CXCR4 ligand suitable for radiopharmaceutical applications and method for preparation thereof

Abstract

Provided are a CXCR4 ligand compound of formula (I) or a salt thereof, wherein RB1 represents hydrogen or iodine; RB2 represents hydrogen or methyl, RB3represents a group -(CH2)m- with m being selected from 1, 2, 3 and 4, L represents a divalent linking group, or is absent; and RCH represents a chelating group or a chelate group comprising a chelated radioactive or non-radioactive metal cation. As further aspects, provided are the compounds in accordance with the invention for use in the treatment of diseases or disorders, or for use in a method of diagnosis in vivo of a disease or disorder.

Description

[0001] CXCR4 Ligand suitable for Radiopharmaceutical Applications and Method for Preparation thereof

[0002] The present application relates to CXCR4 ligand compounds which are useful for radiopharmaceutical applications, including imaging and therapy, and to methods for their preparation.

[0003] Worldwide the field of nuclear medicine continues to emerge and gain more attention, especially as the scope of non-invasive imaging modalities and therapeutic applications rises. Just recently [177Lu]Lu-PSMA-617 (Pluvicto, Novartis) was approved by the FDA for the therapy of pre-treated prostate specific membrane antigen positive (PSMA+) metastatic castration-resistant prostate cancer (1). The current approval is in line with previously FDA approved [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE (Lutathera, Novartis) (2) for imaging and therapy of neuroendocrine tumors (NETs), respectively. Remarkably, this type of approach demonstrated that radio nuclide therapy (RNT) has both a palliative effect and can prolong progression-free and overall survival (3). While the somatostatin receptor 2 (sst2) and PSMA are primarily found for NETs and prostate cancer, respectively, the C-X-C chemokine receptor 4 (CXCR4) is overexpressed on a large variety of tumors, ranging from lymphoproliferative diseases such as multiple myeloma (MM), lymphomas (B-cell, T-cell, NonHodgkin) to breast and prostate cancer (4-9). The interaction between CXCR4 and its endogenous ligand CLXCL12 involves the chemotaxis of CXCR4+cells along a CXCL12 gradient to their respective sites. Binding to the ligand results in receptor internalization and activation of several signal transduction pathways. Physiologically this involves the recruitment of stem and progenitor cells, their retention and differentiation and leucocyte trafficking during immune response (10). In malignant tissue however, the CXCL12 / CXCR4 interaction promotes cell proliferation, angiogenesis, increased tumor invasiveness and distant metastasis (11-15). CXCR4 expression on malignant tissue was also found to enhance resistance to therapy and induce immune evasion (16,17). High CXCR4 expression is therefore often linked to high chance of recurrence and low overall survival.

[0004] The current standard of positron emission tomography (PET) imaging of CXCR4 expressing malignancies is [68Ga]Ga-Pentixafor, a cyclo-pentapeptide derivative (18,19). [68Ga]Ga-Pentixafor has shown the potential of in vivo imaging of CXCR4 expression in the field of nuclear medicine for over 20 different tumor and inflammatory entities, given abundant CXCR4 expression on the cell surface of various leukocyte subsets (20-37). Despite compelling clinical results, the target to background ratios (TBR), especially regarding inflammation imaging, can be rather low, reaching only a factor of 2-3 in conditions like atherosclerosis (38,39). While this may be sufficient for lesion detection, it can hinder the detection of low-level CXCR4 expression. In general, low target expression levels require significantly improved affinities to achieve high target accumulation. In addition, [68Ga]Ga-Pentixafor bears limitations resulting from its structural constrains, as a loss in target affinity upon complexation of other metals (eg.Cu-64, Lu-177 etc.) is observable (40).

[0005] Iodination at the tyrosine residue resulted in a partial flexibility of the resulting ligands towards metal chelation, which enabled chelation of different metals while retaining receptor affinity. However, this also increased overall lipophilicity (41). Therefore, the therapeutic counterparts of [68Ga]Ga-PentixaFor, i.e. [90Y]Y-, [177Lu]Lu-PentixaTher are partially accumulated in the liver leading to lower TBRs in the abdominal area during therapy control. This leaves room for further improvement of the ligand design to increase the detection sensitivity of CXCR4-directed PET imaging, and therefore resulting TBRs.

[0006] In 2011 , Inokuchi et al. (42) investigated differences between the cyclic penta-peptide FC131 (cyclo[2-Nal-G-y-R-R-], the first cyclic penta-peptide addressing CXCR4) and amidine bearing derivatives thereof. A 30-fold increase in CXCR4 affinity was observed for FCA004 (cyclo[2-Nal(=NH)-G-y-R-R-]) as amidine-based peptidomimetic CXCR4 addressing pentapeptide, compared to FC131. As FCA004 is incapable of conjugation, it does not allow for ligand design, in particular the conjugation with a chelating moiety. Such amidine bearing peptidomimetic are also disclosed in a corresponding patent application (43).

[0007] Recent optimizations addressed the linker sequence that connects the pentapeptide core with the DOTA-metal chelate (44), featuring a neutrally charged amino acid (AA) such as glycine or alanine that is connected to the aromatic 4-amino benzoic acid (ABA) and a consecutive positively charged AA (lysine, di-amino propionic acid, arginine). The aim was to introduce an optimized linker sequence with sufficient length to remove the chelating moiety from the CXCR4 binding pocket. Thereby, diverse and unrestricted metal complexation that maintains high affinity and low lipophilicity for the respective ligands should be enabled. The approach succeeded in improving CXCR4 affinity and hydrophilicity with a variety of metals incorporated and the concept was further optimized (44,45). Nevertheless, this led to higher kidney accumulation by tubular reabsorption in mice, most likely due to the presence of positive charges (46, 47). An issue is the resulting predetermined sequence and complex ligand design that limits further structural changes.

[0008] Before this background, a need remained for CXCR4 ligand compounds with a robust core structure to support flexible ligand design including tolerance towards different metal chelates without the drawback of decreasing target affinity or a need for complex ligand structures.

[0009] In a first aspect, the invention thus provides a compound of formula (I) or a salt thereof: wherein

[0010] RB1represents hydrogen or iodine, preferably hydrogen;

[0011] RB2represents hydrogen or methyl, preferably methyl;

[0012] RB3represents a group -(CH2)m- with m being selected from 1, 2, 3 and 4, more preferably a group -(CH2)3-;

[0013] L represents a divalent linking group, or is absent; and

[0014] RCHrepresents (I) a chelating group or (II) a chelate group comprising a chelated radioactive or non-radioactive metal cation. It was found in the context of the invention that the compounds in accordance with the invention show a high affinity as ligand compounds towards human CXCR4 (hCXCR4) which is maintained after complexation of diverse radiometals. Thus, the compounds provide highly potent CXCR4-directed ligands with high tolerance towards different metal chelates.

[0015] It should be understood that, unless indicated to the contrary, any reference to a compound of the invention herein encompasses the compounds of formula (I) (and the preferred embodiments of this formula disclosed herein, such as formula (IA)), and the salts thereof. Thus, to the extent that groups contained in the compounds of the invention as discussed herein can form a salt, e.g. via protonation or via deprotonation, the indication of the structure of these groups encompasses the respective salts as well. Likewise, any racemates, enantiomers, or diastereomers of any chiral compounds of formula (I) and their salts are encompassed, unless a specific stereochemistry of the compound under consideration is indicated in a specific context. The compounds of the invention may also be referred to herein as ligand compounds of the invention, or briefly as ligands.

[0016] As further aspects, provided are the compounds in accordance with the invention for use in the treatment of diseases or disorders, or for use in a method of diagnosis in vivo of a disease or disorder.

[0017] Still a further aspect is a method for the preparation of the compounds in accordance with the present invention.

[0018] The following items summarize aspects of the invention, and the summary is further supplemented by the detailed description of the invention provided below.

[0019] List of Items

[0020] 1. A compound of formula (I) or a salt thereof: wherein

[0021] RB1represents hydrogen or iodine, preferably hydrogen;

[0022] RB2represents hydrogen or methyl, preferably methyl;

[0023] RB3represents a group -(CH2)m- with m being selected from 1, 2, 3 and 4, more preferably a group -(CH2)3-;

[0024] L represents a divalent linking group, or is absent; and

[0025] RCHrepresents (I) a chelating group or (II) a chelate group comprising a chelated radioactive or non-radioactive metal cation.

[0026] 2. The compound or salt in accordance with item 1 , wherein RB1represents hydrogen, RB2represents methyl, and RB3represents a group -(CH2)3-.

[0027] 3. The compound or salt in accordance with item 1 or 2, wherein L is a divalent unit which is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2, 3, 4 or 5 amino acid subunits, preferably from a divalent amino acid unit and a divalent oligopeptide unit comprising 2 or 3 amino acid subunits.

[0028] 4. The compound or salt in accordance with item 1 or 2, wherein the residue -L-RCHis a residue of the formula (L-1 ): wherein n is 0 or 1 , preferably 1 ;

[0029] L1is absent or is a divalent linking group, and is preferably absent;

[0030] RCHis as defined in item 1 ; and the bond marked with the waved line attaches the residue to the remainder of the compound of formula (I).

[0031] 5. The compound or salt in accordance with item 4, which is a compound of formula (IA) or a salt thereof: wherein

[0032] RB1and RB2are defined as in item 1 or 2; RCHis defined as in item 1 ; n is 0 or 1 , preferably 1 ; and

[0033] L1is absent or is a divalent linking group, and is preferably absent.

[0034] 6. The compound or salt in accordance with item 4 or 5, wherein L1is absent or is a divalent linking group which is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2, 3 or 4 amino acid subunits, is preferably absent or is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2 amino acid subunits, and is more preferably absent.

[0035] 7. The compound or salt in accordance with item 6, which is a compound of formula (IB) or a salt thereof: wherein RCHis defined as in item 1.

