenzotriazole hydrate (HOBt, 0.4 mmol, 4 equiv) was added to the reaction mixture to suppress unwanted cyclization reactions. Fmoc deprotection of the terminal amino group resulted in the key resin-immobilized and sidechain-protected intermediate RI-AE105, which was used as the starting material for synthesizing the new DOTA-uPAR-ALB peptides. AE105 was produced by cleavage of Rl- AE105 from the resin and simultaneous removal of the acid-labile protecting groups using a trifluoroacetic acid (TFA) solution containing 2.5% Milli-Q water and 2.5% triisopropyl silane (TIPS) ( v / v / v). This reaction was carried out two times for a total of 2 h, after which the volatile solvents were removed using N2stream to obtain the desired crude AE105 peptide. Scheme 1. Synthesis of AE105 and of the resin-immobilized intermediate R1-AE105: Synthesis of DOTA-uPAR-ALB-01

[0285] Dde-Lys(Fmoc)-OH was conjugated to the terminal a-amino functionality of RI-AE105 following the procedure reported above. The Fmoc group present on the sidechain of the newly inserted lysine residue was removed and the resulting primary ε-amino group was subsequently coupled with 4-(p-iodophenyl)butanoic acid. The Dde protecting group present at the α-amino group of the lysine residue was removed using a solution of 2% ( v / v hydrazine hydrate in DMF two times for 30 minutes. The resultant primary amine was reacted with tri-tert-buty I 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetate (DOTA- tris(‘Bu)ester). Cleavage from the resin and general deprotection of the peptide and DOTA chelator yielded the crude DOTA-uPAR-ALB-01 (Scheme 2). Scheme 2. Synthesis of DOTA-uPAR-ALB-01 : Synthesis of DOTA-uPAR-ALB-02

[0286] Dde-Lys(Fmoc)-OH (0.4 mmol, 4.00 equiv) was conjugated to the resin-immobilized AE105 peptide chain (RI-AE105; 0.1 mmol, 1 .00 equiv). After Fmoc deprotection, the ε-amino group of the lysine residue was conjugated to 1 -(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16- pentaoxa-4-azanonadecan-19-oic acid (Fmoc-N-amido-PEG4-acid) followed by conjugation of 4-(p-iodophenyl)butyric acid. The Dde protecting group of the lysine residue was cleaved with a mixture of 2% hydrazine in DMF two times for 15 minutes before conjugation of the DOTA-tris(tBu)ester to the resin-immobilized peptide. Cleavage from the resin and general deprotection of the peptide and DOTA-chelator yielded the crude DOTA-uPAR-ALB-02 (Scheme 3).

[0287] Scheme 3. Synthesis of DOTA-uPAR-ALB-02: Synthesis of DOTA-uPAR-ALB-03

[0288] DOTA-uPAR-ALB-03 was synthesized according to the procedure used for the preparation of DOTA-uPAR-ALB-02, however, a 4-(aminomethyl)benzoic acid (AMBA) entity was introduced before the conjugation of the 4-(p-iodophenyl)butanoic acid (Scheme 4).

[0289] Scheme 4. Synthesis of DOTA-uPAR-ALB-03: Synthesis of DOTA-uPAR-ALB-04

[0290] The synthesis of DOTA-uPAR-ALB-04 was performed in analogy to the procedure described for DOTA-uPAR-ALB-01 , but an additional lysine residue was included as a spacer before the conjugation of DOTA-tris(tBu)ester. The subsequent Dde deprotection, followed by cleavage from the resin and general deprotection of the peptide and DOTA-chelator, yielded the crude uPAR-ALB-04 (Scheme 5).

[0291] Scheme 5. Synthesis of DOTA-uPAR-ALB-04:

[0292] Synthesis of DOTA-uPAR-ALB-05

[0293] The synthesis of DOTA-uPAR-ALB-05 was performed in analogy to the procedure described for DOTA-uPAR-ALB-01 , however, in this case, Fmoc-N-amido-PEG4-acid was introduced as an additional spacer between the AE105 peptide and the lysine which connects the 4-(p- iodophenyl)butanoic acid-based albumin-binder and the macrocyclic DOTA chelator (Scheme 6). Scheme 6. Synthesis of DOTA-uPAR-ALB-05:

[0294] Synthesis of DOTA-uPAR-ALB-11

[0295] Dde-Lys(Fmoc)-OH (0.4 mmol, 4.00 equiv) was conjugated to the resin-immobilized AE105 peptide chain (RI-AE105; 0.1 mmol, 1.00 equiv). After Fmoc deprotection, the ε-amino group of the lysine residue was reacted with a Fmoc-Namido-PEC4-acid entity followed by conjugation of 4-(p-tolyl)butanoic acid. The Dde protecting group of the lysine residue was cleaved using a mixture of 2% hydrazine in DMF two times for 30 minutes before conjugation of the DOTA-tris(‘Bu)ester. Cleavage from the resin and general deprotection of the peptide and DOTA-chelator yielded the crude DOTA-uPAR-ALB-1 1 (Scheme 7). Scheme 7. Synthesis of DOTA-uPAR-ALB-1 1 :

[0296] Purification and characterization of AE105 and DOTA-uPAR-ALB peptides

[0297] The crude peptides were dissolved in a 1 :1 (v / v mixture of acetonitrile (ACN) and Milli-Q water before purification using semipreparative HPLC (Merck-Hitachi LaChrom HPLC system equipped with a D-7000 interface, L-7200 autosampler, L-7400 UV detector, L-7100 pump) and a reversed-phase C18 column (Sunfire™, 5 pm, 10x150 mm, Waters, Milford, MA, USA). The desired peptides were eluted using variable linear gradients of Milli-Q water containing 0.1 % TFA (eluent A) and ACN (eluent B) (Table 1 ). The reaction products were determined by evaluating absorbance at λ=254 nm. The product-containing fractions were collected in a round bottom flask, frozen in liquid nitrogen and lyophilized overnight.

[0298] Characterization of the uPAR-targeting peptides

[0299] The chemical purity of the final products was determined by LC-MS analysis using an Acquity SQD2 LC-MS (Waters, Milford, MA, USA) system equipped with a reversed-phase C18 column (Acquity UPLC BEH, 1.7 μm, 2.1 x 50 mm, Waters, Milford, MA, USA). The compounds were eluted using a linear gradient of Milli-Q water containing 0.1 % formic acid (98-2%) and ACN containing 0.1 % formic acid (2-98%) over 4 min at a flow rate of 0.5 mL / min and subsequently detected by determining their absorbance at λ = 254 nm.

[0300] The chemical identity of the final products was confirmed by high-resolution mass spectrometry (HRMS) analysis (ESI-QTOF-MS, Bruker maXis, Billarica, US-MA or MALDI- TOF-MS, Bruker UltraFlex II, Billarica, US-MA).

[0301] As shown in Table 2 below, the chemical purity of the DOTA-AE105 reference compound delivered by piCHEM was >95%. The compounds AE105 and DOTA-uPAR-ALB peptides were obtained in a 6-32% overall yield after 20-29 synthetic steps. The purity of the HPLC- purified final products was >99% as determined by LC-MS analysis. The m / z ratio calculated for the respective compounds correlated well with HRMS data, confirming the chemical identity of the produced peptides.

[0302] Example 2: Radiolabeling and Radiolytic Stability of the uPAR-Targeting Peptides

[0303] The DOTA-AE105 and DOTA-uPAR-ALB peptides were labeled with lutetium-177 followed by investigation of the radiopeptides' radiolytic stability.

[0304] Stock solutions of the DOTA-AE105 and the DOTA-uPAR-ALB peptides were prepared in Milli-Q water at a concentration of 1 mM. In the case of DOTA-uPAR-ALB-02 and DOTA- uPAR-ALB-03, dimethyl sulfoxide (DMSO) was added to facilitate the dissolution (28% and 36%, respectively). The radiolabeling of the peptides was performed under standard labeling conditions at pH 4.5. Lutetium-177 (no-carrier-added177LuCl3in 0.04 M HCI; ITM Medical Isotopes GmbH, Germany) was added to a 1 :5 (v / v) mixture of sodium acetate (0.5 M, pH 8) and HCI (0.05 M, pH 1 -2) followed by addition of the respective peptide (stock solution of 1 mM, i.e. 1 nmol corresp. 1 pL) to obtain molar activities up to 100 MBq / nmol. The reaction mixture was incubated for 10 min at 95 °C. Quality control (QC) of the radiolabeled peptides was performed by HPLC (Merck Hitachi HPLC system, Darmstadt, Germany, equipped with a radiodetector LB 508, Berthold Technologies) using a C-18 reversed-phase column (Xterra™ MS C-18, 5 pm, 15 cm x 4.6 cm, Waters, Milford, MA, U.S.) and a linear gradient of Milli-Q water containing 0.1 % TFA (95-20%) and ACN (5- 80%) over 15 min at a flow rate of 1 .0 mL / min. The stability of [177Lu]Lu-DOTA-AE105 and the,77Lu-DOTA-uPAR-ALB radiopeptides (50 MBq / nmol; QC: >95% intact product) was assessed in vitro. The radiopeptide solutions were diluted with 0.9% NaCI to obtain an activity concentration of 150 MBq / 300 pL in the absence and presence of L-ascorbic acid (3 mg in 20 pL) together with NaOAc (0.5 M, 30 pL) to compensate for the acidic pH. Aliquots of the solutions (without and with L-ascorbic acid) were sampled after an incubation period of 1 h, 4 h and 24 h at room temperature (RT) followed by analysis using HPLC. The integrated peak area of the intact radioligand peak was expressed as the percentage of the sum of the integrated peak areas of each peak present in the chromatogram. The final amount of intact radiopeptide at the given timepoints was expressed by correcting the obtained percentage of the product peak to the peak obtained at t = 0, which was set as 100%.

[0305] As shown in Table 3, in the absence of L-ascorbic acid, radiolytic degradation of the177Lu- DOTA-uPAR-ALB peptides was observed in all cases. This was almost completely prevented by the addition of L-ascorbic acid as a radical scavenger. Under these conditions, >93% intact radiopeptides were observed over 24 h (Table 4).

[0306] Example 3: Stability of the Radiopeptides in Blood Plasma

[0307] The [177Lu]Lu-DOTA-AE105 and177Lu-DOTA-u PAR-ALB peptides were investigated with regard to their stability after incubation in blood plasma.

[0308] Based on the stability data (see above), it was decided to add L-ascorbic acid (3 mg, 20 pL) as a scavenger after radiolabeling of the peptides. The acidic pH value was compensated by the addition of NaOAc (0.5 M, 30 pL). The radiopeptides were added to mouse blood plasma (Lot: 32321 , Rockland Inc.) or in human blood plasma (Stiftung Blutspende SRK Aargau-Solothurn, Switzerland) at a concentration of 10 MBq / 200 pL and incubated at 37 °C for up to 24 h. Control samples were prepared by dilution of the radiopeptides in 0.9% NaCl to obtain the same activity concentration. Aliquots of each sample were taken after 1 h, 4 h, and 24 h (2 pL, -100 kBq) and investigated by means of thin layer chromatography (TLC) using two different methods. The first method made use of normal phase TLC plates (MERCK Analytical Chromatography, TLC Silica gel 60 F254) as stationary phase and 10% NH4Ac / MeOH (1 :1 ; v / v) as mobile phase. The second method made use of reversed-phase TLC plates (MERCK Analytical Chromatography, TLC Silica gel 60 RP-18 F254S) as stationary phase and ACN / citrate buffer (pH 5.5) (3:7; v / v as mobile phase. In addition, a dilution of [177Lu]LuCl3 / HCI 0.04 M (10 MBq / 200 μL) was added to each TLC plate and run with the corresponding mobile phases. After the eluent reached the front line, the TLC plates were dried and exposed on a phosphor screen (PERKIN ELMER Super resolution screen PSR10450013) for 1 min. The screens were read using a Cyclone Plus phosphor imager (PERKIN ELMER) and analyzed using the OptiQuant Software, version 5.0.