[0036] 8. The compound or salt in accordance with any of items 1 to 7, wherein RCHin formula (I), (IA) or (IB) represents

[0037] (i) a chelating group which is provided by a chelating agent selected from the group consisting of diethylenetriaminepentamethylenephosphonic acid (EDTMP), diethylenetriaminepentaacetic acid (DTPA), bis(carboxymethyl)-1 ,4,8,11-tetraaza- bicyclo[6.6.2] hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4- (1 ,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5- [acetyl(hydroxy)amino]-,pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]- amino]pentyl]-N-hydroxybutandiamide (DFO), 1 ,4,7, 10-tetraazacyclododecane-1 ,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acidj-pentanedioic acid (DOTAGA or DOTA-GA),

[0038] 1.4.7.10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), N,N'- dipyridoxylethylendiamine-N,N,-diacetate-5,5,-bis(phosphate) (DPDP), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N,,N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), 3-[3-[4-[5-(2- carboxyethyl)-2-hydroxyphenyl]-1,4-bis(carboxymethylamino)butyl]-4-hydroxyphenyl]- propanoic acid (HBED-CC), hydroxyethyldiaminetriacetic acid (HEDTA), l-(p-nitrobenzyl)-

[0039] 1.4.7.10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7- triazacyclononane (NODAGA), 1 ,4,7-triazacyclononanetriacetic acid (NOTA), 4,11- bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1 ,4,8,11- tetraazacyclododecane-1 , 4, 8, 11 -tetraacetic acid (TETA), terpyridine-bis(methyleneamine) tetraacetic acid (TMT), 1 ,4,7,10-tetraazacyclotridecan-N,N',N",N",-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N’-bis[(6-carboxy-2-pyridil)methyl]-4,13- diaza-18-crown-6 (Ffemacropa), 4-amino-4-{2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro- pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo- 1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2- carboxyethyl)phosphinic acid (TRAP), 2-(4,7,10-tris(2-amino-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1-yl)acetic acid (DO3AM), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10- tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-

[0040] 1.4.7.10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4- aminobenzyl)-3,6, 10,13,16,19-hexaazabicyclo[6.6.6]-eicosan-1 ,8-diamine (SarAr), 6-Amino- 6-methylperhydro-1 ,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), (6-pentanoic acid)-6- (amino)methyl-1 ,4-diazepine triacetate (DATA), pentadeca-1 ,4,7,10,13-penta- aminopentaacetic acid (PEPA), hexadeca-1 ,4,7,10,13,16-hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bis (carboxymethyl)-1,4,7,10- tetraazacyclododec-1-yl) acetic acid (BPAMD), N (4-{[bis (phosphonomethyl)) carbamoyl] methyl}-7,10-bis(carboxymethyl)-nona-1 ,4,7-triamine triacetic acid (BPAM), 1 ,2-[{6- (carboxylate) pyridin-2-yl} methylamine] ethane (DEDPA, H2DEDPA), deferoxamine (DFO), deferiprone, (4-acetylamino-4-yl) {2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2- ylmethyl) -carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4- dihydro-pyridin-2-ylmethyl)-amide] (CP256), YM103, tetraazycyclodecane-phosphinic acid (TEAP), 6,6'-[{9-hydroxy-1 ,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa2), 1 ,2-[{6- (carboxylato)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2- pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N'-bis(2-hydroxy-5- sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (HeSbbpen), triethylenetetramine- N,N,N',N",N"',N"'-hexaacetic (TTHA), 2-aminomethylpiperidine triacetic acid (2-AMPTA), 2-(N- (2-Hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), 4-nitro-2-hydroxybenzyl-2-{[(6)- trans-2-[benzyl(carboxymethyl)amino] cyclohexyl] (carboxymethyl)amino}acetic acid (RESCA), 6-carboxy-1, 4, 8, 11 -tetraazaundecane (N4), S-acetylmercaptoacetyltriglycine (MAG3) and S-acetylmercaptoacetyltriserine (MAS3), or

[0041] (ii) a chelate group wherein any one of these chelating groups forms a chelate complex comprising a chelated radioactive or non-radioactive metal cation.

[0042] 9. The compound or salt in accordance with any of items 1 to 8, wherein RCHin formula (I), (IA) or (1B) represents

[0043] (i) a chelating group which is provided by a chelating agent selected from the group consisting of 1,4,7,10-tetraazacyclododecan-N,N,,N",N",-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acidj-pentanedioic acid (DOTAGA or DOTA-GA), 1 ,4,7,10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), 2-(4,7,10- tris(2-amino-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1-yl)acetic acid (D03AM), 1 ,4,7- triazacyclononanetriacetic acid (NOTA) and 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)- 1 ,4,7-triazacyclononane (NODAGA), or

[0044] (ii) a chelate group wherein any one of these chelating groups forms a chelate complex comprising a chelated radioactive or non-radioactive metal cation.

[0045] 10. The compound or salt in accordance with item 9, wherein RCHin formula (I), (IA) or (IB) represents a chelating group of formula (CH-1), ora chelate group wherein the chelating group of formula (CH-1) forms a chelate complex comprising a chelated radioactive or nonradioactive metal cation: 11. The compound or salt in accordance with item 10, wherein the chelate group is a group of formula (CH-2), (CH-3) or (CH-4): wherein M represents a chelated radioactive or non-radioactive metal cation and the waved line marks the bond which attaches the respective group to the remainder of the compound.

[0046] 12. The compound or salt in accordance with any of items 1 to 11 , wherein the chelated metal cation is selected from cations of62Cu,64Cu,67Cu,66Ga,68Ga,67Ga,90Y,86Y,99mTc,152Tb,155Tb,161Tb,149Tb,177Lu,212Bi,213Bi,212Pb and225Ac, and from cations of nonradioactive isotopes of any of these metals.

[0047] 13. The compound or salt in accordance with item 12, wherein the chelated metal cation is a radioactive metal cation selected from cations of67Ga,68Ga,64Cu,177Lu and90Y. 14. The compound or salt in accordance with any of items 1 to 13, which is a radiolabeled compound or salt wherein RCHin formula (I) or (IA) represents a chelate group comprising a chelated radioactive metal cation.

[0048] 15. A pharmaceutical composition comprising or consisting of one or more compounds or salts in accordance with any of items 1 to 14.

[0049] 16. The pharmaceutical composition in accordance with item 15, which further comprises a pharmaceutically acceptable excipient.

[0050] 17. The compound or salt in accordance with any of items 1 to 14 for use as a medicament.

[0051] 18. The compound or salt in accordance with any of items 1 to 14 or the pharmaceutical composition of item 15 or 16 for use in the treatment of a tumor.

[0052] 19. The compound or salt or the pharmaceutical composition for use in accordance with item 18, wherein the tumor is preferably selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukaemia (AML), mucosa-associated lymphoid tissue (MALT) lymphoma, myelodysplastic syndromes, adrenocortical carcinoma, neuroendocrine tumors (NETs), non-small cell lung cancer (N-SCLC) and small cell lung cancer (SCLC).

[0053] 20. The compound or salt in accordance with any of items 1 to 14 or the pharmaceutical composition of item 15 or 16 for use in the treatment of a hematologic disease, wherein the hematologic disease is preferably selected from acute leukemia, lymphoma and multiple myeloma.

[0054] 21. The compound or salt in accordance with any of items 1 to 14 or the pharmaceutical composition of item 15 or 16 for use in a method of diagnosis in vivo of a disease or disorder.

[0055] 22. The compound or salt or the pharmaceutical composition for use in accordance with item 21, wherein the disease or disorder is a tumor.

[0056] 23. The compound or salt or the pharmaceutical composition for use in accordance with item 22, wherein the tumor is selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukaemia (AML), mucosa-associated lymphoid tissue (MALT) lymphoma, myelodysplastic syndromes, adrenocortical carcinoma, neuroendocrine tumors (NETs), non-small cell lung cancer (N-SCLC) and small cell lung cancer (SCLC).

[0057] 24. The compound or salt or the pharmaceutical composition for use in accordance with item 21, wherein the disease or disorder is an inflammatory disease or disorder.

[0058] 25. The compound or salt or the pharmaceutical composition for use in accordance with item 24, wherein the inflammatory disease or disorder is selected from inflammation associated with myocardial infarction, vasculitis, sarcoidosis, chronic osteomyelitis, inflammation associated with ischemic stroke, atherosclerosis, and bone infection.

[0059] 26. The compound or salt or the pharmaceutical composition for use in accordance with item 21 , wherein the disease or disorder is an endocrinologic disease or disorder.

[0060] 27. The compound or salt or the pharmaceutical composition for use in accordance with item 26, wherein the endocrinologic disease or disorder is primary aldosteronism.

[0061] 28. The compound or salt or the pharmaceutical composition for use in accordance with any of items 21 to 27, wherein the method of diagnosis involves nuclear diagnostic imaging.

[0062] 29. A method for the synthesis of a compound or salt of any of items 1 to 14 which comprises:

[0063] (i) a step of reacting a compound of the formula (S-2) wherein

[0064] RS5represents an alkyl group, preferably a C1-C6 alkyl group, more preferably ethyl; and

[0065] RS6represents a protective group for an amino group, preferably a fluorenylmethoxycarbonyl protecting group (Fmoc); with a tetrapeptide of the formula (S-3)

[0066] wherein

[0067] RS7represents a protective group for a phenolic hydroxy group, preferably a t-butyl group; RS8represents a protective group for an amino group, preferably a t-butoxycarbonyl

[0068] (Boc) group;

[0069] RS9represents a protective group for a guanidino group, preferably a 2, 2, 4,6,7- pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf) group; and

[0070] RB1, RB2and RB3are defined as in item 1 or 2; to provide a pentapeptide containing an amidine bond;

[0071] (ii) a step of cyclizing the pentapeptide provided in step (i) after deprotection of its N- terminal amino group to obtain a cyclic peptide containing an amidine bond. Detailed Description of the Invention

[0072] As noted above, the invention provides a compound of formula (I) or a salt thereof: wherein

[0073] RB1represents hydrogen or iodine, preferably hydrogen;

[0074] RB2represents hydrogen or methyl, preferably methyl;

[0075] RB3represents a group -(CH2)m- with m being selected from 1, 2, 3 and 4, more preferably a group -(CH2)3-;

[0076] L represents a divalent linking group, or is absent; and

[0077] RCHrepresents (i) a chelating group or (ii) a chelate group comprising a chelated radioactive or non-radioactive metal cation.

[0078] In line with the above, compounds in accordance with the invention are particularly preferred wherein, in formula (I), RB1represents hydrogen, RB2represents methyl, and RB3represents a group of formula -(CH2)3-. The stereochemistry of the compounds in accordance with the invention is preferably as shown in the following formula (l-S): wherein RB1, RB2, RB3, L and RCHare defined as for formula (I), including preferred embodiments.

[0079] The group L represents a divalent linking group, or is absent. As will be understood from the formulae provided herein, in case L is absent, RCHis directly attached via a covalent bond to the nitrogen atom of the moiety -NH-L-RCHshown in the formula. Preferably, L represents a divalent linking group.

[0080] As noted above, the robust core structure of the cyclic CXCR4 targeting moiety (also referred to herein as cyclic pentapeptide containing an amidine bond, or simply as cyclic pentapeptide) provides flexibility in the design of the ligand compound, and thus in the choice of groups L and / or RCH.

[0081] It is generally preferred that L is a divalent linking group which is selected from a divalent amino acid unit and a divalent oligopeptide unit. More preferably, L is selected from a divalent linking group which is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2, 3, 4 or 5 amino acid subunits, and still more preferably from a divalent amino acid unit and a divalent oligopeptide unit comprising 2 or 3 amino acid subunits.

[0082] Reference made herein to an amino acid is directed, in line with the skilled person’s understanding, to a compound which comprises at least one amino group and at least one carboxylic acid group in the same molecule. One or more further functional groups may be contained in an amino acid. Such an amino acid may be a natural or a synthetic amino acid.

[0083] Accordingly, an amino acid unit which can be comprised by a compound in accordance with the invention, e.g. as L or as a part of L, is a unit which is provided by an amino acid. A specific amino acid unit can be identified by the name of the amino acid from which it can be derived, e.g. as a lysine unit, glutamic acid unit, etc. Unless specifically indicated in a given context or by a given chemical formula, an amino acid unit may be a monovalent amino acid unit, a divalent amino acid unit, or a tri- or higher valent amino acid unit. As will be understood by a skilled person, a monovalent amino acid unit can be provided by converting one of the functional groups comprised by an amino acid into a coupling group which attaches the amino acid unit to an adjacent unit or group in the compound in accordance with the invention. Likewise, a divalent amino acid unit can be provided by converting two of the functional groups comprised by an amino acid into coupling groups which attach the amino acid unit to two adjacent moieties or groups in the compound in accordance with the invention. Typically, functional groups used for this purpose are an amino group which is converted to a coupling group -NH- or a carboxylic acid group which is converted to a coupling group -C(O)-. Preferably, a coupling group -NH- or -C(O)- comprised by such an amino acid unit forms an amide or peptide bond -C(O)-NH- with an adjacent unit or group. A tri- or higher valent amino acid unit can be derived accordingly from an amino acid comprising one or more further functional groups in addition to the at least one amino group and at least one carboxylic acid group characterizing an amino acid. As noted above, the divalent linking group L may be a divalent amino acid unit. If the divalent linking group L is a divalent amino acid unit, it is preferred that the divalent amino acid unit forms an amide bond with the nitrogen atom of the moiety -RB3-NH- and another amide bond with -RCH. An example of such an amino acid unit is a 4-(aminomethyl)benzoic acid (AMBA) unit, i.e. a unit derived from AMBA, generally by using the carboxylic acid functional group to form an amide bond with the nitrogen atom of the moiety -RB3-NH- and by using the amino functional group to form another amide bond with - RCH.

[0084] As further noted above, L may be a divalent oligopeptide unit. In line with the common use of the term, an oligopeptide unit as referred to herein is a unit containing two or more amino acid subunits which are attached to each other via an amide or peptide bond (-C(O)-NH-). Such amino acid units forming an oligopeptide unit may also be referred to as amino acid subunits of the oligopeptide unit. An amide or peptide bond formed between the amino acid moieties or units of the peptide moiety can be, but does not have to be, an o-peptide bond. Unless indicated otherwise in a specific context, an oligopeptide unit contains two to ten amino acid subunits. If L represents a divalent oligopeptide unit, it is preferably an oligopeptide unit comprising 2, 3, 4 or 5 amino acid subunits, and still more preferably a divalent oligopeptide unit comprising 2 or 3 amino acid subunits. Amino acid subunits forming an oligopeptide unit may form e.g. an unbranched chain of amino acid subunits. As noted above, the bonds formed between the amino acid subunits in such a chain can be, but do not have to be, a-peptide bonds. If the divalent linking group L is a divalent oligopeptide unit, it is preferred that the divalent oligopeptide unit forms an amide bond with the nitrogen atom of the moiety -RB3-NH- and another amide bond with -RCH.

[0085] Preferably, the residue -L-RCHin formula (I) or (l-S), respectively, is a residue of the formula (L-1):

[0086] (L-1) wherein n is 0 or 1 , preferably 1 ;

[0087] L1is absent or is a divalent linking group, and is preferably absent;

[0088] RCHis as defined above; and the bond marked with the waved line attaches the residue to the remainder of the compound of formula (I).

[0089] If L1is absent, RCHforms a direct covalent bond with the nitrogen atom of the moiety -NH-L1-RCHshown in the formula. If L1is a divalent linking group, it is preferably a divalent amino acid unit, or a divalent oligopeptide unit comprising 2, 3 or 4, more preferably comprising 2 amino acid subunits. In line with the above, a preferred compound in accordance with the invention is a compound of formula (IA) or a salt thereof: wherein RB1, RB2and RCHare defined as for formula (I), including preferred embodiments thereof, and n and L1are as defined for formula (L-1 ), including preferred embodiments thereof.

[0090] The stereochemistry of the compound of formula (IA) is preferably as indicated in formula (IA-S):

[0091] (IA-S) wherein RB1, RB2and RCHare defined as for formula (I), including preferred embodiments thereof, and n and L1are as defined for formula (L-1 ), including preferred embodiments thereof.

[0092] The group RCHin formula (I) (and thus also in the preferred variants thereof, such as (l-S), (IA), (IA-S) and the preferred substructure (L-1)) represents (i) a chelating group or (ii) a chelate group comprising a chelated radioactive or non-radioactive metal cation. In line with the skilled person’s understanding, the chelating group is typically a group which is suitable as a chelating ligand to form a chelate complex with a complexed radioactive or non-radioactive metal cation. The chelate group is a group wherein the chelating group has already formed a chelate complex comprising a chelated radioactive or non-radioactive metal cation. As will be understood by the skilled reader, the formation of the chelate complex may involve certain changes in the structure of the chelating group, such as the deprotonation of a carboxylic acid group to provide a carboxylate anion which coordinates to the metal cation in the chelate complex. As exemplary chelating groups, reference may be made to chelating groups provided by a chelating agent selected from diethylenetriaminepentamethylenephosphonic acid (EDTMP), diethylenetriaminepentaacetic acid (DTPA), bis(carboxymethyl)-1 ,4,8,11-tetraaza- bicyclo[6.6.2] hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4- (1,4, 8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-

[0093] [acetyl(hydroxy)amino]-,pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]- amino]pentyl]-N-hydroxybutandiamide (DFO), 1 ,4,7, 10-tetraazacyclododecane-1 ,7-diacetic acid (D02A), 1,4,7,10-tetraazacyclododecan-N,N',N",N,"-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA or DOTA-GA),

[0094] 1.4.7.10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), N,N'- dipyridoxylethylendiamine-N,N'-diacetate-5,5,-bis(phosphate) (DPDP), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N,,N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), 3-[3-[4-[5-(2- carboxyethyl)-2-hydroxyphenyl]-1,4-bis(carboxymethylamino)butyl]-4-hydroxyphenyi]- propanoic acid (HBED-CC), hydroxyethyldiaminetriacetic acid (HEDTA), l-(p-nitrobenzyl)-

[0095] 1.4.7.10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7- triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11- bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1 ,4,8,11- tetraazacyclododecane-1, 4, 8, 11 -tetraacetic acid (TETA), terpyridine-bis(methyleneamine) tetraacetic acid (TMT), 1 ,4,7,10-tetraazacyclotridecan-N,N',N",N",-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13- diaza-18-crown-6 (Fhmacropa), 4-amino-4-{2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro- pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo- 1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2- carboxyethyl)phosphinic acid (TRAP), 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10- tetraazacyclododecan-1-yl)acetic acid (DO3AM), 1 ,4,7,10-tetraazacyclododecane-1,4,7,10- tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-

[0096] 1.4.7.10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4- aminobenzyl)-3,6, 10,13,16,19-hexaazabicyclo[6.6.6]-eicosan-1 ,8-diamine (SarAr), 6-Amino- 6-methylperhydro-1 ,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), (6-pentanoic acid)-6- (amino)methyl-1,4-diazepine triacetate (DATA), pentadeca-1 ,4,7,10,13-penta- aminopentaacetic acid (PEPA), hexadeca-1 ,4,7,10,13,16-hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bis (carboxymethyl)-1,4,7,10- tetraazacyclododec-1-yl) acetic acid (BPAMD), N (4-{[bis (phosphonomethyl)) carbamoyl] methyl}-7,10-bis(carboxymethyl)-nona-1,4,7-triamine triacetic acid (BPAM), 1 ,2-[{6- (carboxylate) pyridin-2-yl} methylamine] ethane (DEDPA, H2DEDPA), deferoxamine (DFO), deferiprone, (4-acetylamino-4-yl) {2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2- ylmethyl) -carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4- dihydro-pyridin-2-ylmethyl)-amide] (CP256), YM103, tetraazycyclodecane-phosphinic acid

[0097] (TEAP), 6,6'-[{9-hydroxy-1 ,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa2), 1 ,2-[{6- (carboxylato)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2- pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N’-bis(2-hydroxy-5- sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (HeSbbpen), triethylenetetramine- N,N,N',N",N'",N"'-hexaacetic (TTHA), 2-aminomethylpiperidine triacetic acid (2-AMPTA), 2-(N- (2-Hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), 4-nitro-2-hydroxybenzyl-2-{[(6)- trans-2-[benzyl(carboxymethyl)amino] cyclohexyl] (carboxymethyl)amino}acetic acid (RESCA), 6-carboxy-1, 4, 8, 11 -tetraazaundecane (N4), S-acetylmercaptoacetyltriglycine (MAG3) and S-acetylmercaptoacetyltriserine (MAS3).

[0098] Preferred chelating groups RCHare chelating groups which are suitable to form a chelate complex with a metal cation selected from cations of Cu, Ga, Y, Tb, Lu, Bi, Pb, Tc and Ac, more preferably with a metal cation selected from cations of Cu, Ga, Y, and Lu, such as a Cu2+cation, a Ga3+cation, a Y3+cation or a Lu3+cation.

[0099] Chelating agents which are able to provide such preferred chelating groups are known in the art and commercially available. For example, RCHpreferably represents a chelating group provided by a chelating agent selected from the group consisting of 1 ,4,7,10- tetraazacyclododecan-N,N,,N",N",-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acidj-pentanedioic acid (DOTAGA or DOTA-GA), 1 ,4,7,10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), 2-(4,7,10- tris(2-amino-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1-yl)acetic acid (DO3AM), 1 ,4,7- triazacyclononanetriacetic acid (NOTA) and 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)- 1 ,4,7-triazacyclononane (NODAGA).

[0100] Preferably, RCHrepresents a chelating group which is provided by a chelating agent selected from the group consisting of DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, more preferably from DOTA and NOTA, or a chelate group wherein any one of these chelating groups comprises a chelated radioactive or non-radioactive metal cation.

[0101] As will be understood by the skilled reader, the above exemplary and preferred chelating groups can be provided by converting a functional group, such as an amino group, a carboxylic acid group or an amide group, comprised by the corresponding chelating agent, into a coupling group which serves to attach the chelating group (or the chelate group comprising it) to the remainder of the compound in accordance with the invention. Preferably, the chelating group comprises a coupling group -NH- or -C(O)- which forms an amide or peptide bond -C(O)-NH- with a group -C(O)- or -NH- provided at the point of attachment of -RCH. It is particularly preferred if the chelating group comprises a coupling group -C(O)- which forms an amide or peptide bond -C(O)-NH- with a group -NH- provided at the point of attachment of -RCH.

[0102] Exemplary chelate groups RCHare chelate groups wherein any one of the exemplary chelating groups comprises a chelated radioactive or non-radioactive metal cation.

[0103] Preferred chelate groups RCHare chelate groups comprising a chelated radioactive or nonradioactive metal cation selected from cations of Cu, Ga, Y, Tc, Tb, Lu, Bi, Pb and Ac, for example cations of62Cu,64Cu,67Cu,66Ga,68Ga,67Ga,90Y,86Y,99mTc,152Tb,155Tb,181Tb,149Tb,177Lu,212Bi,213Bi,212Pb and225Ac, and, if existent, from cations of nonradioactive isotopes of any of these metals for which non-radioactive isotopes exist. More preferably, the chelated radioactive or non-radioactive metal cation is selected from a metal cation selected from cations of Cu, Ga, Y and Lu, such as cations of68Ga,64Cu,177Lu and90Y.

[0104] It will be understood that chelate groups combining the above preferred chelating groups, such as a chelating group which is provided by a chelating agent selected from the group consisting of DOTA, DOTAGA, DOTAM, D03AM, NOTA and NODAGA, more preferably from DOTA and NOTA, and the above preferred chelated metal cations selected from cations of Cu, Ga, Y and Lu, such as cations of68Ga,64Cu,177Lu and90Y, are specifically preferred.

[0105] In line with the above, a particularly preferred chelating group RCHis a group of the following formula (CH-1), and particularly preferred chelate groups RCHare chelate groups obtained by forming a chelate complex from the chelating group of formula (CH-1 ) and a radioactive or non-radioactive metal cation, such as the preferred metal cations disclosed above. As exemplary chelate groups, the groups of the following formulae (CH-2), (CH-3) and (CH-4) can be indicated. In each of the formulae (CH-1) to (CH-4), the waved line marks the bond which attaches the respective group to the remainder of the compound in accordance with the invention, and in formulae (CH-2), (CH-3) and (CH-4), M represents a chelated radioactive or non-radioactive metal cation.