[0309] The reversed phase TLC analysis of [177Lu]Lu-DOTA-AE105 showed multiple degradation products in both murine (-73% intact radiopeptide) and human blood plasma (-66% intact radiopeptide) already after 1 h incubation time. After 4 h incubation, the majority of [177Lu]Lu-DOTA-AE105 was degraded, resulting in only <7% and -1 1 % intact radiopeptide in mouse and human blood plasma, respectively. [177Lu]Lu -DOTA-uPAR-ALB-01 , [177Lu]Lu - DOTA-uPAR-ALB-02, [177Lu]Lu -DOTA-uPAR-ALB-03, [177Lu]Lu -DOTA-uPAR-ALB-05, [177Lu]Lu -DOTA-uPAR-ALB-1 1 were stable (>95% intact radiopeptide) in murine and human blood plasma for up to 24 h. [177Lu]Lu-DOTA-uPAR-ALB-04 showed >76% intact radiopeptide after 24 h when incubated in human blood plasma, and >84% intact radiopeptide after 24 h when incubated in mouse blood plasma.

[0310] Example 4: PBS / n-Octanol Distribution Coefficient (logD Values)

[0311] The distribution coefficients (logD values) of [177Lu] Lu-DOT A-AE105 and the177Lu-DOTA- uPAR-ALB peptides were determined in a mixture of / 7-octanol and phosphate-buffered saline (PBS) to estimate their hydrophilic / lipophilic properties.

[0312] [177Lu]Lu-DOTA-AE105 and the177Lu-DOTA-uPAR-ALB peptides (50 MBq / nmol) were diluted in PBS pH 7.4 to obtain an activity concentration of 10 MBq / 500 pL. The diluted radiopeptides (-0.5 MBq, 25 pL, 0.01 nmol) were added to a mixture of PBS pH 7.4 (1475 pL) and / 7-octanol (1500 pL). The vials were vortexed vigorously for 1 min followed by centrifugation (6 min, 560 ref) for phase separation. Aliquots were taken from each phase and measured in a y-counter ((PerkinElmer, Wallac Wizard 1480)). The distribution coefficients were calculated as the logarithmic value of the ratio of counts per minute (cpm) measured in the / 7-octanol phase relative to the cpm measured in the PBS phase. The results were listed as average ± SD of the data obtained from 3 independent experiments, each performed with five replicates.

[0313] As shown in Table 5, among all radiopeptides, [, 77lu]Lu-DOTA-AE105 was the most hydrophilic candidate demonstrated by its relatively low logD value of -1 .38 ± 0.15. Among the p-iodophenyl-comprising radiopeptides, [177Lu]Lu-DOTA-uPAR-ALB-01 was somewhat more lipophilic (logD value: 0.78 ± 0.04) than [177Lu]Lu-DOTA-uPAR-ALB-02 (logD value: 0.25 ± 0.03) and [177Lu]Lu-DOTA-uPAR-ALB-05 (logD value: 0.25 ± 0.13) both of which modified with a hydrophilic PEC spacer. [177Lu]Lu-DOTA-uPAR-ALB-03 (logD value: 0.51 ± 0.13) showed the lowest logD value due to the lipophilic AMBA linker integrated into the chemical structure. The radiopeptides comprising a / >iodophenyl-based albumin-binding entity were more lipophilic (logD values: 0.24-0.78) than [177Lu| Lu-DOT A-uPAR-ALB-1 1 (logD value: -0.26 ± 0.09), which was modified with a p-tolyl-based albumin-binder. [177Lu]Lu-DOTA-uPAR-ALB-04 showed a distribution coefficient (logD value: -0.29 ± 0.11 ) in the same range as [177Lu] Lu-DOT A-uPAR-ALB-11 (Table 5).

[0314] Example 5: Albumin-bound Fraction of Radiopeptides in Mouse and Human Blood

[0315] Plasma

[0316] The binding of the, 77Lu-DOTA-uPAR-ALB peptides to serum albumin in mouse and human blood plasma was determined and compared. The albumin-binding properties of177Lu-DOTA-uPAR-ALB peptides in mouse blood plasma (Rockland Immunochemicals, Inc., USA) and human blood plasma (Stiftung Blutspende SRK Aargau -So loth urn, Switzerland) were determined using an ultrafiltration method and compared to that of [177Lu]Lu-DOA-AE105, which does not comprise a designated albumin- binder. The177Lu-DOTA-uPAR-ALB peptides (50 MBq / nmol, ~300 kBq, 0.006 nmol in 15 pL) were added to samples of mouse and human blood plasma (150 μL), followed by incubation of the samples at 37 °C for 30 min. Ice-cold PBS (150 μL, pH 7.4) was added before loading the blood plasma sample on Amicon centrifugal filters (cut-off of 10 kDa; Merck Millipore) followed by centrifugation (14'000 ref, 30 min, 4 °C) to allow the separation of the plasma protein-bound from the plasma-unbound (free) fractions of each sample. The inserts of the filter devices were inverted and centrifuged at 200 ref for 3 min to recover the protein-bound radiopeptide. The activity of the protein-bound fraction was measured using a y-counter (PerkinElmer, Wallac Wizard 1480). The activity in the filtrate and filter unit was measured in a y-counter (PerkinElmer, Wallac Wizard 1480) and the counts were combined assuming that the fraction retained in the filter membrane was not bound to proteins. The protein-bound fraction was expressed as percentage of the whole activity (i.e. plasma protein-bound activity, activity measured in the filtrate and activity measured in the filter (set as 100%)). These experiments were performed 3 times for each radiopeptide.

[0317] As shown in Table 6, the177Lu-DOTA-uPAR-ALB peptides showed a fraction of >87% and >88% bound to albumin in mouse and human blood plasma, respectively. In contrast, [177Lu]Lu-DOTA-AE105 showed moderate binding to protein in mouse (52%) and human blood plasma (43%).

[0318]

[0319] Example 6: Relative Albumin-Binding Affinity of the Radiopeptides

[0320] The relative affinity of the radiopeptides to albumin in mouse and human blood plasma was determined to compare the properties of the candidates.

[0321] The relative albumin-binding affinities of177Lu-DOTA-uPAR-ALB peptides in mouse blood plasma (Rockland Immunochemicals, Inc., USA) and human blood plasma (Stiftung Blutspende SRK Aargau-Solothurn, Switzerland) were determined using an ultrafiltration method. The amount of mouse serum albumin (MSA) and human serum albumin (HSA) in mouse and human blood plasma was defined as 550 μM and 800 μM, respectively, based on measurements using a dry chemistry analyzer (DRI-CHEM 4000i, FUJIFILM, Japan). A fixed amount of radiopeptide (50 MBq / nmol, ~300 kBq, 15 gL, 0.006 nmol) was added to a defined volume (150 μL) of mouse and human blood plasma and various dilutions thereof in PBS pH 7.4, resulting in defined [MSA]-to-[radiopeptide] or [HSA]-to-[radiopeptide] molar concentration ratios of 0.01-12500 and 0.01-20000, respectively. The albumin- bound fraction was determined using the ultrafiltration device as described above. The data were analyzed using a semi-logarithmic plot assuming a maximum binding of 100%. The Hill equation was fitted to the data points, and the half-maximum binding (B50) was determined based on the obtained binding curves (GraphPad Prism software, version 8.3). To quantitatively express and compare the albumin-binding affinity of the radiopeptides, the albumin-binding affinity was expressed relative to that of [177Lu]Lu-uPAR-ALB-01 which was set as 1 .0. The results were presented as the average of 3 independent experiments.

[0322] As shown in Table 7 and graphically represented in Figure 2, [177Lu]Lu-DOTA-uPAR-ALB-01 and [177Lu]Lu-DOTA-uPAR-ALB-04 showed similar binding affinities to albumin in human and murine blood plasma. [177Lu]Lu-DOTA-uPAR-ALB-05 revealed 1.6-fold lower affinities to mouse albumin and 5.5-fold lower affinity to human albumin than [177Lu]Lu-DOTA- uPAR-ALB-01 (Figure 2A / C). While [177Lu]Lu-DOTA-uPAR-ALB-02 showed a comparable binding profile as I177Lu] Lu-DOT A-uPAR-ALB-01 and [177Lu]Lu-DOTA-uPAR-ALB-04, [177Lu]Lu-DOTA-uPAR-ALB-03 bound stronger to albumin in mouse blood plasma and slightly less to albumin in human plasma (Figure 2B / D). [177Lu]Lu-DOTA-uPAR-ALB-1 1 modified with the / >tolyl-based albumin-binder, showed 3-fold lower albumin-binding affinity than [177Lu]Lu-DOTA-uPAR-ALB-01 , [177Lu] Lu-DOT A-uPAR-ALB-02 and [177Lu]Lu- DOTA-uPAR-ALB-04. Example 7:

[0323] HEK cells transfected with human uPAR, herein referred to as HEK-uPAR cells, were obtained from Innoprot, Innovative Technologies in Biological Systems S.L. (Bizkaia, Spain). The cells were cultured in DMEM medium supplemented with 10% fetal calf serum, L- glutamine, 1 % non-essential amino acids and antibiotics. Hygromycin B (50 pg / ml) was added to maintain uPAR expression. The cells were subcultured twice a week using trypsin / EDTA and cultured under standard cell culture conditions using 5% CO2at 37 °C in a humidified atmosphere.

[0324] Uptake and internalization studies were performed with all uPAR-targeting radiopeptides using HEK-uPAR cells.

[0325] HEK-uPAR cells were seeded in polylysine-coated 12-well plates (1 x 106cells in 2 ml per well) using DMEM cell culture medium with supplements. The cells were incubated at 37 °C and 5% CO2overnight to allow adhesion and growth. After removal of the supernatant, the HEK-uPAR cells were rinsed with PBS before adding DMEM without supplements (975 pl per well). The radiopeptides (50 MBq / nmol) were added to each well in a volume of 25 pl (0.75 pmol, 38 kBq). In some wells, the HEK-uPAR cells were coincubated with an excess of AE105 (5 pM) to block uPAR. After incubation of the cells for 2 h or 4 h at 37 °C, these were rinsed with ice-cold PBS to determine the total uptake of the radiopeptides. In order to assess the internalized fraction, an acidic glycine buffer (pH 2.8, 50 mM glycine, 100 mM NaCI) was applied to the cells to release uPAR-bound radiopeptides from the cell surface. The cells were lysed using NaOH solution (1 M, aq., 1 ml) and the lysates were transferred to RIA tubes for counting the activity in a y-counter ((PerkinElmer, Wallac Wizard 1480)). The protein concentration of each sample was determined using a Micro BCA Protein Assay kit (Pierce, Thermo Scientific) to standardize the measured activity to the average content of protein in a single well. The uptake and internalized fraction were expressed as the percentage of total added activity and presented as the average ± SD of n = 3 independent experiments.

[0326] As shown in Figure 3, the HEK-uPAR cell uptake of [177Lu]Lu-DOTA-AE105 was higher (44 ± 4% and 46 ± 5% after 2 h and 4 h, respectively) than for the albumin-binding radiopeptides, which showed uptake in the range of 21-33% and 18-34% after 2 h and 4 h, respectively. The177Lu-DOTA-uPAR-ALB peptides showed an internalized fraction of 16- 24% and 12- 26% after 2 h and 4 h, respectively, whereas the internalized fraction of [177Lu]Lu-DOTA-AE105 was 11 + 1 % and 17 + 3% after 2 h and 4 h, respectively. The unspecific uptake determined in blocking experiments was low (0.9-3.2% after 4 h incubation) for177Lu-DOTA-uPAR-ALB peptides and the same held true for [177Lu]Lu-DOTA- AE105 (1.6% after 4-h incubation).

[0327] Among all177Lu-DOTA-uPAR-ALB peptides, [177Lu]Lu-DOTA-uPAR-ALB-02 and [, 77Lu]Lu- DOTA-uPAR-ALB-1 1 showed the highest uptake in HEK-uPAR cells (32 ± 1 % and 33 ± 2% after 2 h; 31 ± 1 % and 34 + 4% after 4 h, respectively). [177Lu]Lu-DOTA-uPAR-ALB-05 showed a slightly lower uptake in HEK-uPAR cells (30 + 1 % and 23 ± 3% after 2 h and 4 h, respectively).

[0328] Example 8: uPAR-binding Affinity (KPValues)

[0329] The uPAR-binding affinity of the radiopeptides was investigated using HEK-uPAR cells.

[0330] HEK-uPAR cells were seeded in polylysine-coated 48-well plates (0.25 x 106in 0.5 mL per well) using DMEM culture medium with supplements. The cells were incubated at 37 °C and 5% CO2overnight to allow adhesion and growth. After removing the supernatant, the well plates with HEK-uPAR cells were placed on ice to avoid internalization of the peptides. Cells were rinsed with PBS followed by the addition of DMEM culture medium without supplements (450 pL / well) in the presence or absence of AE105 (40 μm) used as a blocking agent. The radiopeptides (5 MBq / nmol) were diluted in PBS to obtain peptide concentrations in the range of 10-16000 nM. From each dilution, 50 pL were added to each well to obtain peptide concentrations in the range of 1-1600 nM. The cells were incubated at 4 °C for one hour before rinsing twice with PBS (0.5 mL, pH = 7.4). The cells were lysed using NaOH solution (1 M, aq., 0.6 mL) and the lysates were transferred to RIA tubes for counting the activity in a y-counter (PerkinElmer, Wallac Wizard 1480). The KDvalues were determined by plotting specific binding (total binding minus unspecific binding) against the molar concentration of the added radiopeptide. A nonlinear regression analysis was performed using GraphPad Prism software (version 8.3.1 ).

[0331] As shown in Table 8, the uPAR-affinity of [177Lu]Lu-DOTA-AE105 was in the nanomolar range (KDvalue: 20 ± 1 nM). The determined uPAR-binding affinities of the177Lu-DOTA- uPAR-ALB peptides were in a similar range (KDvalues: 10-57 nM). [177Lu]Lu-DOTA-uPAR- ALB-05 showed the highest uPAR-binding affinity, whereas it was lowest for [177Lu]Lu- DOTA-uPAR-ALB-03 and [177Lu]Lu-DOTA-uPAR-ALB-04. The Kovalues of [177Lu]Lu-DOTA- uPAR-ALB-01 , [177Lu]Lu-DOTA-uPAR-ALB-02 and [177Lu]Lu-DOTA-uPAR-ALB-1 1 were in the range of 30-40 nM.

[0332] Example 9: SPECT / CT Imaging Studies in a xenografted nude mice model

[0333] All applicable international, national, and / or institutional guidelines for the care and use of animals were followed. In particular, all animal experiments were carried out according to the guidelines of the Swiss Regulations for Animal Welfare. The preclinical studies have been ethically approved by the Cantonal Committee of Animal Experimentation and permitted by the responsible cantonal authorities (License N° 75721 ). Five-week-old female CD1 nude (Crl:CD1 -Foxnnu) mice were obtained from Charles River Laboratories (Sulzfeld, Germany) and fed with standard rodent chow ad libitum. The mice were subcutaneously inoculated with HEK-uPAR cells (7 x 106cells in 100 pL PBS) on the right shoulder. Single photon emission computed tomography / computed tomography (SPECT / CT) imaging studies were performed to investigate the whole-body distribution of uPAR-targeting radiopeptides in HEK-uPAR xenografted nude mice.

[0334] SPECT / CT experiments were performed with mice approximately 3-4 weeks after HEK- uPAR cell inoculation. The mice were scanned 1 h, 4 h and 24 h after injection of the respective radiopeptide (25 MBq, 0.5 nmol, 100 pL, diluted in 0.9% NaCI containing 0.05% BSA). Imaging studies were performed using a four-head, multiplexing, multihole small-animal SPECT / CT camera (NanoSPECT / CT™, Mediso Medical Imaging Systems, Budapest, Hungary). Each head was outfitted with a thungsten-based aperture of nine 1.4 mm-diameter pinholes and a thickness of 10 mm. CT scans of 7-9 min duration were followed by SPECT scans of 45-50 minutes. The images were acquired using Nucline Software (version 10.2, MEdiso Ltd., Budapest, Hungary). The real-time CT reconstruction used a cone-beam filtered beckprojection. The reconstruction of SPECT data was performed with HiSPECT software (version 1.4.3049, Scivis GmbH, Gottingen, Germany) using y- energies of 56.1 keV (± 10%), 112.9 keV (± 10%) and 208.4 keV (± 10%) for lutetium- 177. The images were prepared using VivoQuant post-processing software (version 3.5, inviCRO Imaging Services and Software, Boston, U.S.). A Gauss post-reconstruction filter (Full width at half maximum, 1 .0 mm) was applied and the scale of activity was set as indicated on the images (minimum value = 0.15 Bq / voxel, maximum value =20 Bq / voxel).

[0335] As shown in Figure 4, [177Lu]Lu-DOTA-AE105 showed rapid clearance from the blood mainly via kidneys, which showed the highest accumulation at 1 h after injection, while only moderate uptake of the radiopeptide was seen in the xenograft. After 4 h, [177Lu]Lu- DOTA-AE105 was almost entirely cleared from the blood circulation and the signal in the xenograft and kidneys was comparable, but low.

[0336] The,77Lu-DOTA-uPAR-ALB peptides showed considerable retention in the blood and heart early after injection, which can be ascribed to their albumin-binding properties. At 1 h after injection of [177Lu]Lu-DOTA-uPAR-ALB-01 and [177Lu]Lu-DOTA-uPAR-ALB-04, accumulation of activity in the xenograft was rather low, whereas [177Lu]Lu-DOTA-uPAR- ALB-02 and [177Lu]Lu-DC)TA-uPAR-ALB-05 visualized the xenograft better at this early timepoint. The best visualization of the xenograft was achieved after injection of [177Lu]Lu- DOTA-uPAR-ALB-1 1 which was modified with the p-tolyl-based albumin-binder. In this case, the signal of activity in the HEK-uPAR xenograft was substantial already after 1 h (Figure 4).

[0337] At 4 h after injection (Figure 5), the situation was not much different compared to the 1 h p.i. time point At 24 h post injection (Figure 6), the xenograft was still best visible after injection of [177Lu]Lu-DOTA-uPAR-ALB-11 but also observable after injection of [177Lu]Lu- DOTA-uPAR-ALB-02 as well as [177Lu]Lu-DOTA-uPAR-ALB-03.

[0338] The renal uptake of all177Lu-DOTA-uPAR-ALB peptides was low, except for [177Lu]Lu- DOTA-uPAR-ALB-1 1 which showed substantial kidney uptake at 1 h p.i., but the activity was cleared effectively over time and almost entirely excreted at 24 h p.i..

[0339] Blood retention of the177Lu-DOTA-uPAR-ALB peptides was high, in particular for [177Lu]Lu- DOTA-uPAR-ALB-03, which showed the most pronounced retention in the blood that persisted over 24 h (Figures 5 and 6).

[0340] Overall, the albumin-binding affinity of the radiopeptides had a substantial impact on their tissue distribution profiles, not only with regard to the blood residence time, but also with regard to the renal excretion and, most importantly, accumulation in the xenograft. While high albumin-binding properties, as was the case for [177Lu]Lu-DOTA-uPAR-ALB-03, led to lower accumulation in the xenograft at early time points (1 h, 4h p.i.) and increased accumulation at a later time point (24h p.i.), moderate albumin-binding properties, as is the case for [177Lu]Lu-DOTA-uPAR-ALB-1 1 , results in less retention of activity in the blood but faster accumulation in the xenograft.

[0341] Example 10: Biodistribution Studies

[0342] The radiopeptides [177Lu]Lu-DOTA-uPAR-ALB-02, [177Lu]Lu-DOTA-uPAR-ALB-03 and [177Lu]Lu-DOTA-uPAR-ALB-1 1 which show distinct tissue distribution patterns in imaging experiments using SPECT / CT, were used in order to quantify the uptake in xenografts and normal tissue. Biodistribution studies were performed in HEK-uPAR xenografted nude mice.

[0343] The studies were performed approximately 3-4 weeks after HEK-uPAR cell inoculation. The mice were injected with uPAR-targeting radiopeptides (5 MBq, 0.5 nmol, 100 pL) in 0.9% NaCI containing 0.05% BSA and sacrificed at 4 h, 24 h or 48 h after injection of the radiopeptides. Selected tissues and organs were collected, weighed and measured using a y- counter (PerkinElmer, Wallac Wizard 1480). The results were listed as a percentage of the injected activity per gram of tissue mass (% lA / g) using counts of a standard (defined volume of the original injection solution) measured at the same time to enable the calculation of decay-corrected values.

[0344] Biodstribution data were obtained at variable timepoints after injection of [177Lu]Lu-DOTA- AE105 (Table 9), [177Lu]Lu-DOTA-uPAR-ALB-02 (Table 10), [177Lu]Lu-DOTA-uPAR-ALB-03 (Table 1 1 ) and [177Lu]Lu-DOTA-uPAR-ALB-1 1 (Table 12). The most relevant differences among the radiopeptides were observed regarding their residence time in the blood (Figure 7), their accumulation in HEK-uPAR xenografts (Figure 8), the kidneys (Figure 9) and the liver (Figure 10).

[0345] Decay-corrected data of accumulated activity are shown as % lA / g tissue, representing the average ± SD (n = 3).

[0346] Table 10. Biodistribution data and tumor-to-background ratios obtained in HEK-uPAR- bearing mice at various time points after injection of [177Lu] Lu-DOT A-u PAR-ALB-02.