[0106]

[0107] In formula (CH-2), M can be, e.g., a Cu metal cation, such as a ^Cu cation. In formula (CH-3), M can be, e.g., a metal cation selected from a cation of Y and Lu, such as a cation of90Y, and177Lu, and in formula (CH-4), M can be, e.g., a Ga metal cation, such as a cation68Ga cation. In view of the above, it will be understood that a strongly preferred compound in accordance with the invention is a compound of the following formula (IB) or a salt thereof: wherein RCHis as defined as above, including any preferred embodiments thereof, and is particularly preferably a group of the chelating group of the formula (CH-1 ) or a chelate group obtained by forming a chelate complex from the chelating group of formula (CH-1) , such as a chelate group of the above formulae (CH-2), (CH-3) and (CH-4), and a radioactive or non- radioactive metal cation, such as a cation of68Ga, ^Cu,177Lu and90Y.

[0108] The stereochemistry of the compound of formula (IB) is preferably as indicated in formula (IB-S), with RCHbeing defined as for formula (IB):

[0109] The compound of formula (IB-S) wherein RCHis a chelating group of formula (CH-1) as shown above is also referred to herein under the designations D0TA-Amba-CPCR4A(1) or simply as “PentaxaFor”. Thus, as particularly preferred embodiments of the invention, reference can be made to a compound of formula (IB-S) and its salts wherein RCHis a chelating group of formula (CH-1) or a chelate group obtained by forming a chelate complex from the chelating group of formula (CH-1), such as a chelate group of the above formulae (CH-2), (CH-3) and (CH-4), and a radioactive or non-radioactive metal cation, such as a cation of68Ga, ^Cu,177Lu and 90y

[0110] A synthetic approach suitable for the preparation of the compounds in accordance with the invention is illustrated in the context of the experimental data contained as examples herein. It was found in this context that an efficient synthesis of a cyclic pentapeptide containing an amidine bond could not be efficiently accomplished by the synthetic approach indicated by Inokuchi et al. in (42). Hence, the present invention provides, as a further aspect, a method for the synthesis of a compound in accordance with the present invention, which method comprises: (i) a step of reacting a compound of the formula (S-2) (S-2) wherein

[0111] RS5represents an alkyl group, preferably a C1-C6 alkyl group, more preferably ethyl; and

[0112] RS6represents a protective group for an amino group, preferably a fluorenylmethoxycarbonyl protecting group (Fmoc); with a tetrapeptide of the formula (S-3) wherein

[0113] RS7represents a protective group for a phenolic hydroxy group, preferably a t-butyl group;

[0114] RS8represents a protective group for an amino group, preferably a t-butoxycarbonyl (Boc) group; RS9represents a protective group for a guanidino group, preferably a 2, 2, 4,6,7- pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf) group; and

[0115] RB1, RB2and RB3are defined as hereinabove, including preferred meanings thereof; to provide a pentapeptide containing an amidine bond;

[0116] (ii) a step of cyclizing the pentapeptide provided in step (i) after deprotection of its N- terminal amino group to obtain a cyclic peptide containing an amidine bond.

[0117] A compound of formula (S-2) as a reactant can be prepared, e.g., by first converting the carboxylic acid group of an N-protected, preferably Fmoc protected, 2-naphtyl alanine, into an amide group, followed by imidate formation. A compound of formula (S-3) can be prepared using solid phase peptide synthesis.

[0118] As will be understood from the above, the stereochemistry of the compound of formula (S-2) is preferably as indicated in formula (S-2S), and the stereochemistry of the compound of formula (S-3) is preferably as indicated in formula (S-3S): (S-2S)

[0119]

[0120] The definitions of the variables RS5to RS9and RB1to RB3in formulae (S-2S) and (S-3S) correspond of course to those provided above for these variables in formulae (S-2) and (S-3), respectively.

[0121] Following step (ii) above, the protective group RS8which is contained in a side chain of the resulting pentapeptide containing an amidine bond provided in step (ii) can be replaced by a linker structure L*, or, if desired, directly by a chelating moiety RCH. As will be understood by the skilled reader, L* represents a precursor of the linking group L as defined above which, at this stage, is not yet a divalent group, such as an amino acid unit or an oligopeptide unit. RCHrepresents a chelating unit as defined above.

[0122] Preferably, the protective group RS8which is contained in a side chain of the resulting pentapeptide containing an amidine bond provided in step (ii) is replaced in a subsequent step by a linker structure L*, e.g. a linker structure in the form of an amino acid unit or an oligopeptide unit, followed by the attachment of a chelating moiety RCHto the linker structure to provide a pentapeptide containing an amidine bond containing the moiety -RB3-NH-L-RCHas shown in formula (I). It will be understood that for all the variable groups referred to in the context of the discussion of the method of synthesis, i.e. in particular RB1, RB2, RB3, L and RCH, the same definitions and the same preferences apply as in the compounds in accordance with the invention.

[0123] As noted above, the compounds in accordance with the invention encompass compounds of formula (I) and its preferred forms such as the compounds of formula (IA) or (IB), as well as salts of the compounds of formula (I), or of any preferred versions thereof, such as salts of the compounds of formula (IA) or (IB). Such salts are generally pharmaceutically acceptable salts, i.e. salts formed with pharmaceutically acceptable anions or cations. Salts may be formed, e.g., by protonation of an atom carrying an electron lone pair in a compound in accordance with the invention which is susceptible to protonation, such as a nitrogen atom, with an inorganic or organic acid, or by separating a proton from an acidic group in a compound in accordance with the invention, such as a carboxy group, e.g. by neutralization with a base. It will be understood that the reference to compounds of formula (I) and salts thereof will also encompass salts which involve charged forms of groups or moieties which may be contained in the compounds of formula (I), and which are further defined herein by their structure herein, such as charged forms of the chelating group (RCH). Charged groups which may be present in the compounds in accordance with the invention and which may provide the compounds in the form of a salt include groups which are continuously charged, such as a quaternary ammonium group comprising an ammonium cation wherein the nitrogen is substituted by four organyl groups, or charged chelate complexes.

[0124] As exemplary anions which may be present as counterions in salt forms of the compounds of the invention if the salt form comprises a positively charged form of the compound, mention may be made, for example, of an anion selected from chloride, bromide, iodide, sulfate, nitrate, phosphate (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate, hydrogencarbonate or perchlorate; acetate, trifluoroacetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate; sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate. Since trifluoroacetic acid is frequently used during the synthesis of peptides, trifluoroacetate salts are typical salts which are provided if a compound comprising a peptide structure is formed. Such trifluoroacetate salts may be converted e.g. to acetate salts during their workup. Thus, trifluoroacetate salts or acetate salts are frequently encountered as salt forms. As exemplary cations which may be present as counterions in salt forms of the compounds of the invention if the salt form comprises a negatively charged form of the compound, mention may be made, for example, of a cation selected from alkali metal cations, such as lithium, sodium or potassium, alkaline earth metal cations, such as calcium or magnesium; and ammonium (including ammonium ions substituted by organic groups).

[0125] Pharmaceutical Aspects

[0126] The compounds in accordance with the invention comprise a chelating group or a chelate group comprising a chelated radioactive or non-radioactive metal cation. Thus, the compounds in accordance with the invention encompass radiolabeled compounds and non-radiolabeled compounds. Radiolabeled compounds of the invention are compounds containing a chelated radioactive metal cation, i.e. a radioactive metal cation which is complexed in a chelate group. Non-radiolabeled compounds in accordance with the invention may also be considered as precursors of radiopharmaceutical compounds, and in particular of the radiolabeled compounds in accordance with the invention as radiopharmaceuticals.

[0127] In another aspect, the invention provides a pharmaceutical composition, such as a radiopharmaceutical composition, comprising a compound in accordance with the invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable excipient. A radiopharmaceutical composition is a pharmaceutical composition comprising a radiolabeled compound in accordance with the invention. Examples of pharmaceutically acceptable excipients are well known in the art, e.g., a phosphate buffered saline solution, an amino acid buffered solution (with or without saline), water for injection, an emulsion, such as oil / water emulsion, a wetting agent, or a sterile solution, etc.

[0128] A composition comprising a non-radiolabeled compound in accordance with the invention, optionally in combination with a pharmaceutically acceptable excipient, can be provided, e.g., as a precursor composition for a radiopharmaceutical composition. In a related aspect, the invention provides a kit comprising a non-radiolabeled compound in accordance with the invention which does not contain a radioactive component, optionally in combination with a pharmaceutically acceptable excipient, in combination with instructions for radiolabeling the compound.

[0129] In a related aspect, the compounds in accordance with the invention, such as the radiolabeled compounds in accordance with the invention, are provided for use as a medicament. A compound in accordance with the invention, such as a radiolabeled compound, can be suitable for use in therapy or for use in diagnosis. Likewise, a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, can be suitable for use in therapy (i.e. as a therapeutic composition) or for use in diagnosis (i.e. as a diagnostic composition).

[0130] Since a compound of the invention and pharmaceutical composition in accordance with the invention can be used in therapy, i.e. in the treatment of a disease or disorder, the invention provides, as a further aspect, a compound in accordance with the invention, such as a radiolabeled compound, or a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, for use in the treatment of a disease or disorder. The treatment is preferably a treatment of a disease or disorder via radioligand therapy. As a preferred example for a radiolabeled compound in accordance with the invention for use in the treatment of a disease or disorder, reference can be made to a compound which comprises a chelate group comprising a chelated90Y cation ora177Lu cation. However, it will be understood that suitability for a therapeutic and a diagnostic application is not mutually exclusive, i.e. a compound in accordance with the invention may be suitable for both applications. For example, a compound comprising a complexed177Lu cation can be used both for therapeutic and diagnostic imaging applications.

[0131] For example, the treatment may comprise administering a radiolabeled compound or a radiopharmaceutical composition in accordance with the invention to a subject. The subject may be a human or an animal, and is preferably human. Thus, the treatment referred to above aims at the treatment of a disease or disorder of the human or animal body.

[0132] In a related aspect, the invention provides a method for the treatment of a disease or disorder, the method comprising administering a therapeutically effective amount of a compound in accordance with the invention or a pharmaceutical composition in accordance with the invention to a patient in need of such a treatment.

[0133] As will be understood, the disease or disorder to be treated is typically one which is associated with the expression or overexpression of CXCR4.

[0134] An example is a tumor, generally a CXCR4-positive tumor, such as preferably a tumor selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukaemia (AML), mucosa-associated lymphoid tissue (MALT) lymphoma, myelodysplastic syndrome, adrenocortical carcinoma, neuroendocrine tumor (NETs), non-small cell lung cancer (N-SCLC) and small cell lung cancer (SCLC).

[0135] Preferred examples of diseases to be treated also include hematologic diseases, generally CXCR4 positive, such as a disease selected from acute leukemia, lymphoma and multiple myeloma.