[0347] [177Lu] Lu DOTA-uPAR-ALB-02

[0348] Decay-corrected data of accumulated activity are shown as % I A / g tissue, representing the average ± SD (n = 3). Table 11. Biodistribution data and tumor-to-background ratios obtained in HEK-uPAR- bearing mice at various time points after injection of [177Lu]Lu-DOTA-uPAR-ALB-03.

[0349] [177Lu] Lu-DOT A-uPAR-ALB-03

[0350] Decay-corrected data of accumulated activity are shown as % I A / g tissue, representing the average ± SD (n = 3).

[0351] Table 12. Biodistribution data and tumor-to-background ratios obtained in HEK-uPAR- bearing mice at various time points after injection of [177Lu]Lu-DOTA-uPAR-ALB-1 1 .

[0352] [177Lu]Lu-DOTA-uPAR-ALB-11

[0353] Blood 5.0 ± 0.6 0.03 ± 0.00 0.02 ± 0.00

[0354] Heart 1 .8 ± 0.2 0.12 ± 0.02 0.08 ± 0.01

[0355] Lung 3.1 ± 0.2 0.29 ±0.08 0.1 7 ± 0.02

[0356] Spleen 1.1 ± 0.1 0.49 ± 0.05 0.37 ± 0.05

[0357] Kidneys 4.0 ± 0.4 1.7 ± 0.1 1.1 ± 0.1

[0358]

[0359] Decay-corrected data of accumulated activity are shown as % I A / g tissue, representing the average ± SD (n = 3).

[0360] As shown in Figure 7, [177Lu]Lu-DOTA-AE105 was quickly cleared from the blood (<0.1 % lA / g, 4 h p.i., Table 9). In all cases of albumin-binding radiopeptides, blood retention was enhanced as compared to that of [177Lu]Lu-DOTA-AE105. [177Lu]Lu-DOTA-uPAR-ALB-03 showed the most pronounced retention in blood circulation (15% lA / g, 13% lA / g and 8% lA / g at 4 h, 24 h and 48 h, respectively, Table 1 1 ).

[0361] High retention in the blood was also seen for [177Lu] Lu-DOT A-uPAR-ALB-02 at 4 h p.i. but it decreased faster over time (6 % I A / g and 1 .7% lA / g after 24 h and 48 h, respectively, Table 10).

[0362] [177Lu]Lu-DOTA-uPAR-ALB-1 1 showed increased retention in the blood as compared to [177Lu]Lu-DOTA-AE105 (Table 12), however, due to the reduced albumin-binding affinity, it was less pronounced than in the cases of [177Lu]Lu-DOTA-uPAR-ALB-02 and [177Lu]Lu- DOTA-uPAR-ALB-03.

[0363] As a result of the modification with an albumin-binding entity and related blood residence time, the accumulation in the uPAR xenografts was increased for all novel radiopeptides as compared to that of [177Lu]Lu-DOTA-AE105 (see Figure 8). [177Lu] Lu-DOT A-AE105 showed only moderate accumulation in the HEK-uPAR xenograft (<1 % after 4 h and 24 h). Uptake in the xenografts was higher for [177Lu]Lu-DOTA-uPAR-ALB-02 (11 + 1 .6% lA / g) and [177Lu]Lu-DOTA-uPAR-ALB-03 (4 + 0.3% lA / g) at 4 h p.i. and highest for [177Lu]Lu-DOTA- uPAR-ALB-1 1 (>15% lA / g). At the 24 h p.i. and 48 h p.i. timepoints, the three177Lu-DOTA- uPAR-ALB peptides revealed similar uptake in the xenografts (7.5-10% lA / g at 24 h p.i.; 5.3-7.0% lA / g at 48 h p.i.)

[0364] As shown in Figure 9, retention in the kidneys was enhanced for all tested albumin-binding radiopeptides. In contrast, [177Lu]Lu-DOTA-AE105 showed only low retention in the kidneys (<2% lA / g, 4 h p.i.). [177Lu]Lu-DOTA-uPAR-ALB-02 and [, 77Lu]Lu-DOTA-uPAR-ALB-03 showed similar kidney accumulation (5.5% lA / g, and 4.1 % lA / g, respectively) at 4 h after injection. After 48 h, however some residual activity could still be found after injection of both radiopeptides (>2 and >3% lA / g for [177Lu]Lu-DOTA-uPAR-ALB-02 and [177Lu]Lu- DOTA-uPAR-ALB-03, respectively). The renal retention of [177Lu]Lu-DOTA-uPAR-ALB-11 was in the same range ( 4.0 + 0.4% lA / g) after 4 h, however, it was faster cleared than [177Lu]Lu-DOTA-uPAR-ALB-02 and [, 77Lu]Lu-DOTA-uPAR-ALB-03 (1.6 and 1.1 % lA / g, after 24 h and 48 h p.i., respectively).

[0365] As shown in Figure 10, the liver uptake of the radiopeptides was low at all investigated timepoints (<4% lA / g), but clearly higher than for [177Lu]Lu-DOTA-AE105. The highest liver uptake was observed for [177Lu]Lu-DOTA-uPAR-ALB-03 over the whole time of investigation. The accumulation of [177Lu]Lu-DOTA-uPAR-ALB-02 in the liver was similar to that of [177Lu]Lu-DOTA-uPAR-ALB-03 after 4 h, but faster cleared to <2% lA / g at 24 h p.i. and ~1 % lA / g at 48 h p.i.. On the other hand, the liver uptake was low for [177Lu]Lu-DOTA- uPAR-ALB-11 (<2% lA / g at 4 h p.i.; <0.5% lA / g at 24 h p.i.). Since [177Lu]Lu-DOTA-AE105 was rapidly cleared from the blood circulation, no significant liver uptake was observed for this radiopeptide (<0.2% lA / g).

[0366] In all cases, the xenograft-to-blood ratios increased over time and reached a maximum value at 48 h after injecting the radiopeptide (Figure 1 1 ). [177Lu]Lu-DOTA-AE105 showed particularly high xenograft-to-blood ratios at early time points after injection due to its rapid blood clearance. The xenograft-to-blood ratios obtained after injection of [177Lu] Lu-DOT A- uPAR-ALB-02 were lower and lowest for [177Lu]Lu-DOTA-uPAR-ALB-03. [177Lu] Lu-DOT A- uPAR-ALB-1 1 showed a moderate blood retention but substantial accumulation in the xenograft.

[0367] As shown in Figure 12, the xenograft-to-kidney ratios of accumulated activity were lowest for [177Lu]Lu-DOTA-AE105 (<1 ). The highest ratio was obtained for [177Lu]Lu-DOTA-uPAR- ALB-1 1 (3.9-4.9), followed by [177Lu]Lu-DOTA-uPAR-ALB-02 (2.0-3.3) and [177Lu]Lu- DOTA-uPAR-ALB-03 (1.0-2.0). The ratios were higher for all albumin-binding radiopeptides at later timepoints, which can mainly be ascribed to renal clearance of activity over time.

[0368] As shown in Figure 13, the xenograft-to-liver ratios were high for all radiopeptides tested. The highest ratio was obtained for [177Lu] Lu-DOT A-uPAR-ALB-1 1, followed by [177Lu]Lu- DOTA-uPAR-ALB-02 (4-7 between 4 h and 48 h p.i.) and [177Lu]Lu-DOTA-uPAR-ALB-03 (1 .3-2.2, between 4 h and 48 h p.i.).

[0369] Example 11 : Synthesis of 2ndGeneration uPAR-Targeting Peptides

[0370] In order to further investigate the impact of chemical modifications of the structure of DOTA-uPAR-ALB peptides on the pharmacokinetic properties of the resultant radiopeptides, a number of further uPAR-targeting peptides, called as 2ndgeneration uPAR-targeting peptides, were synthesized based on DOTA-uPAR-ALB-1 1 by exchanging the linker entities or the DOTA chelator.

[0371] The synthesis of the 2ndgeneration uPAR-targeting peptides was performed using solid- phase peptide synthesis according to the synthetic procedures previously described for the 1stgeneration uPAR-targeting peptides in Example 1. All commercially available solvents and chemicals were used without further purification.

[0372] Synthesis of DOTA-uPAR-ALB-14

[0373] The synthesis of DOTA-uPAR-ALB-14 was performed in analogy to the procedure described for DOTA-uPAR-ALB-1 1 in Example 1 , but instead of using the Dde-Lys(Fmoc)-OH, Dde- Dap(Fmoc)-OH ((25)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-[1 -(2-hydroxy-4,4- dimethyl-6-oxocyclohexen-1 -yl)ethylideneamino]propanoic acid) was used as a shorter trifunctional linker in the respective synthesis step (Scheme 8).

[0374] Scheme 8. Synthesis of DOTA-uPAR-ALB-14:

[0375] Synthesis of DOTA-uPAR-ALB-15

[0376] The synthesis of DOTA-uPAR-ALB-15 was performed in analogy to the procedure described for DOTA-uPAR-ALB-11 in Example 1 , but instead of using the Fmoc-N-amido-PEGi-acid, the Fmoc-Namido-PEG3-acid (1 -(9H-fluoren-9-yl)-3-oxo-2,7,10,13-tetraoxa-4- azahexadecan-16-oic acid) was used as a shorter linker in the respective synthesis step (Scheme 9). Scheme 9. Synthesis of DOTA-uPAR-ALB-15:

[0377] Synthesis of DOTAGA~uPAR-ALB-17

[0378] The synthesis of DOTAGA-uPAR-ALB-17 was performed in analogy to the procedure described for DOTA-uPAR-ALB-1 1 in Example 1 , but instead of conjugating the DOTA- tris(‘Bu)ester, (A)-DOTAGA-tetra(‘Bu)ester ((A)-5-[(2-methylpropan-2-yl)oxy]-5-oxo-4- [4,7,10-tris[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1 ,4,7,10-tetrazacyclododec-1 - yl]pentanoic acid) was conjugated as a different macrocyclic chelator in the respective synthesis step (Scheme 10).

[0379] Scheme 10. Synthesis of DOTAGA-uPAR-ALB-17:

[0380] Synthesis of DOTA-uPAR-ALB-18

[0381] The synthesis of DOTA-uPAR-ALB-18 was performed in analogy to the procedure described for DOTA-uPAR-ALB-1 1 in Example 1 , but instead of introducing a Fmoc-N-amido-PEG4- acid spacer, a Fmoc-N-amido-PEG5-acid (1 -(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16,19- hexaoxa-4-azadocosan-22-oic acid) was used as a longer linker in the respective synthesis step (Scheme 11 ).

[0382] Scheme 11 . Synthesis of DOTA-uPAR-ALB-18:

[0383] Purification and Characterization of 2ndGeneration uPAR-ALB Peptides

[0384] In each case, the crude peptide was dissolved in a 1 :1 (v / v) mixture of acetonitrile (ACN) and Milli-Q water. The subsequent purification step was performed using a semipreparative HPLC (Merck-Hitachi LaChrom HPLC system including a D-7000 interface, L-7200 autosampler, L-7400 UV detector, L-7100 pump) equipped with a reversed-phase C18 column (Sunfire™, 5 gm, 10x150 mm, Waters, Milford, MA, USA). The desired peptide was eluted using variable linear gradients of Milli-Q water containing 0.1 % TFA (eluent A) and ACN (eluent B) (Table 13). The desired product was detected by evaluating absorbance at X=254 nm. The product-containing fraction was collected in a round bottom flask, frozen in liquid nitrogen and lyophilized overnight.