[0136] Since compounds of the invention and pharmaceutical compositions in accordance with the invention can be used in a method of diagnosis, the invention provides as a further aspect a compound in accordance with the invention, such as a radiolabeled compound, or a pharmaceutical composition in accordance with the invention, such as a radiopharmaceutical composition, for use in a method of diagnosis in vivo of a disease or disorder. The method of diagnosis in vivo preferably involves nuclear diagnostic imaging, e.g. via Positron Emission Tomography (PET), Single-Photon-Emission Computed Tomography (SPECT), or by a gamma camera. It will be understood that the method of detection will generally be selected to be suitable for the radionuclide used, and vice versa. For example, a radiolabeled compound in accordance with the invention which comprises a chelate group comprising a chelated68Ga cation, a chelated67Ga cation or a64Cu cation represents as a preferred radiolabeled compound suitable for use in a method of diagnosis.

[0137] For example, the method of diagnosis may comprise administering a radiolabeled compound in accordance with the invention to a subject and detecting the compound in the subject, or monitoring the distribution of the compound in the subject, thereby detecting or monitoring the disease or disorder to be diagnosed. The subject may be a human or an animal and is preferably human. Thus, the method of diagnosis in vivo referred to above aims at the detection or the monitoring of a disease or disorder of the human or animal body. Alternatively, a method of diagnosis may also comprise adding a radiolabeled compound in accordance with the invention to a sample, e.g. a physiological sample obtained from a subject in vitro or ex vivo, and detecting the compound in the sample.

[0138] Thus, in a related aspect, the invention provides a method for the diagnosis of a disease or disorder, the method comprising administering a compound in accordance with the invention or a pharmaceutical composition in accordance with the invention to a patient, and detecting the compound in the subject or monitoring the distribution of the compound in the subject, typically via nuclear diagnostic imaging.

[0139] As will be understood, the disease or disorder to be diagnosed is typically one which is associated with the expression or overexpression of CXCR4. An example is a tumor, generally a CXCR4-positive tumor, such as preferably a tumor selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), acute myeloid leukaemia (AML), mucosa-associated lymphoid tissue (MALT) lymphoma, myelodysplastic syndrome, adrenocortical carcinoma, neuroendocrine tumor (NETs), non-small cell lung cancer (N-SCLC) and small cell lung cancer (SCLC).

[0140] Preferred examples of diseases also include hematologic diseases, generally CXCR4 positive, such as a disease selected from acute leukemia, lymphoma and multiple myeloma.

[0141] Still a further example is an inflammatory disease or disorder such as inflammation associated with myocardial infarction, vasculitis, sarcoidosis, chronic osteomyelitis, inflammation associated with ischemic stroke, atherosclerosis or bone infections. In the context of such a disease or disorder, a compound in accordance with the invention or a pharmaceutical composition in accordance with the invention may be used to detect the CXCR4-expressing immune cell infiltration in areas of inflammation.

[0142] In addition, endocrinologic diseases or disorders can be mentioned as examples, such as primary aldosteronism.

[0143] The following examples are provided to further illustrate the invention.

[0144] Examples

[0145] Reagents, Solvents and biochemical

[0146] All reagents obtained from commercial vendors were of analytical grade and were used without further purification, unless stated otherwise. All solvents including trace-pure water (TP-H2O) were obtained from Merck KGaA (Darmstadt, Germany). Millipore-water was purified by a Barnstead MicroPure-System by Thermo Fischer Scientific Inc. (USA). Protected amino acids as well as 2-CTC resin were purchased from Iris Biotech GmbH (Marktredwitz, Germany) and Merck KGaA (Darmstadt, Germany). Coupling reagents, bases, and other small molecules were obtained from Merck KGaA (Germany), Molekula GmbH (Germany), Macrocyclics Inc. (USA) and CheMatech (Dijon, France). All organic and inorganic chemicals were purchased from Iris Biotech GmbH (Marktredwitz, Germany), Merck KGaA (Darmstadt, Germany) and Alfa Aesar (Karlsruhe, Germany). [177Lu]LuCl3 solution in 0.04 M HCIaq. was purchased from ITM (Garching, Germany) and was used without further purification. [68Ga]GaCl3 solution in 0.04 M HCIaq. was obtained from ITM (Garching, Germany) and was used without further purification. [125l]Nal solution in 0.04 M NaOHaq. was purchased from Hartmann Analytic (Braunschweig, Germany) and was used without further purification. [64Cu]CuCl2 solution in 0.1 M HCIaq. was purchased from ACOM Sri (Montecosaro, Italy). RPMI 1640 (2.0 g / L NaHCOs, w / o L-Glutamine, low endotoxin, Biochrom, Berlin, Germany) and Dulbecco’s Modified Eagle Medium F-12 (DMEM / F-12) (1:1) + GlutaMAXTM-l (Biochrom, Berlin, Germany), FCS (Biochrom, Berlin, Germany), non-essential amino acids (NEA, Merck Millipore, Germany), penicillin / streptomycin (10.000 U / mL or 10.000 pg / mL, Merck Millipore, Germany), 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer (1 M, pH 7.0-7.6, Merck Millipore, Germany) as well as trypsin / EDTA (0.05%:0.02%; w:v, Biochrom, Berlin, Germany) in PBS were used for the cultivation and splitting of Jurkat, 449 Mouse lymphoma and Chem- 1 cells. In vitro experiments were carried out using the previously mentioned biochemicals; HBSS and BSA were received from Merck KGaA (Darmstadt, Germany).

[0147] Equipment and analytics

[0148] 20 mL PP reactors with PE frits, used in solid-phase peptide synthesis, were made by B. Braun (Melsungen, Germany). Analytical reversed phase high-performance liquid chromatography (RP-HPLC) was performed on a Shimadzu Corp. (Kyoto, Japan) gradient system, with an SPD-20A dual wavelength UV-vis detector (Ai = 220 nm, A2 = 254 nm) and a Multokrom 100- 5 C18 column (125 x 4.6 mm, 5 pm particle size). A flow rate of 1.0 mL / min over 15 minutes was applied for linear gradients. As eluent, a mixture of acetonitrile (Ultra Gradient HPLC grade, with addition of 2 vol% H2O and 0.1 vol% TFA) and purified water (from Millipore system, 0.1 vol% TFA) was used. Lab Solutions software from Shimadzu Corp. (Kyoto, Japan) was used for visualization of the obtained chromatograms. Semi-preparative RP-HPLC runs were performed on Shimadzu Corp. (Kyoto, Japan) gradient systems, with an SPD-20A dual wavelength UV-vis detector (A1 = 220 nm, A2 = 254 nm) and a Multokrom 100-5 C18 column (250 x 10 mm, 5 pm particle size). A flow rate of 10.0 mL / min over 20 minutes was applied for linear gradients. As eluent, a mixture of acetonitrile (Ultra Gradient HPLC grade, with addition of 5 vol% H2O and 0.1 vol% TFA) and purified water (from Millipore system, 0.1 vol% TFA) was used. Radio-RP-HPLC was performed on a Shimadzu Corp. (Kyoto, Japan) gradient system, with an SPD-20A dual wavelength UV-vis detector (A1 = 220 nm, A2 = 254 nm), a HERM LB500 (Nal(TI) scintillation crystal) radio-detector (Berthold Technologies GmbH, Bad Wildbad, Germany) and a Multokrom 100-5 C18 column (125 x 4.6 mm, 5 pm particle size). A flow rate of 1.0 mL / min over 15 minutes was applied for linear gradients. As eluent, a mixture of acetonitrile (Ultra Gradient HPLC grade, with addition of 2 vol% H2O and 0. vol% TFA) and purified water (from Millipore system, 0.1 vol% TFA) was used. Lab Solutions software from Shimadzu Corp. (Kyoto, Japan) was used for visualization of the obtained chromatograms. Electrospray-Ionization Mass Spectroscopy (ESI-MS) was performed on an expression CMS mass spectrometer equipped with a quadrupole analyzer by Advion Inc. (Ithaca, USA). Flash chromatography was carried out with a Biotage® SP HPFC system (Biotage, Charlottesville, VA USA) using Biotage SNAP cartridges (KP-C18-HS, 12 g). Linear gradients were run for 10- 30 minutes using a mixture of acetonitrile (Ultra Gradient HPLC grade, 0.1 vol% TFA) and purified water (from Millipore system, 0.1 vol% TFA) as eluent. Radio thin layer chromatography (Radio-TLC) was used to control complexation reactions with radioactive nuclides. Radioactive TLC plates were scanned by Scan-RAM radio-TLC detector from LabLogic Systems Inc. (Brandon, USA). Radioactivity of samples from in vitro and in vivo experiments was detected by a 2480 Wizard2gamma counter by PerkinElmer Inc. (Waltham, USA). All cell cultures (Jurkat, Chem-1 , 449 Mouse Lymphoma) were stored at 37°C, 5% CO2 in a HERAcell 150i-incubator from Thermo Fisher Scientific Inc. (Waltham, USA). Preparation of in vitro experiments and cell splitting were performed under sterile conditions in an MSC- Advantage safety cabinet from Thermo Fisher Scientific Inc. (Waltham, USA). Megafuge 1.0 from Heraeus Thermo Scientific (Darmstadt, Germany) was used for cell splitting and ultrafiltration of blood serum samples (using round bucket #75007570). The phase separation for the determination of lipophilicity and centrifugation of collected in animal experiments blood and urine was performed on a Biofuge 15 from Heraeus Sepatech (Osterode, Germany). Organ samples collected in metabolic stability studies were homogenized using a Retsch MM 400 ball mill by Retsch GmbH (Haan, Germany). Lyophilization was performed with an Alpha 1 .2 freeze-dryer from Christ (Osterode, Germany), connected to a RZ-2 rotary vane pump from Vacuubrand GmbH & Co. KG (Wertheim, Germany).

[0149] General synthetic procedures

[0150] Peptide Synthesis through Fmoc-Strategy

[0151] The peptides were synthesized following the solid phase peptide synthesis using the standard Fmoc-strategy. In a first step the / V-terminal Fmoc-protected amino acid (AA) was linked to the resin and was then Fmoc-deprotected. The same procedure repeats for the next AA except it was coupled to the previous AA. The Fmoc-protecting group was cleaved under basic conditions whereas the chosen sidechain protecting groups were cleaved under acidic conditions. a) 2-CTC Resin Coupling

[0152] As solid support during peptide synthesis 2-chlorotrityl chloride (2-CTC) resin (loading capacity (LC) = 1.6 mmol / g) was used. The respective AA 2.0 equivalents (eq.) was attached to the 2-CTC resin with 2,4,6-collidine (4.0 eq.) in DMF at room temperature (RT) for 2 hours. The residual free Cl-moieties were capped with MeOH for 15 minutes. The resin is washed with DMF (5 times) and DCM (3 times) before drying under reduced pressure over night. The new loading capacity was determined by weight using the following equation (equation 1).