[0385] Characterization of the 2ndGeneration uPAR-Targeting Peptides

[0386] The chemical purity of the final products was determined by LC-MS analysis using an Acquity SQD2 LC-MS (Waters, Milford, MA, USA) system equipped with a reversed-phase C18 column (Acquity UPLC BEH, 1.7 pm, 2.1 x 50 mm, Waters, Milford, MA, USA). The compounds were eluted using a linear gradient of Milli-Q water containing 0.1 % formic acid (98-2%) and ACN containing 0.1 % formic acid (2-98%) over 4 min at a flow rate of 0.5 mL / min and subsequently detected by determining their absorbance at λ = 254 nm.

[0387] The chemical identity of the final products was confirmed by high-resolution mass spectrometry (HRMS) analysis (ESI-QTOF-MS, Bruker maXis, Billarica, US-MA or MALDI- TOF-MS, Bruker UltraFlex II, Billarica, US-MA).

[0388] As shown in Table 14 below, the 2ndgeneration uPAR-targeting peptides were obtained in a 1-8% overall yield after 29 synthetic steps. The purity of the HPLC-purified final products was 98% as determined by LC-MS analysis. The m / z ratio calculated for the respective compounds correlated well with HRMS data, confirming the chemical identity of the produced peptides.

[0389] Example 12: Radiolabeling and Radiolytic Stability of the 2ndGeneration uPAR-Targeting

[0390] Peptides

[0391] The uPAR-targeting peptides were labeled with lutetium-177, followed by the investigation of the radiopeptides' radiolytic stability.

[0392] Stock solutions of the uPAR-targeting peptides were prepared in Milli-Q water at a concentration of 1 mM. Sodium acetate (0.5 M) was added to the stock solution of DOTA- uPAR-ALB-14 (10% v / v), DOTA-uPAR-ALB-15 (10% v / v) and DOTAGA-uPAR-ALB-17 (1 1 % v / v) to assist the dissolution of the compounds. The radiolabeling of the peptides was performed by the addition of lutetium-177 (no-carrier-added177LuCl3 in 0.04 M HCI; ITM Medical Isotopes GmbH, Germany) to a 1 :5 (v / v) mixture of sodium acetate (0.5 M) and HCI (0.05 M) at pH 4.5 followed by addition of the respective peptide (stock solution of 1 mM, i.e. 1 nmol corresp. 1 pl) to obtain molar activities up to 50 MBq / nmol. The reaction mixture was incubated for 10 min at 95 °C. Quality control (QC) of the radiolabeled peptides was performed using HPLC (Merck Hitachi HPLC system, Darmstadt, Germany, equipped with a radiodetector LB 508, Berthold Technologies) with a C-18 reversed-phase column (Xterra™ MS C-18, 5 pm, 15 cm x 4.6 cm, Waters, Milford, MA, U.S.) and a linear gradient of Milli-Q water containing 0.1 % TFA (95-20%) and ACN (5-80%) over 15 min at a flow rate of 1 .0 ml / min. The stability of the177Lu-uPAR-ALB radiopeptides (50 MBq / nmol; QC: >95% intact product) was assessed in vitro. The radiopeptide solutions were diluted with 0.9% NaCI to obtain an activity concentration of 150 MBq / 300 pL in the presence of L-ascorbic acid (3 mg in 20 pL) together with NaOAc (0.5 M, 30 pL) to compensate for the acidic pH. Aliquots of the solutions were investigated after an incubation period of 1 h, 4 h and 24 h at room temperature using HPLC analysis. The integrated area of the intact radioligand peak was expressed as the percentage of the sum of the integrated areas of each peak present in the chromatogram. The final amount of intact radiopeptide at the given timepoints was expressed by correcting the obtained percentage of the product peak area to the peak area obtained at t = 0, which was set as 100%. As shown in Table 15, >88% intact radiopeptides were observed over 24 h.

[0393] The product peak was expressed as percentage of the sum of integrated peak areas of the entire chromatogram (set as 100%) relative to the value obtained immediately after labeling (average of n=3 experiments + SD, if not >95%).

[0394] Example 13: Stability of the 2ndGeneration Radiopeptides in Blood Plasma

[0395] The177Lu-labeled uPAR-targeting peptides were investigated with regard to their stability after incubation in blood plasma.

[0396] Based on the stability data (see above), it was decided to add L-ascorbic acid (3 mg, 20 pL) as a scavenger after radiolabeling of the peptides. The acidic pH value was compensated by the addition of NaOAc (0.5 M, 30 pL). The radiopeptides were added to mouse blood plasma (Lot: 32321 , Rockland Inc.) or to human blood plasma (Stiftung Blutspende SRK Aargau-Solothurn, Switzerland) at a concentration of 10 MBq / 200 pL and incubated at 37 °C for up to 24 h. Control samples were prepared by dilution of the radiopeptides in 0.9% NaCI to obtain the same activity concentration. Aliquots of each sample were taken after 1 h, 4 h and 24 h (2 pL, -100 kBq) and investigated by means of thin layer chromatography (TLC) using two different methods. The first method made use of normal phase TLC plates (MERCK Analytical Chromatography, TLC Silica gel 60 F254) as stationary phase and 10% NH4Ac in Milli-Q water / MeOH (1 :1 ; v / v) as mobile phase. The second method made use of reversed-phase TLC plates (MERCK Analytical Chromatography, TLC Silica gel 60 RP-18 F254S) as stationary phase and ACN / citrate buffer (pH 5.5) (3:7; v / v) as mobile phase. In addition, a dilution of [177Lu] LuCI3 / HCl 0.04 M (10 MBq / 200 pL) was added to each TLC plate and run with the corresponding mobile phases. After the eluent reached the front line, the TLC plates were dried and exposed on a phosphor screen (PERKIN ELMER Super resolution screen PSR10450013) for 1 min. The screens were read using a Cyclone Plus phosphor imager (PERKIN ELMER) and analyzed using the OptiQuant Software, version 5.0.

[0397] The177Lu- uPAR-ALB peptides were stable (>95% intact radiopeptide) in murine and human blood plasma for up to 24 h. The only exception was [177Lu]Lu-DOTAGA-uPAR-ALB-17, which showed degradation products when incubated in murine blood plasma (>63% intact radiopeptide after 24 h).

[0398] Example 14: n-Octanol / PBS Distribution Coefficient (logD Values) of 2ndGeneration Radiopeptides

[0399] The distribution coefficients (logD values) of the177Lu-labeled uPAR-targeting peptides were determined in a mixture of / 7-octanol and phosphate-buffered saline (PBS) to estimate their hydroph i I ic / lipophi lie properties.

[0400] [177Lu]Lu-DOTA-AE105 and177Lu-uPAR-ALB peptides (50 MBq / nmol) were diluted in PBS pH 7.4 to obtain an activity concentration of 10 MBq / 500 pL. The diluted radiopeptides (-0.5 MBq, 25 pL, 0.01 nmol) were added to a mixture of PBS pH 7.4 (1475 pL) and n- octanol (1500 μL). The vials were vortexed vigorously for 1 min followed by centrifugation (6 min, 560 ref) for phase separation. Aliquots were taken from each phase and measured in a y-counter ((PerkinElmer, Wallac Wizard 1480)). The distribution coefficients were calculated as the logarithmic value of the ratio of counts per minute (cpm) measured in the n-octanol phase relative to the cpm measured in the PBS phase. The results were listed as average ± SD of the data obtained from 3 independent experiments, each performed with five replicates.

[0401] As shown in Table 16, the presence of an albumin binder reduced the hydrophilic character of the tested uPAR-targeting radiopeptides of the 2ndgeneration compared to the that of [177Lu]Lu-DOTA-AE105 (logD value: -1 .38 ± 0.18). The only exception was [177Lu]Lu- DOTAGA-uPAR-ALB-17, which was even more hydrophilic than [177Lu]Lu-DOTA-AE105, demonstrated a logD value of -1.56 ± 0.03. [177Lu]Lu-DOTA-uPAR-ALB-18 comprising a PEG; linker showed a logD value that was slightly lower than that of [, 77Lu]Lu-DOTA-uPAR- ALB-15 with the PEG3linker (logD value: -0.50 ± 0.07 and -0.03 ± 0.01 , respectively). Exchanging the lysine residue with a diaminopropanoic acid residue led to a slightly increased logD value of the resultant [177Lu]Lu-DOTA-uPAR-ALB-14 (logD value: -0.13 + 0.08) in comparison to that of [177Lu]Lu-DOTA-uPAR-ALB-1 1 (logD value: -0.26 ± 0.09).

[0402] Example 15: Albumin-bound Fraction of 2ndGeneration Radiopeptides in Mouse and Human Blood Plasma

[0403] The binding of the177Lu-labeled uPAR-targeting peptides to serum albumin in mouse and human blood plasma was determined and compared. The albumin-binding properties of the177Lu-uPAR-ALB peptides in mouse blood plasma (Rockland Immunochemicals, Inc., USA) and human blood plasma (Stiftung Blutspende SRK Aargau-Solothurn, Switzerland) were determined using an ultrafiltration method and compared to that of [177Lu]Lu-DOTA-uPAR-ALB-1 1 . [177Lu] Lu-DOTA-AE1 05 and the albumin-binding, uPAR-targeting radiopeptides of the 2ndgeneration (50 MBq / nmol, -300 kBq, 0.006 nmol in 15 pL) were added to samples of mouse and human blood plasma (1 50 pL), followed by incubation of the samples at 37 °C for 30 min. Ice-cold PBS (1 50 pL, pH 7.4) was added before loading the blood plasma samples on Amicon centrifugal filters (cut- off of 10 kDa; Merck Millipore) followed by centrifugation (14'000 ref, 30 min, 4 °C) to allow the separation of the plasma protein-bound from the unbound (free) fractions of each sample. The inserts of the filter devices were inverted and centrifuged at 200 ref for 3 min to recover the protein-bound radiopeptide. The activity of the protein-bound fraction was measured using a y-counter (PerkinElmer, Wallac Wizard 1480). The activity in the filtrate and filter unit was measured in a y-counter (PerkinElmer, Wallac Wizard 1480) and the counts were combined assuming that the fraction retained in the filter membrane was not bound to proteins. The protein-bound fraction was expressed as percentage of the whole activity (i.e. plasma protein-bound activity, activity measured in the filtrate and activity measured in the filter (set as 1 00%)). These experiments were performed 3 times for each radiopeptide.

[0404] As shown in Table 1 7, the second generation177Lu-uPAR-ALB peptides showed a fraction of >79% and >84% bound to albumin in mouse and human blood plasma, respectively, which was considerably higher than the protein-associated fraction of [177Lu]Lu-DOTA- AE105 measured in the same conditions.

[0405] Example 16: Relative Albumin-Binding Affinity of the 2ndGeneration Radiopeptides

[0406] The relative affinity of the radiopeptides to albumin in mouse and human blood plasma was determined to compare the properties of the candidates.

[0407] The relative albumin-binding affinities of177Lu-uPAR-ALB peptides in mouse blood plasma (Rockland Immunochemicals, Inc., USA) and human blood plasma (Stiftung Blutspende SRK Aargau-Solothurn, Switzerland) were determined using an ultrafiltration method and the data compared to that of [177Lu]Lu-DOTA-AE105. The amount of mouse serum albumin (MSA) and human serum albumin (HSA) in mouse and human blood plasma was defined as 550 μ.M and 800 μm, respectively, based on measurements using a dry chemistry analyzer (DRI-CHEM 4000i, FUJIFILM, Japan). A fixed amount of radiopeptide (50 MBq / nmol, -300 kBq, 15 μL, 0.006 nmol) was added to a defined volume (150 μL) of mouse and human blood plasma and various dilutions thereof in PBS pH 7.4, resulting in defined [MSA]-to- [radiopeptide] or [HSA]-to-[radiopeptide] molar concentration ratios of 0.01-12500 and 0.01-20000, respectively. The albumin-bound fraction was determined using the ultrafiltration device as described above. The data were analyzed using a semi-logarithmic plot assuming a maximum binding of 100%. The Hill equation was fitted to the data points, and the half-maximum binding (B50) was determined based on the obtained binding curves (GraphPad Prism software, version 8.3). To quantitatively express and compare the albumin-binding affinity of the radiopeptides, the albumin-binding affinity was expressed relative to that of [177Lu]Lu-DOTA-uPAR-ALB-1 1 , which was set as 1 .0. The results were presented as the average of 3 independent experiments.

[0408] As shown in Table 18 and graphically represented in Figure 15, the presence of an albumin- binder uPAR-targeting radiopeptide structure considerably increased the affinity of the compounds toward serum proteins compared to that of [177Lu]Lu-DOTA-AE105. All 2nd generation uPAR-targeting radiopeptides revealed a comparable affinity to both human and mouse blood plasma proteins. These radiopeptides had a slightly reduced binding affinity to human (0.50 to 0.68-fold) and mouse blood plasma proteins (0.46 to 0.77-fold) compared to [177Lu]Lu-DOTA-uPAR-ALB-1 1 .

[0409] Example 17: Cell Uptake and Internalization of 2ndGeneration Radiopeptides

[0410] Uptake and internalization studies were performed with all uPAR-targeting radiopeptides using HEK-uPAR cells.

[0411] HEK cells transfected with human uPAR, herein referred to as HEK-uPAR cells, were obtained from Innoprot, Innovative Technologies in Biological Systems S.L. (Bizkaia, Spain). The cells were cultured in DMEM cell culture medium supplemented with 10% fetal calf serum, L-glutamine, 1 % non-essential amino acids and antibiotics. Hygromycin B (50 pg / mL) was added to maintain uPAR expression. The cells were subcultured twice a week using trypsin / EDTA and cultured under standard cell culture conditions using 5% CO2at 37 °C in a humidified atmosphere.

[0412] HEK-uPAR cells were seeded in polylysine-coated 12-well plates (1 x 106cells in 2 mL per well) using DMEM cell culture medium with supplements. The cells were incubated at 37 °C and 5% CO2overnight to allow adhesion and growth. After removal of the supernatant, the HEK-uPAR cells were rinsed with PBS before adding DMEM without supplements (975 pL per well). The radiopeptides (50 MBq / nmol) were added to each well in a volume of 25 pL (0.75 pmol, 38 kBq). In some wells, the HEK-uPAR cells were coincubated with an excess of AE105 (5 μm) to block uPAR. After incubation of the cells for 2 h or 4 h at 37 °C, they were rinsed with ice-cold PBS to determine the total uptake of the radiopeptides, in order to assess the internalized fraction, an acidic stripping buffer (pH 2.8, 50 mM glycine, 100 mM NaCI) was applied to the cells to release uPAR-bound radiopeptides from the cell surface. The cells were lysed using NaOH solution (1 M, aq., 1 mL) and the lysates were transferred to RIA tubes for counting the activity in a y-counter (PerkinElmer, Wallac Wizard 1480). The protein concentration of each sample was determined using a Micro BCA Protein Assay kit (Pierce, Thermo Scientific) to standardize the measured activity to the average content of protein in a single well. The uptake and internalized fraction were expressed as the percentage of total added activity and presented as the average + SD of n = 3 independent experiments.

[0413] As shown in Figure 16, the HEK-uPAR cells uptake of the albumin-binding radiopeptides was between 20% and 31 % of total added activity over the entire incubation period. These are similar values as previously seen for the uptake of [177Lu]Lu-DOTA-uPAR-ALB-1 1 (33 + 2% and 34 + 4% after 2 h and 4 h, respectively), however, slightly lower than for the reference compound [177Lu]Lu-DOTA-AE105. The 2ndgeneration uPAR-targeting radiopeptides showed an internalized fraction of 14-20% and 15-22% of total added activity after 2 h and 4 h, respectively. The unspecific uptake of the radiopeptides (0.5- 1.1 % of total added activity after a 4-h incubation period), determined in the presence of excess AE105 peptide to block uPAR was very low.

[0414] [177Lu]Lu-DOTA-uPAR-ALB-15 showed similar uptake in HEK-uPAR cells (31 ± 4% after 2 h and 4 h incubation) as was found for [177Lu]Lu-DOTA-uPAR-ALB-1 1 (33 ± 2% and 34 ± 4%, respectively). A slightly lower cell uptake was, however, found for [177Lu]Lu-DOTAGA- uPAR-ALB-17 and [177Lu]Lu-DOTA-uPAR-ALB-18 (20 ± 3% and 24 ± 3% after 2 h incubation and 20 + 2% and 20 ± 3% after 4 h incubation, respectively). Among the uPAR- targeting radiopeptides of the 2ndgeneration, [177Lu]Lu-DOTA-uPAR-ALB-15 showed the highest internalization (20 + 3% after 2 h incubation; 22 ± 3% after 4 h incubation, respectively). The internalized fraction of the other albumin-binding radiopeptides was in a similar range (14-17% and 15-18% after 2 h and 4 h, respectively) as that of [177Lu]Lu- DOTA-AE105 (10 + 1 % and 17 + 3% after 2 h and 4 h, respectively).

[0415] Example 18: uPAR-binding Affinity (KDValues) of 2ndGeneration Radiopeptides

[0416] The uPAR-binding affinity of the radiopeptides was investigated using HEK-uPAR cells.

[0417] HEK-uPAR cells were seeded in polylysine-coated 48-well plates (0.25 x 106in 0.5 mL per well) using DMEM culture medium with supplements. The cells were incubated at 37 °C and 5% CO2overnight to allow adhesion and growth. The well plates with HEK-uPAR cells were placed on ice for the entire experiment. After removal of the medium, the HEK-uPAR cells were rinsed with PBS followed by the addition of DMEM culture medium without supplements (450 pL / well) with or without the addition of AE105 (40 μm) to block uPAR. The cells were incubated for 30 min on ice. The respective radiopeptides (5 MBq / nmol) were diluted in PBS at peptide concentrations 10-16'000 nM. From each dilution, 50 pL were added to each well to obtain peptide concentrations in the range of 1-1600 nM. The cells were incubated at 4 °C on ice for one hour on an elliptical shaker before rinsing twice with PBS (0.5 mL, pH = 7.4). The cells were lysed using NaOH solution (1 M, aq., 0.6 mL) and the lysates were transferred to RIA tubes for counting the activity in a y-counter (PerkinElmer, Wallac Wizard 1480). The KDvalues were determined by plotting the specific binding (total binding minus unspecific binding) against the molar concentration of the added peptide. A nonlinear regression analysis was performed using GraphPad Prism software (version 8.3.1 ). The results were expressed as average KD± SD of n = 3 independent experiments.

[0418] As shown in Table 19, the KDvalues of the radiopeptides were all in a similar range (KDvalues: 31-74 nM) as was previously determined for [177Lu]Lu-DOTA-uPAR-ALB-1 1 (KDvalue 41 + 1 1 nM) and slightly higher than [177Lu]Lu-DOTA-AE105 (KDvalue 20 ± 1 nM). [177Lu]Lu-DOTAGA-uPAR-ALB-17 showed the highest uPAR-binding affinity (KDvalue 31 ± 6 nM), whereas it was lowest for [177Lu]Lu-DOTA-uPAR-ALB-14 and [177Lu]Lu-DOTA-uPAR- ALB-18 (KDvalue 74 ± 18 nM and 74 + 12 nM, respectively).

[0419] Example 19: SPECT / CT Imaging Studies of 2ndGeneration Radiopeptides

[0420] Single photon emission computed tomography / computed tomography (SPECT / CT) imaging studies were performed to investigate the whole-body distribution profiles of the uPAR- targeting radiopeptides in HEK-uPAR xenografted nude mice.

[0421] All applicable international, national, and / or institutional guidelines for the care and use of animals were followed. In particular, all animal experiments were carried out according to the guidelines of the Swiss Regulations for Animal Welfare. The preclinical studies have been ethically approved by the Cantonal Committee of Animal Experimentation and permitted by the responsible cantonal authorities (License N° 75721 ). Five-week-old female CD1 nude (Crl:CD1 -Foxnnu) mice were obtained from Charles River Laboratories (Sulzfeld, Germany) and fed with standard rodent chow ad libitum. The mice were subcutaneously inoculated with HEK-uPAR cells (7 x 106cells in 100 pL PBS) on the right shoulder.

[0422] SPECT / CT experiments were performed with mice approximately 3-4 weeks after HEK- uPAR cell inoculation. The mice were scanned 1 h, 4 h, 24 h and 48 h after injection of the respective radiopeptide (25 MBq, 0.5 nmol, 100 pL, diluted in 0.9% NaCl containing 0.05% BSA). Imaging studies were performed using a four-head, multiplexing, multi-pinhole small-animal SPECT / CT camera (NanoSPECT / CT™, Mediso Medical Imaging Systems, Budapest, Hungary). Each head was outfitted with a thungsten-based aperture of nine 1.4 mm-diameter pinholes and a thickness of 10 mm. CT scans of 7-9 min duration were followed by SPECT scans of 45-50 minutes. The images were acquired using Nucline Software (version 10.2, MEdiso Ltd., Budapest, Hungary). The real-time CT reconstruction used a cone-beam filtered beckprojection. The reconstruction of SPECT data was performed with HiSPECT software (version 1.4.3049, Scivis GmbH, Gottingen, Germany) using y- energies of 56.1 keV (± 10%), 1 12.9 keV (± 10%) and 208.4 keV (± 10%) for lutetium-177. The images were prepared using VivoQuant post-processing software (version 3.5, inviCRO Imaging Services and Software, Boston, U.S.). A Gauss post-reconstruction filter (full width at half maximum, 1 .0 mm) was applied and the scale of activity was set as indicated on the images (minimum value = 0.15 Bq / voxel, maximum value = 20 Bq / voxel).