[0153] ■ 1000 (1)

[0154] On-Resin Peptide Coupling b) Standard Amino Acid Coupling

[0155] The dried resin was swollen in DMF for 20 minutes. A solution of the corresponding AA (1.5 eq.), 2-(1 H-Benzotriazole-1 -yl)-1 , 1 ,3,3-tetramethyluronium tetrafluoroborate (TBTU, 1.5 eq.), 1-hydroxy-7-benzotriazole (HOAt, 1.5 eq.) and / V, / V-diisopropylethylamine (DIPEA, 4.0 eq.) in DMF were added to the resin-bound free amine peptide. After 2-3 hours of coupling at RT the resin was washed with DMF (5 times). It was additionally washed three times with DCM before drying under reduced pressure. c) p-Nosyl protection of terminal amines

[0156] 2,4,6-collidine (10.0 eq.) and p-nitrobenzenesulphonyl chloride (5.0 eq.) were dissolved separately in M-methyl-2-pyrrolidone (NMP, 1.54 pL / pmol dissolved reagent), added to the beads successively, and shaken for 30 minutes. Upon reaction completion, the resin was washed 3 times with NMP and 3 times with tetrahydrofuran (THF). d) a-A / -methylation

[0157] For the a-M-methylation of the p-NS-protected peptide, triphenylphosphine (5.0 eq.) and methanol (10.0 eq.) were dissolved in dry THF (3.08 pL / pmol dissolved reagent), added to the resin, and shaken for 10 minutes. Then, diisopropyl azodicarboxylate (DIAD, 5.0 eq.) dissolved in dry THF (3,08 pL / pmol) were added to the resin and the reaction mixture was shaken for another 1 h. Upon reaction completion, the resin was washed 4 times with THF. e) Peptide Coupling in Solution

[0158] A solution of the respective peptide (1.5 eq.), HATU (1 .5 eq.), HOAt (1.5 eq.) and DIPEA (4.0 eq.) in DMF were added to the free amine peptide dissolved in DMF. After 2-3 hours of stirring at RT the solvent was removed under reduced pressure f) Peptide Cyclization in Solution

[0159] DIPEA (6.0 eq) and HATU (0.1 eq.) were dissolved in DMF (100 pL / pmol peptide). HATU (3.0 eq.) and the respective peptide (1.0 eq.) were dissolved in DMF (100 pL / pmol peptide) separately and then slowly added to the reaction mixture (20 pL / min) under constant stirring. The reaction mixture was then stirred for another 20 minutes. Upon reaction completion, the solvent was removed in vacuo. On-Resin Cleavage of Protecting Groups g) A / a-Fmoc-deprotection

[0160] For the A / a-Fmoc-deprotection, the resin-bound AA / peptide was shaken in a solution of piperidine (20%) (v:v) in DMF for 10 minutes at RT. The deprotection procedure was repeated once for additional 15 minutes and the resin was washed 8 times with DMF. It was additionally washed three times with DCM before drying under reduced pressure if no further coupling was conducted. h) p-Nosyl deprotection

[0161] To cleave the p-Nosyl protecting group, 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 5.0 eq.) was dissolved in NMP (3.08 pL / pmol) and shaken with the resin beads for 10 minutes. Then, 2-mercaptoethanol (10.0 eq.) dissolved in NMP (3.08 pL / pmol) were added to the reaction mixture and shaken for 30 minutes. Upon reaction completion, the resin beads were washed 5 times with NMP. If further synthetic steps were planned, the resin was washed additional 3 times with DMF.

[0162] Cleavage of Protecting Groups in Solution

[0163] I) Fmoc-deprotection

[0164] The peptide dissolved in a solution of piperidine (20%) (v:v) in DMF was stirred for 20 minutes at RT or until no more protected peptide can be observed by ESI-MS and the solvent was removed under reduced pressure. j) Removal of Acid Labile Side Chain Protecting Groups

[0165] The peptide was dissolved in a solution of TFA and water (95:5) (v:v), and stirred for 1-2 hours before removing the solvents under nitrogen flow.

[0166] Peptide Cleavage k) Resin Cleavage under Retention of Protecting Groups

[0167] For the cleavage under retention of protecting groups, a solution of HFIP in DCM (1 :4) (v:v) was added to the resin-bound peptide for 1 .5 hours at RT. The solution was captured, the deprotection procedure was repeated once for 1.5 hours and the resin was washed 3 times with DCM. The solvents were removed under nitrogen flow.

[0168] Synthetic procedures and characterization

[0169] Synthesis of Fmoc-2-Nal-NH2

[0170] Fmoc-2-Nal-OH (1.0 eq), N,N'-Diisopropylcarbodiimide (DIC) (1.2 eq) and HOAt (1.2 eq) were dissolved in DMF (5 mL / mmol) and preactivated for 5 minutes. NH3 H2O (25% solution in water, 1.2 eq) were added subsequently, and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by flash chromatography (50-90% MeCN in H2O, tR = 6.5 min) and freeze-dried under vacuum to deliver the desired product.

[0171] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mLlmin) tR= 12.7 min, k' = 6.47.

[0172] MS (ESI, positive): calculated monoisotopic mass for C28H24N2O3: 436.18; found by ESI-MS: m / z = 437.1 [M+H]+.

[0173] Synthesis of Fmoc-2-Nal-C(=NH)-OEt

[0174] Et3O BF4 (1.1 eq.) was dissolved in dry DCM (20 mL / mmol AA) and cooled down to 0 °C. Fmoc-2-Nal-NH2 (1.0 eq.) were slowly added to form a white suspension, and the reaction mixture was stirred overnight. 10 mL water were added, and the product was extracted with DCM (3 x10 mL). The combined organic phases were dried over MgSO4, and the solvent was removed in vacuo. The raw product was obtained in form of a white solid and was used directly without further purification.

[0175] MS (ESI, positive): calculated monoisotopic mass for C30H28N2O3: 464.21 ; found by ESI-MS: m / z = 465.3 [M+H]+.

[0176] Synthesis of H2N-G-y(fBu)-N(Me)-orn(Boc)-R(Pbf)-OH

[0177] Fmoc-Arg(Pbf)-OH (2.0 eq.) was loaded according to (a). Fmoc-orn(Boc)-OH was Fmoc-deprotected following (g) and subsequent / V-methylation was performed following (c), (d), (h). Fmoc-tyr(fBu)-OH, and Fmoc-Gly-OH (1.5 eq. each) were coupled and Fmoc-deprotected according to (b), (g). After the last amino acid was coupled, the peptide was Fmoc-deprotected (g) and cleaved off the resin according to (k). The crude product was directly used without further purification.

[0178] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mLlmin)-. tR= 8.3 min, k' = 3.37.

[0179] MS (ESI, positive): calculated monoisotopic mass for C45H70N8O11S: 930.49; found by ESI-MS: m / z = 931.4 [M+H]+.

[0180] Synthesis of H2N-G-y(fBu)-R(Pbf)-R(Pbf)-OH

[0181] Fmoc-Arg(Pbf)-OH (2.0 eq.) was loaded according to (a). Fmoc-Arg(Pbf)-OH, Fmoc-tyr(tBu)- OH, Fmoc-Gly-OH (1.5 eq. each) were Fmoc-deprotected and coupled according to (b), (g). After the last amino acid was coupled, the peptide was Fmoc-deprotected (g) and cleaved off the resin according to (k). The crude product was directly used without further purification.

[0182] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mLlmin)-. fe = 9.7 min, k' = 4.39. MS (ESI, positive): calculated monoisotopic mass for C53H78N10O12S2: 1110.5; found by ESIMS: m / z = 1111.6 [M+H]+.

[0183] Synthesis of Fmoc-2-Nal-C(=NH)-G-y(tBu)-N(Me)-orn(Boc)-R(Pbf)-OH

[0184] H2N-Gly-tyr(tBu)- / V(Me)-orn(Boc)-Arg(Pbf)-OH (1.0 eq.) and Fmoc-2Nal-C(=NH)-OEt (2.0 eq.) were dissolved in dry 1 ,4-dioxane (10 mL / mmol peptide) and stirred under reflux in argon atmosphere for 20 minutes. The solvent was removed in vacuo and the crude mixture was purified by preparative RP-HPLC (60-90 vol% MeCN in H2O in 20 min, fa = 17.5 min). The product was obtained in form of a white solid (92% yield).

[0185] RP-HPLC (30-90 vol% MeCN / l-bO, 15 min, Multokrom 100-5 C18, 1 mLlmin)'. fa = 15.5 min, k'= 7.63.

[0186] MS (ESI, positive): calculated monoisotopic mass for C73H92N10O13S: 1348.66; found by ESIMS: m / z = 675.7 [M+2H]2+.

[0187] Synthesis of Fmoc-2-Nal-C(=NH)-G-y(tBu)-R(Pbf)-R(Pbf)-OH

[0188] H2N-Gly-tyr(fBu)-Arg(Pbf)-Arg(Pbf)-OH (1.0 eq.) and Fmoc-2Nal-C(=NH)-OEt (2.0 eq.) were dissolved in 1 ,4-dioxane (10 mL / mmol peptide) and stirred under reflux for 20 minutes. The solvent was then removed in vacuo and the crude mixture was purified by preparative RP- HPLC (60-90% MeCN in H2O in 20 min, fa = 17.5 min). The product was obtained in form of a white solid (89% yield).

[0189] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mLlmin)'. fa = 14.5 min, k' = 7.05.

[0190] MS (ESI, positive): calculated monoisotopic mass for C81H100N12O14S2: 1528.69; found by ESIMS: m / z = 765.8 [M+2H]2+.

[0191] Synthesis of cyclo[2-Nal-C(=NH)-G-y-N(Me)-orn-R-] (CPCR4A)

[0192] Fmoc-2Nal-C(=NH)-Gly-tyr(tBu)- / V(Me)-orn(Boc)-Arg(Pbf)-OH (1.0 eq.) was Fmoc- deprotected following (i), purified via HPFC (high performance flash chromatography, 30-90% MeCN in H2O over 30 min) and cyclized according to the general procedure (f). Side chain deprotection was performed following (j). The crude mixture was purified. Racemization at the Arginine site was observed upon intra molecular cyclisation, so that the two formed isomers were separated by preparative RP-HPLC (25-60 vol% MeCN in H2O in 1 h, fa = 9.0 min). Each of the CPCR4A isomers (CPCR4A(1) and CPCR4A(2)) was obtained in the form of a white solid (23% overall yield).

[0193] RP-HPLC (10-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mLlmin)'. fa = 5.3 min, k' = 1.79. MS (ESI, positive): calculated monoisotopic mass for C36H48N10O5: 700.85; found by ESI-MS: m / z = 351.8 [M+2H]2+.

[0194] Synthesis of cyclo[2-Nal-C(=NH)-G-y-R-R-] (FCA004)

[0195] Fmoc-2Nal-C(=NH)-Gly-tyr(tBu)-Arg(Pbf)-Arg(Pbf)-OH (1.0 eq.) was Fmoc-deprotected following (i), purified via HPFC (30-90% MeCN in H2O over 30 min) and cyclized according to the general procedure (f). Side chain deprotection was performed following (j). The crude mixture was purified by preparative RP-HPLC (25-60 vol% MeCN in H2O in 1 h, fa = 9.0 min). FCA004A was obtained form of a white solid (26%).

[0196] RP-HPLC (10-60 vol% MeCN / FW, 15 min, Multokrom 100-5 C18, 1 mL / min)-. fa = 7.4 min, k' = 1.96.

[0197] MS (ESI, positive): calculated monoisotopic mass for C36H48N12O5: 728.86; found by ESI-MS: m / z = 729.7 [M+H]+.

[0198] Synthesis of cyclo[2-Nal-G-y-N(Me)-orn-R-] (CPCR4)

[0199] Fmoc-Gly-OH (2.0 eq.) was loaded according to (a) and Fmoc-deprotected following (g). Fmoc-2-Nal-OH, Fmoc-Arg(Pbf)-OH and Fmoc-orn(Boc)-OH were coupled successively according to (b), (g) and subsequent / V-methylation was performed following (c), (d), (h). Fmoc-tyr(fBu)-OH was coupled and Fmoc-deprotected according to (b), (g). The peptide was cleaved off the resin according to (k), cyclized following (f) and final deprotection was performed according to (j). The crude product was purified via RP-HPLC (25-60% MeCN in H2O in 30 min). CPCR4 was obtained in form of a white solid (88%).