[0423] As shown in Figure 17, the uPAR-targeting radiopeptides of the 2ndgeneration showed considerable retention in the blood and heart early after injection, which can be ascribed to their albumin-binding properties. At 1 h after injection, all uPAR-targeting radiopeptides showed activity uptake in the HEK-uPAR xenografts. The best visualization of the xenograft was achieved at 1 h and 4 h after injection of [177Lu] Lu-DOT A-uPAR-ALB-15 and [,77Lu]Lu- DOTA-uPAR-ALB-18 (Figures 17 / 18). At later timepoints xenografts were still well visible after injection of [177Lu]Lu-DOTA-uPAR-ALB-15, [177Lu]Lu-DOTAGA-uPAR-ALB-17 and [177Lu]Lu-DOT A-uPAR-ALB-18 and to a lesser extend also after injection of [177Lu]Lu- DOT A-uPAR-ALB-14 (Figures 19 / 20). The weakest signal in the xenograft was detecte after injection of [177Lu]Lu-DOTA-AE105, which showed rapid clearance from the blood circulation. Substantial uptake of all radiopeptides was seen in the kidneys. The kidney accumulation of [177Lu]Lu-DOTA-uPAR-ALB-18 was similar to that [177Lu]Lu-DOTA-uPAR- ALB-11 , however, it was somewhat higher for [177Lu]Lu-DOTA-uPAR-ALB-14, [177Lu]Lu- DOTA-uPAR-ALB-15 and [177Lu]Lu-DOTAGA-uPAR-ALB-17 at all investigated imaging timepoints.

[0424] Example 20: Biodistribution Studies of 2ndGeneration Radiopeptides

[0425] Biodistribution studies were performed for the quantitative comparison of the accumulated activity in HEK-uPAR xenografts and normal organs and tissues. Biodistribution studies were performed approximately 3-5 weeks after HEK-uPAR cell inoculation. The mice were injected with uPAR-targeting radiopeptides (5 MBq, 0.5 nmol, 100 pL) in 0.9% NaCl containing 0.05% BSA and sacrificed at the respective timepoint after injection of the radiopeptides. Selected tissues and organs were collected, weighed and measured using a y-counter ((PerkinElmer, Wallac Wizard 1480)). The results were listed as a percentage of the injected activity per gram of tissue mass (% lA / g) using counts of a standard (defined volume of the original injection solution) measured at the same time to enable the calculation of decay-corrected values. Biodistribution data obtained 4 h after injection of [177Lu]Lu-DOTA-uPAR-ALB-14, [177Lu]Lu- DOTA-uPAR-ALB-15 and [177Lu] Lu-DOT A-uPAR-ALB-17 (Table 20), as well as [177Lu]Lu- DOTA-uPAR-ALB-18 (Table 21 ) were compared to that obtained after injection of [177Lu]Lu- DOTA-uPAR-ALB-1 1 (Table 12) and [177Lu]Lu-DOTA-AE105 (Table 9). The differences in the accumulation of the radiopeptides were investigated in the blood (Figure 21 ), in HEK- uPAR xenografts (Figure 22), the kidneys (Figure 23) and the liver (Figure 24).

[0426] Decay-corrected data of accumulated activity are shown as % I A / g tissue, representing the average ± SD (n = 3).

[0427] Table 21. Biodistribution data and tumor-to-background ratios obtained in HEK-uPAR- bearing mice at 4 h, 24 h and 48 h after injection of [177Lu]Lu-DOTA-uPAR-ALB-18.

[0428] Decay-corrected data of accumulated activity are shown as % lA / g tissue, representing the average + SD (n = 3).

[0429] As shown in Figure 21 , the investigated radiopeptides of the 2ndgeneration revealed a similar blood retention compared to [177Lu]Lu-DOTA-uPAR-ALB-11 , ranging from 3.4% to 6.0% lA / g at 4 h p.i.. Compared to the fast clearance of [177Lu]Lu-DOTA-AE105 (<1% lA / g after 4 h and 24 h, Table 9), all albumin-binding radiopeptides showed an enhanced blood retention (Tables 20-22). [177Lu]Lu-DOTAGA-uPAR-ALB-17 showed the most pronounced retention in the blood (6.0% lA / g) (Table 20) while [177Lu]Lu-DOTA-uPAR-ALB-18 showed the lowest (3.4% lA / g) at 4 h p.i. (Table 21 ).

[0430] As shown in Figure 22, despite similar blood residence times, the xenograft accumulation was somewhat lower for most of the radiopeptides of the 2ndgeneration than for [177Lu]Lu- DOTA-uPAR-ALB-1 1 . [177Lu]Lu-DOTA-uPAR-ALB-14 and [177Lu]Lu-DOTAGA-uPAR-ALB- 17 showed moderate accumulation in the HEK-uPAR xenograft (9.0 + 0.5% lA / g and 8.0 ± 0.7% I A / g at 4 h p.i., respectively). On the other hand, the uptake of [177Lu]Lu-DOTA-uPAR- ALB-15 (12 ± 1 % lA / g) and [177Lu]Lu-DOTA-uPAR-ALB-18 (14 + 0% lA / g) in the xenograft at 4 h p.i. was comparable to that of [177Lu]Lu-DOTA-uPAR-ALB-1 1 (16 ± 2%> lA / g). At the 24-h p.i. and 48-h p.i. timepoints, [177Lu]Lu-DOTA-uPAR-ALB-11 (Table 12) and [177Lu]Lu- DOTA-uPAR-ALB-18 (Table 21 ) showed similar uptake in the xenografts (7.3 ± 0.4% lA / g and 7.9 + 0.9% I A / g as well as 5.2 ± 0.3% lA / g and 5.3 ± 0.7% lA / g, respectively.

[0431] As shown in Figure 23, retention in the kidneys of the uPAR-targeting radiopeptides of the 2ndgeneration was relatively low and comparable to that of [177Lu]Lu-DOTA-uPAR-ALB-1 1 . The values ranged between 3.7% to 4.6% I A / g at 4 h after the injection of the radiopeptides. Renal retention of [177Lu]Lu-DOTA-uPAR-ALB-18 was very similar to that of [177Lu]Lu- DOTA-uPAR-ALB-1 1 with 3.7 + 0.4% lA / g and 4.0 + 0.4% lA / g at 4 h p.i. followed by effective excretion to <1 .5% lA / g at 48 h p.i. (Tables 21 / 12).

[0432] As shown in Figure 24, the liver uptake of the radiopeptides of the 2ndgeneration was low (<2% lA / g) at all investigated timepoints although clearly higher than for [177Lu] Lu-DOT A- AE105 (Table 9). Among the 2ndgeneration radiopeptides, the lowest liver accumulation was seen after injection of [177Lu]Lu-DOTA-uPAR-ALB-18 (1 .2 + 0.1 % lA / g at 4 h p.i., Table 21 ), whereas [177Lu]Lu-DOTA-uPAR-ALB-14 (2.0 ± 0.2% lA / g at 4 h p.i., Table 20) revealed a slightly higher accumulation compared to [177Lu]Lu-DOTA-uPAR-ALB-1 1 (1.8 ± 0.2% lA / g, at 4 h p.i., respectively, Table 12).

[0433] As shown in Figure 25, the 2ndgeneration radiopeptides showed lower xenograft-to-blood ratios compared to [, 77Lu]Lu-DOTA-uPAR-ALB-1 1 (Table 12), except [177Lu]Lu-DOTA- uPAR-ALB-18, which showed a slightly higher ratio at 4 h p.i. (4.1 + 0.7). [177Lu] Lu-DOT A- AE105 showed particularly high xenograft-to-blood ratios at early timepoints after injection due to its rapid blood clearance (Table 9). At the 24-h timpoint, the xenograft-to-blood ratio of [177Lu]Lu-DOTA-uPAR-ALB-18 (144 ± 4) was slightly lower than that of [177Lu]Lu-DOTA- uPAR-ALB-1 1 (274 ± 25) (Tables 21 / 12).

[0434] As shown in Figure 26, the xenograft-to-kidney ratios of accumulated activity of the radiopeptides of the 2ndgeneration ranged from 1.7 to 3.8 and were, therewith, lower than those of [177Lu]Lu-DOTA-uPAR-ALB-1 1 (3.9-4.9 between 4 h and 48 h, Table 12). The xenograft-to-kidney ratios of [177Lu]Lu-DOTA-uPAR-ALB-18 were similar but still lower than that for [177Lu]Lu-DOTA-uPAR-ALB-1 1 , in particular at 24 h and 48 h p.i. (3.5 + 0.4 and 3.8 ± 0.7, respectively).

[0435] As shown in Figure 27, the xenograft-to-liver ratios were high for all radiopeptides due to their low accumulation in the liver. The highest ratios were obtained for [177Lu]Lu-DOTA- uPAR-ALB-18 (1 1 + 1 after 4 h, 20 + 3 after 24 h and 18 ± 3 after 48 h), similar to those obtained for [177Lu]Lu-DOTA-uPAR-ALB-11 (9-24 between 4 h and 48 h p.i.).

[0436] Example 21 : Investigations of67Ga-labeled uPAR-Targeting Peptides

[0437] To investigate suitability of the uPAR-targeting complexes of the present invention as diagnostic agents, DOTA-uPAR-ALB-11 and DOTA-uPAR-ALB-18 were labeled with gallium-67 and investigated in vitro and in vivo. In this respect, it is noted that clinically, diagnostic scans performed to investigate tumor accumulation of a specific tumor-targeting agent are commonly performed with68Ga- labeled analogues to the177Lu-based therapeutics. To facilitate the experiments, gallium-67 was used in this study as a surrogate radioisotope for gallium-68 due to the more convenient half-life of 3.26 d vs. only 68 min.

[0438] Labeling and Stability Studies:

[0439] The uPAR-targeting peptides DOTA-uPAR-ALB-1 1 and DOTA-uPAR-ALB-18 were labeled with gallium-67 (no-carrier-added [67Ga]GaCl3in ~0.1 M HCI, Curium Netherlands B.V., the Netherlands, via b.e. imaging GmbH (Switzerland); purified at PSI) at molar activities of up to 50 MBq / nmol. Quality control was performed using the same HPLC system as reported for the177Lu-labeled counterparts. The radiolytic stability was tested at an activity concentration of (10 MBq / 100 pL) in 0.9% NaCI.

[0440] As a result, the radiolabeling with gallium-67 was achieved with a radiochemical purity of >98% at a molar activity of 50 MBq / nmol. In the presence of ascorbic acid, the radiopeptides were stable (>95%) over 24 h at the concentration that was used to inject animals for SPECT imaging.

[0441] Cell Uptake Studies:

[0442] Uptake and internalization of [67Ga]Ga-DOTA-uPAR-ALB-11 and [67Ga]Ga-DOTA-uPAR- ALB-18 in HEK-uPAR cells was performed in two independent experiments each in triplicate according to the same protocol as was used for the177Lu-labeled counterparts.

[0443] It was found that the uptake and internalization of [67Ga]Ga-DOTA-uPAR-ALB-1 1 and [67Ga]Ga-DOTA-uPAR-ALB-18 in HEK-uPAR cells was comparable to the data obtained with the177Lu-labeled counterparts. As shown in Figure 28, the uptake of [67Ga]Ga-DOTA- uPAR-ALB-1 1 reached 36 ± 4% and 30 + 1 % after a 2-h and 4-h incubation period, respectively, with an internalized fraction of 24 ± 4 and 24 + 1 , respectively. The cell uptake of [67Ga]Ga-DOTA-uPAR-ALB-18 was 28 + 4% and 32 ± 1 % after a 2-h and 4-h incubation period, respectively, with an internalized fraction of 20% after 2 h and 4 h. SPECT Studies

[0444] SPECT / CT experiments were performed with mice, approximately 3-4 weeks after HEK- uPAR cell inoculation. The mice were scanned 1 h and 4 h after injection of the respective radiopeptide (10 MBq, 0.5 nmol, 100 pl, diluted in 0.9% NaCl containing 0.05% BSA). The studies were performed as described for the177Lu-labeled counterparts using the same small-animal SPECT / CT scanner (NanoSPECT / CT™, Mediso Medical Imaging Systems, Budapest, Hungary). The reconstruction of SPECT data was performed with HiSPECT software (version 1.4.3049, Scivis GmbH, Gottingen, Germany) using y-energies of 93.20 keV (± 10%), 184.60 keV (± 10%) and 300.00 keV (+ 10%) for gallium-67. A Gauss post- reconstruction filter (full width at half maximum, 1.0 mm) was applied and the scale of activity was set as indicated on the images (minimum value = 0.1 Bq / voxel, maximum value = 10 Bq / voxel).