[0200] RP-HPLC (10-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min) fa = 6.2 min, k' = 1.48.

[0201] MS (ESI, positive): calculated monoisotopic mass for C36H47N9O6: 701.36; found by ESI-MS: m / z = 351.9 [M+2H]2+, 702.4 [M+H]+.

[0202] Synthesis of cyclo[2-Nal-G-3-iodo-y-N(Me)-orn-R-] (I-CPCR4)

[0203] 1 .0 eq CPCR4 were dissolved in MeCN:H2O (1 :1 , v:v). 0.5 eq / V-iodosuccinimide were added, and the reaction mixture was stirred for 5 minutes before purification by preparative RP-HPLC (20-50 vol% MeCN in H2O in 1 h, fa = 12.6 min) to deliver the desired product in form of a white solid (yield 16%).

[0204] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min)-. fa = 3.5 min, k' = 0.84.

[0205] MS (ESI, positive): calculated monoisotopic mass for C36H46IN9O6: 827.26; found by ESI-MS: m / z = 827.6 [M+H]+. Synthesis of cyclo[2-Nal-G-y-R-R-] (FC131)

[0206] Fmoc-Gly-OH (2.0 eq.) was loaded according to (a) and Fmoc-deprotected following (g). Fmoc-2-Nal-OH, two times Fmoc-Arg(Pbf)-OH and Fmoc-tyr(tBu)-OH were coupled successively according to (b), (g). The peptide was cleaved off the resin according to (k), cyclized following (f) and final deprotection was performed according to (j). The crude product was purified via RP-HPLC (30-65% MeCN in H2O in 30 min). FC131 was obtained in form of a white solid (86%).

[0207] RP-HPLC (10-60 vol% MeCN / l-teO, 15 min, Multokrom 100-5 C18, 1 mLlmiri)'. fa = 8.6 min, k' = 2.44.

[0208] MS (ESI, positive): calculated monoisotopic mass for C36H47N11O6: 729.37; found by ESI-MS: m / z = 365.8 [M+2H]2+, 730.5 [M+H]+.

[0209] Synthesis of H2N-AMBA-CPCR4A(1)

[0210] Fmoc-AMBA-OH (1.1 eq.) was coupled to CPCR4A(1 ) (1.0 eq.) according to the general procedure (e). The solvent was then removed in vacuo, and the crude mixture was purified by preparative RP-HPLC (20-60 vol% MeCN in H2O in 1 h, fa = 7.6 min) to deliver the desired product in form of a white solid (yield 79%).

[0211] RP-HPLC (10-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min): fa = 6.8 min, k' = 2.58.

[0212] MS (ESI, positive): calculated monoisotopic mass for C44H55N11O6: 833.43; found by ESI-MS: m / z = 834.1 [M+H]+.

[0213] Synthesis of H2N-AMBA-CPCR4

[0214] Fmoc-AMBA-OH(1.1 eq.) was coupled to CPCR4 (1 .0 eq.) according to the general procedure (e). The solvent was then removed in vacuo, and the crude mixture was purified by preparative RP-HPLC (20-60 vol% MeCN in H2O in 1 h, fa = 8.2 min) to deliver the desired product in form of a white solid (66% yield).

[0215] RP-HPLC (30-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min)'. fa = 7.7 min, k' = 3.05.

[0216] MS (ESI, positive): calculated monoisotopic mass for C44H54N10O7: 834.42; found by ESI-MS: m / z = 834.8 [M+H]+.

[0217] Synthesis of DOTA-AMBA-CPCR4A(1) (PentaxaFor)

[0218] 2,2’,2”,2”’-(1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetrayl)tetraacetic acid (DOTA) hexahydrate(4.0 eq.), A / -hydroxysuccinimide (NHS, 5.0 eq.)), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDCI, 5.0 eq.), and DIPEA (8.0 eq.) were dissolved in H2O (3 mL per mmol peptide) and pre-activated for 30 min. H2N-AMBA-CPCR4A(1) (1.0 eq.) was dissolved in DMF (3 mL per mmol peptide), and was slowly added to the reaction mixture under vigorous stirring. Upon reaction completion, the solvent was removed in vacuo, and the crude mixture was purified via preparative RP-HPLC (20-60 vol% MeCN in H2O in 1 h, JR = 5.7 min). The product was obtained in form of a white solid (46% yield).

[0219] RP-HPLC (10-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min) tR= 5.7 min, k' = 2.00.

[0220] MS (ESI, positive): calculated monoisotopic mass for C60H81N15O13: 1219.6; found by ESI-MS: m / z = 610.3 [M+2H]2+, 1219.7 [M+H]+.

[0221] Synthesis of DOTA-AMBA-CPCR4 (PentixaFor)

[0222] DOTA hexahydrate (4.0 eq.), NHS (5.0 eq.), EDCI (5.0 eq.), and DIPEA (8.0 eq.) were dissolved in H2O (3 mL per mmol peptide) and pre-activated for 30 minutes. H2N-AMBA- CPCR4 (1 .0 eq.) was dissolved in DMF (3 mL per mmol peptide) and was slowly added to the reaction mixture under vigorous stirring. Upon reaction completion, the solvent was removed in vacuo, and the crude mixture was purified via preparative RP-HPLC (20-60 vol% MeCN in H2O in 1 h, JR = 13.3 min). The product was obtained in form of a white solid (50% yield).

[0223] RP-HPLC (10-90 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min): tR= 6.3 min, k' = 2.32.

[0224] MS (ESI, positive): calculated monoisotopic mass for CeoHsoN-uO-u: 1220.6; found by ESI-MS: m / z = 610.7 [M+2H]2+, 1220.9 [M+H]+.

[0225] Synthesis of DOTA-AMBA-I-CPCR4 (PentixaTher)

[0226] PentixaTher was obtained via the iodination of the purified PentixaFor scaffold. PentixaFor (1 .0 eq.) was dissolved in MeCN:H2O (1 :1, v:v). / V-iodosuccinimide (0.5 eq.) was added, and the reaction mixture was stirred for 5 minutes before purification by preparative RP-HPLC to deliver the desired product in form of a white solid.

[0227] RP-HPLC (15-45% MeCN / H2O in 15 min): tR= 10.60 min, k' = 4.30.

[0228] MS (ESI, positive): calculated monoisotopic mass for C60H79IN14O14: 1346.59, found by ESI-MS: m / z = 1347.7 [M+H]+, 676.2[M+2H]2+.

[0229] Cold-labeling methods

[0230] Unlabeled tracer stock solution (2 mM in dimethyl sulfoxide (DMSO) or TP-H2O, 1 .0 eq.) and the respective metal salt (20 mM in TP-H2O, 3.0 eq.) were mixed in a Lo-Bind tube and diluted with dry DMSO (final ligand concentration 1 mM) and stirred 30 min at 80°C. The new stock solution was diluted with HBSS to create the desired dilution series.

[0231] [na‘Lu]Lu-PentaxaFor: RP-HPLC (10-60 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min): tR= 7.6 min, k' = 3.00.

[0232] MS (ESI, positive): calculated monoisotopic mass for CBOHZSN-ISO-ISLU: 1391.5; found by ESIMS: m / z = 696.4 [M+2H]2+, 1392.1 [M+H]+.

[0233] [natGa]Ga-PentaxaFor:

[0234] RP-HPLC (10-60 vol% MeCN / FW, 15 min, Multokrom 100-5 C18, 1 mL / min): tR = 7.5 min, k' = 2.95.

[0235] MS (ESI, positive): calculated monoisotopic mass for CeoH / gNisO Ga: 1286.52; found by ESIMS: m / z = 644.3 [M+2H]2+, 1286.7 [M+H]+.

[0236] [natY]Y-PentaxaFor:

[0237] RP-HPLC (10-60 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min): tR = 7.6 min, k' = 3.00.

[0238] MS (ESI, positive): calculated monoisotopic mass for C60H78N15O13Y: 1305.50; found by ESIMS: m / z = 653.6 [M+2H]2+, 1305.4 [M+H]+.

[0239] Radio labelling

[0240] Labelling with Lu-177

[0241] 1 nmol of unlabelled tracer was dissolved in 10 pL of aqueous 1 M NaOAc solution (pH=5.4). 10-60 MBq [177Lu]LuCh in aqueous 0.04 M HCI solution were added, and the reaction mixture was diluted with 0.04 M HCI solution to 100 pL total volume and heated to 75-80°C for 15 min. Labelling with Ga-68

[0242] 1 nmol of unlabelled tracer was dissolved in 10 pL of aqueous 0.2 M NaOAc solution (pH=4.0). 10-40 MBq of [68Ga]GaCl3 in aqueous 0.04 M HCI solution were added (1 :1 , v:v), and the reaction mixture was heated to 75-80°C for 15 minutes.

[0243] Labeling with Cu-64

[0244] 1 nmol of unlabelled tracer was dissolved in 10 pL of aqueous 1 M NaOAc solution (pH=5.4). 20-50 MBq [64Cu]CuCh in 0.1 M HCI were added and the reaction mixture was heated to 80 °C for 15 min.

[0245] Radiochemical purities were determined by radio-RP-HPLC (10-60 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / min) and Radio-TLC (iTLC: 0.1 M Na2HCit-5H2O in H2O, NP-silica: 1 M NH4OAC / DMF (1 :1 , v:v)).

[0246] Radioiodination of aromatic side chains with [125l]Nal

[0247] The respective peptide (1.0 eq.) was dissolved in 20 pL DMSO. 280 pL TRIS iodination buffer (25 mM Tris- HCI, pH=7.5, 0.4 M NaCI) were added, and the solution was transferred into an iodogen-coated (2.0 eq.) Lo-Bind tube. 10.0-30.0 MBq [125l]Nal (~0.01-0.02 eq.) in aqueous 0.04 M NaOH were added to the reaction mixture. After 15 minutes at room temperature, the crude mixture was removed from the iodogen-coated tube and then purified by preparative Radio-RP-HPLC (20-45 vol% MeCN in H2O in 20 min).

[0248] Lipophilicity

[0249] 0.5-1.0 MBq of the respective radio ligand were diluted to 500 pL with PBS (without Ca2+and Mg2+, pH=7.4) and 500 pL 1 -octanol were added. The solution was vortexed for 3 min at 3000 rpm, followed by centrifugation (5000 rpm, 5 min). The activity in 100 pL aliquots of each phase was measured in a y -counter. hCXCR4 affinity

[0250] For affinity assays Jurkat cells were resuspended in HBSS (Hanks’ balanced salt solution, +1% BSA). 200 pL of the suspension (400.000 cells) were incubated with 25 pL of the reference radio ligand [125I]I-FC131 (400.000 cpm / 25 pL) and 25 pL of the competitor at different concentrations (lO^-IO-10M), 25 pL HBSS (1% BSA) for the control experiment, respectively. After 2 hours at 4-9 °C temperature, the incubation was terminated via centrifugation (1300 rpm, 3 min.). The cell pellets were washed with HBSS (w 0.35 glL NaHCOa, w Ca2+, w Mg2+, w / o Phenol red) and centrifuged, twice each. Radioactivity for both supernatant / wash and the cell bound fraction was determined by a y-counter. The experiment was performed in triplicate with n = 3 per concentration. IC50 values were calculated using GraphPad Prism (Graph Pad Software, San Diego, USA).