[0445] As shown in Figure 29, the SPECT / CT imaging studies performed with [67Ga]Ga-DOTA- uPAR-ALB-1 1 and [67Ga]Ga-DOTA-uPAR-ALB-18 showed high accumulation of activity in the HEK-uPAR xenografts. Although initial retention of activity in the kidneys was relatively high, it was cleared effectively over time resulting in tumor-to-kidney ratios of visually detectable activity accumulation that was clearly above 1 .

Claims

CLAIMS1 . A radiolabeled complex targeting the urokinase-type plasminogen activator receptor (uPAR) comprising(a) a targeting peptide moiety binding the urokinase-type plasminogen activator receptor (uPAR),(b) a chelating moiety,(c) a radionuclide, and(d) an albumin-binding moiety, wherein the targeting peptide moiety, the chelating moiety and the albumin-binding moiety are linked via a common trifunctional linker moiety (L1 ).

2. The radiolabeled complex according to claim 1 , wherein the targeting peptide moiety comprises 7 to 20 amino acids, preferably 8 to 15 amino acids, more preferably 9 to 13 amino acids.

3. The radiolabeled complex according to claim 1 or 2, wherein the targeting peptide moiety comprises the amino acid sequence (Asp)-([beta]-cyclohexyl-L-alanine)-(Phe)-(D-Ser)-(Xaa5)-(Xaa6)-(Leu)-(Trp)-(Xaa9), wherein(Xaa5) is selected from (D-Arg), (D-Lys), (D-Cys), and (D-Ser);(Xaa6) is selected from (Tyr) and (Pro); and(Xaa9) is selected from (Ser) and (Cys).

4. The radiolabeled complex according to any one of the previous claims, wherein the targeting peptide moiety comprises the amino acid sequence (Asp)-([beta]-cyclohexyl- L-alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser), or a derivative or mutated form thereof, or a cyclized variant thereof.

5. The radiolabeled complex according to any one of the previous claims, wherein the trifunctional linker moiety (L1 ) comprises an amino acid residue or a derivative thereof.

6. The radiolabeled complex according claim 5, wherein the amino acid residue of the linker moiety (L1 ) is selected from the group consisting of a lysine residue, an arginine residue, a glutamine residue, an asparagine residue, or a derivative of said amino acid residues.

7. The radiolabeled complex according to any one of the previous claims, wherein the trifunctional linker moiety (L1) comprises a lysine residue or a derivative thereof.

8. The radiolabeled complex according to any one of the previous claims, wherein a linker moiety (L2) is located between the trifunctional linker moiety (L1 ) and the albumin-binding moiety.

9. The radiolabeled complex according to any one of the previous claims, wherein a linker moiety (L3) is located between the trifunctional linker moiety (L1 ) and the targeting peptide moiety and / or between the trifunctional linker moiety (L1 ) and the chelating moiety.

10. The radiolabeled complex according to anyone of claims 8 and 9, wherein the linker moieties (L2) and / or (L3) are selected from the group consisting of amino acids, polyethyleneglycols (PEGs), poly( / V-vinylpyrrolidone), polyacrylamides, polybetaines, poly(2-oxazoline)s, polyesters, polysarcosine, and alkyl groups, and are preferably selected from amino acids and polyethyleneglycols (PEGs).11 . The radiolabeled complex according to anyone of claims 8 to 10, wherein the linker moiety (L2) is a PEG based linker, preferably comprising 1 to 30 PEG units, more preferably comprising 1 to 10 PEG units, still more preferably comprising 3 to 5 PEG units.

12. The radiolabeled complex according to anyone of claims 9 to 1 1 , wherein the linker moiety (L3) is a PEG based linker, preferably comprising 1 to 30 PEG units, more preferably comprising 1 to 10 PEG units, still more preferably comprising 3 to 5 PEG units, or an amino acid residue, preferably a lysine residue, or a derivative thereof.

13. The radiolabeled complex according to anyone of claims 8 to 12, wherein the trifunctional linker moiety (L1 ) is a lysine residue or a derivative thereof, such as a diaminopropionic acid residue, and the linker moiety (L2) is a PEG moiety, preferably a PEG3to PEG5moiety.

14. The radiolabeled complex according to anyone of claims 8 to 13, wherein the trifunctional linker moiety (L1 ) is a lysine residue or a derivative thereof, such as a diaminopropionic acid residue, and the linker moiety (L3) is a further lysine residue or a derivative thereof and / or a PEG moiety, preferably a PEG3to PEG5moiety.

15. The radiolabeled complex according to any one of the previous claims, wherein an aliphatic or aromatic spacer moiety (SI) is located between the trifunctional linker moiety (LI ) and the albumin-binding moiety.

16. The radiolabeled complex according to any one of claims 8 to 15, wherein an aliphatic or aromatic spacer moiety (SI ) is located between the linker moiety (L2) and the albumin-binding moiety.

17. The radiolabeled complex according to claim 15 or 16, wherein the spacer moiety (SI) is an amino- and carboxy-substituted aromatic structure, preferably a 4- (aminomethyl)benzoic acid moiety.

18. The radiolabeled complex according to any one of the previous claims, wherein the albumin-binding moiety is selected from an iodophenyl moiety, a tolyl moiety, and an ibuprofen moiety, preferably from a tolyl moiety and a iodophenyl moiety, more preferably a tolyl moiety.

19. The radiolabeled complex according to any one of the previous claims, wherein the chelating moiety is a macrocyclic chelator, preferably selected from the group consisting of DOTA, NOTA, NODAGA, DOT AGA, DOT AM, TRAP, AAZTA, NOPO, PCTA, DO3AP, DO3APPrA, and DO3APABn, or derivatives thereof.

20. The radiolabeled complex according to any one of the previous claims, wherein the chelator is selected from DOTA and DOTAGA.21 . The radiolabeled complex according to any one of the previous claims, wherein the radionuclide is selected from the group consisting of99mTc,111In,67Ga,68Ga,86Y,90Y, 177Lu,149Tb,152Tb,155Tb,161Tb,186Re,188Re,61Cu,64Cu,67Cu,55Co,57Co,43Sc,44Sc,47Sc, 225Ac,211At,212Bi,213Bi,212Pb,227Th,153Sm,166Ho,166Dy,165Er,169Er,103Pd,109Pd,103mRh, 18F,123|,124I and131preferably selected from the group consisting ofi nln,67Ga,68Ga, 86Y, 90Y / 177LU,161Tb61Cu, 64^ 67^ 55^ 57Q,, 43^ 44^ 47S225A c,213Bi, 212Pb,153Sm,166Ho,225Ac,211At, and166Dy.

22. The radiolabeled complex according to any one of the previous claims, wherein the radionuclide is selected from177Lu (Luteti um-177),161Tb (Terbium 161 ),67Ga (Gallium-67), and68Ga (Gallium-68).

23. The radiolabeled complex according to any one of the previous claims, wherein the targeting peptide moiety comprises the nonapeptide (Asp)-([beta]-cyclohexyl-L- alanine)-(Phe)-(D-Ser)-(D-Arg)-(Tyr)-(Leu)-(Trp)-(Ser), the chelator is selected from DOTA and DOTAGA, the radionuclide is selected from177Lu and67 / 68Ga, the albumin-binding moiety is selected from an iodophenyl moiety and a tolyl moiety, and the trifunctional linker moiety (L1 ) comprises at least one lysine residue or a derivative thereof, such as a diaminopropionic acid residue.

24. The radiolabeled complex according to claim 23, wherein a linker moiety (L2), preferably a PEG-linker moiety, more preferably a PEG3 to PEG5moiety, is located between the trifunctional lysine linker moiety (L1 ) and the albumin-binding moiety.

25. The radiolabeled complex according to claim 24, wherein an aliphatic or aromatic spacer moiety (S1 ), preferably an AMBA moiety or glutamic acid moiety, is located between the linker moiety (L2), preferably a PEG linker moiety, more preferably PEG3 to PEG5 moiety, and the albumin-binding moiety.

26. The radiolabeled complex according to any one of the previous claims, which comprises a conjugate represented by any one of the following formulae:and a radionuclide complexed by the conjugate.

27. The radiolabeled complex according to claim 26, wherein the radionuclide is selected from177Lu (Lutetium-177),161Tb (Terbium-161 ),67Ga (Gallium-67), and68Ga (Gallium-68).

28. The radiolabeled complex according to claim 27, wherein the radionuclide is177Lu.

29. A pharmaceutical composition comprising a radiolabeled complex according to any one of claims 1 to 28.

30. The pharmaceutical composition according to claim 29, further comprising a stabilizer against radiolytic degradation.

31. The pharmaceutical composition according to claim 30, wherein the stabilizer comprises ascorbic acid and / or a salt thereof, preferably sodium ascorbate.

32. The pharmaceutical composition according to any one of claims 29 to 31 , wherein the composition is an aqueous solution.

33. The pharmaceutical composition according to any one of claims 29 to 32, wherein ascorbic acid and / or a salt thereof, in particular sodium ascorbate, are the only stabilizers in the pharmaceutical composition.

34. The pharmaceutical composition according to any one of claims 29 to 33, wherein the concentration of ascorbic acid is in a range of about 0.5 mg / ml to about 5.0 mg / ml, and the concentration of a salt of ascorbic acid, in particular sodium ascorbate, is in a range of about 10 mg / ml to about 100 mg / ml.

35. The pharmaceutical composition according to according to any one of claims 29 to 34, wherein the radionuclide is present at a concentration providing volumetric radioactivity of about 0.25 to about 0.6 GBq / ml.

36. The radiolabeled complex according to any one of claims 1 to 28 or the pharmaceutical composition according to any one of claims 29 to 35 for use in medicine.

37. The radiolabeled complex according to any one of claims 1 to 28 or the pharmaceutical composition according to any one of claims 29 to 35 for use in the diagnosis or treatment of cancer.

38. Use of the radiolabeled complex according to any one of claims 1 to 28 or the pharmaceutical composition according to any one of claims 29 to 35 for the diagnosis or treatment of solid tumors, neuroendocrine tumors and / or hematologic malignancies.

39. Use according to claim 38, wherein the solid tumors are selected from the group consisting of breast, brain, gastric, pancreatic, colorectal, prostate, ovarian, oral and esophageal cancer.

40. Use according to claim 38, wherein the hematologic malignancies are selected from the group consisting of multiple myeloma and acute leukemias.41 . A method for diagnosing or treating cancer or initiating, enhancing or prolonging an anti-tumor-response in a subject in need thereof comprising administering to the subject radiolabeled complex according to any one of claims 1 to 28 or the pharmaceutical composition according to any one of claims 29 to 35.