[0251] Binding and internalization kinetics

[0252] Chem-1 cells were sowed on 24-well plates (100.000 cells / well in 1 mL cultivation medium)

[0253] 24 ± 2 h prior to the internalization experiment.

[0254] The cultivation medium was removed from the well plates before adding 200 pL assay medium (DMEM + 5% BSA). The cells were incubated for 15 minutes (37 °C, 5% CO2) before adding

[0255] 25 pL DMEM + 5% BSA (specific cell binding) and 10 mM AMD in tp-H2O (non-specific cell binding), respectively. 25 pL of a radio ligand mixture (20 nM [125I]I-FC131 , 20 nM solution of the respective radio ligand both in PBS (1 :1 , v:v) were added (final radio ligand concentration was 1 nM each). After 10 min, 30 min, 60 min and 120 min time of incubation (37 °C, 5% CO2), respectively, the supernatant was removed on ice and the cell layer was washed with cold PBS (200 pL) once. The cell layer was treated with 200 pL acid-wash (0.9 wt.% NaCI, 50 mM NaOAc in H2O, pH 4.5) at 0 °C for 15 min, the supernatant was collected and the cells were washed with additional 100 pL acid-wash. The cells were lysed with a 1 M NaOH solution (300 pL) for at least 20 min and washed with 300 pL 1 M NaOH solution. The collected supernatants, cell bound fractions and the cell lysates were quantified in a y-counter to obtain the cellular activity [%] of the total specific cell bound activity for the radio labeled ligand in reference to [125I]I-FC131.

[0256] Binding to human / murine blood cells and serum protein binding

[0257] To 176 pL samples of EDTA whole blood from a healthy donor (human whole blood study) or citrate whole blood from healthy female CD1 mice (murine whole blood study), 4 pL of PBS (n=3, total binding) or 4 pL 10 mM AMD3100 in tp-l-fcO (n=3, non specific binding) were added before the addition of 20 pL of the respective radio ligand (0.5 nmol / mL PBS). After 15 min incubation at RT the erythrocytes were separated by centrifugation (700 g, 5 min) and washed twice with 200 pL PBS. The combined supernatants were then centrifuged (6200 g, 5 min) and the residue of leucocytes and pellets was washed once with 200 pL PBS. The activity in each fraction was determined using a y -Counter.

[0258] For the determination of serum protein binding, 55 pL of the respective radio-labelled ligand (20.0 MBq / pL in PBS) were added to 495 pL of PBS (unspecific interactions), 700 nM human serum albumin (HSA) solution in PBS, human and murine blood serum, respectively, and the mixture was incubated for 30 minutes at 37°C. After incubation, 250 pL aliquots were transfered into Centrifree® Ultracel® PL Regenerated Cellulose ultracentrifugation filter tubes and were centrifuged for 40 minutes at 3000 RPM. Radioactivity of the respective filtrates and supernatants was measured in a y -Counter.

[0259] In vitrolin vivo stability determination

[0260] In vitro

[0261] 2.5-3.0 MBq of the radio ligand were added to 200 pL of human serum from a healthy donor or murine serum collected from healthy CB17-SCID mice and was incubated at 37°C for 1 , 24 and 64 h, respectively. Proteins were then precipitated by addition of 150 pL cold ethanol (0°C) and 450 pL cold acetonitrile (0°C) and separated by centrifugation (5000 RPM, 20 min). The supernatant was collected and centrifuged (5000 RPM, 10 min) using a Costar® Spin-X® centrifuge tube filter (0.45 pm). The filtrate was analyzed by radio-RP-HPLC.

[0262] In vivo

[0263] The studies on living mice were performed after approval by the responsible authorities and were in compliance with the German animal welfare act. Biodistribution of the respective radioligand was determined in Jurkat tumor bearing female CB17-SCID mice. 2.0-5.0 MBq of the radio ligand (total volume 120 pL in saline containing 5% ethanol) were injected into the tail vein of the mice (n = 3, 4-10 weeks, under isoflurane anesthesia), which were then sacrificed 1 h p.i. Urine and blood were collected and centrifuged (5 min, 5000 RPM, 13000 g). Separated blood serum was loaded onto a StrataX cartridge (500 mg, pre-conditioned with 5 mL MeOH and 5 mL tp-FW), washed with 5 mL tp-H2O and eluted with MeCN / tp- W (6:4, v:v, +1% TFA). Liver and kidneys were dissected and collected separately and were homogenized together with 1 mL extraction buffer (HEPES pH=7.4, 20 mM AMD3100 in tp- W, 1 M NaCI in tp-FW, 8:1:1, v:v:v) for 10 min in a ball mill (steel balls d = 3 mm, ceramic balls d = 1 mm). The homogenate was then centrifuged (5 min, 5000 RPM), the supernatant was collected, another 1 mL extraction buffer was added, and the homogenization was repeated once more. The combined supernatants were loaded onto a StrataX cartridges (500 mg, pre-conditioned with 5 mL MeOH and 5 mL tp-l-fcO, per mouse 1 cartridge for both kidneys and 3 for the liver), washed with 5 mL tp-l-fcO and eluted with MeCN / tp-l-hO (6:4, v:v, +1% TFA). The radio activity of the respective eluates and cartridges were then measured by a y-counter to quantify the elution efficiencies. Eluates were further analyzed by Radio-RP- HPLC (10-60 vol% MeCN / H2O, 15 min, Multokrom 100-5 C18, 1 mL / miri).

[0264] Results

[0265] Preclinical data revealed significant improvements regarding target affinity, internalization efficiency and hydrophilic profile of a representative ligand compound in accordance with the invention, PentaxaFor (DOTA-Amba-CPCR4A(1)), and of its metal chelates. The following formula illustrates the structure of a PentaxaFor ligand in a labeled form including a chelate complex formed by its chelating group with an exemplary metal cation M (“M-PentaxaFor”). Table 1. IC50 and logD?.4 values of different CXCR4-addressing ligands. Data is given as means ± SD (n=3 for IC50, n>6 for logD). Affinities were determined against [125l] l-FC 131 in a Jurkat cell-based assay.

[0266] Compound IC50 [nM] logD7.4

[0267] PentaxaFor 27.3 ± 7.6 /

[0268] [Ga]-PentaxaFor 2.7 ± 0.4 -3.7 ±0.04

[0269] [Cu]-PentaxaFor 23.2 ± 4.5 -3.0 ± 0.02

[0270] [Lu]-PentaxaFor 11 .9 ± 0.9 -3.3 ± 0.03

[0271] [Y]-PentaxaFor 9.7 ± 0.6 /

[0272] PentixaFor* 102 ± 16™ /

[0273] [Ga]- PentixaFor* 24.8 ± 2.5™ -2.9 ± 0.1 ™

[0274] [Cu]- PentixaFor* 131 ± 11™ -2.0 ± 0.01

[0275] [Lu]- PentixaFor* 40.9 ± 12M -2.6 ± 0.02

[0276] [Y]- PentixaFor* 40.8 ± 27M /

[0277] PentixaTher* 35.8 ± 13™ /

[0278] [Lu]- PentixaTher* 14.6 ± 1 .0™ -1 .8 ± 0.2M

[0279] [Y]- PentixaTher* 20.4 ± 0.3™ /

[0280] FC131* 6.7 ± 1.5 -0.4 ± 0.01™

[0281] CPCR4* 9.9 ± 1.1 -0.9 ± 0.01™

[0282] FCA004*(D 3.3 ± 0.4 -1 .6 ± 0.02™

[0283] CPCR4A*(D 4.3 ± 1.2 -1 .9 ± 0.06™

[0284] CPCR4A*(2) 5.7 ± 0.8 /

[0285] [a] Data determined with125l-labelled derivative, [b] Data taken from literature (40, 41) * reference compound.

[0286] Figure 1 illustrates in part (A) IC50 values of a CXCR4-addressing ligand in accordance with the invention, and prior art ligands in comparison. In part (B), logD™ values are shown for the ligands.

[0287] Figure 2 (A) shows the internalization efficiency, defined as the amount of internalized compound of the specific bound fraction, values are referenced to I-FC131 and thus are given in [%FC131]. In (B) the specific cellular uptake determined on stable CXCR4 transfected Chem-1 cells is shown.

[0288] In Figure 3 (A) shows the results of time dependent stability studies of the respective radio labelled ligands in murine serum (ms) and human (hs) are illustrated. (B) shows the results of stability studies in healthy CB17-SCID mice 1 h p.i. As previously mentioned, for PentixaFor restrictions regarding hCXCR4 affinity were found upon metal complexation, limiting its application to diagnostic purposes. In contrast, PentaxaFor maintained high affinity upon Lu- and Y-complexation, superior to both PentixaFor and especially its therapeutic counterpart PentixaTher (DOTA-Amba-CPCR4(3-l-tyr)). While the complexation of PentaxaFor with lutetium-177 results in a confined improvement compared to [177Lu]Lu-PentixaTher, the incorporation of yttrium is found to boost CXCR4 affinity below 10 nM, i.e., an affinity twice as high as determined for [90Y]Y-PentixaTher. In addition, a significantly increased hydrophilic profile is found for [177Lu]Lu-PentaxaFor, analogous to [68Ga]Ga-PentaxaFor (-3.32±0.03 vs. -1.76±0.20 for [177Lu]Lu-PentaxaFor and [177Lu]Lu-PentixaTher, respectively). This illustrates the unprecedented potential of the ligand compounds in accordance with the invention for targeted radioligand therapy.

[0289] Results of human studies

[0290] [68Ga]Ga-PentaxaFor was selected for a first proof-of-concept study in a patient suffering from follicular lymphoma grade1 / 2 (Figure 4) The respective PET images were acquired 10-240 min after injection. Overall, higher TBR are observable for [68Ga]Ga-PentaxaFor as compared to [68Ga]Ga-PentixaFor. Most importantly, the capability of [68Ga]Ga-PentaxaFor to clear quickly from non-target tissues based on its optimized pharmacokinetic profile is a significant contributor to its high-contrast PET images, enabling imaging at earlier time points with even higher TBRs compared to [68Ga]Ga-PentixaFor (10 min with [68Ga]Ga-PentaxaFor vs. 1 h with [68Ga]Ga-PentixaFor). A low blood pool uptake and fast renal excretion of [68Ga]Ga- PentaxaFor was observed.

[0291] From a clinical perspective, the fast clearance of [68Ga]Ga-PentaxaFor, allowing imaging after a period as short as 10 minutes after injection promises great potential for optimization of the daily routine workflow in a hospital PET center.

[0292] A total of 13 patients have been evaluated and supported the initial findings of high TBR enabling high contrast imaging at very early time points post injection. The evaluated patients were suffering from different types of malignancy such as follicular lymphoma, marginal zone lymphoma, chronic lymphatic leukaemia and lung carcinoma as well as endocrine disorders (aldosterone-producing adrenal adenoma), respectively, highlighting the versatile applicability of [68Ga]Ga-PentaxaFor. In the field of endocrinology, CXCR4-directed imaging becomes increasingly important in the diagnostic work-up of primary hyperaldosteronism (PA), which is the most common cause of secondary arterial hypertension. High CXCR4 expression has been reported for aldosterone- producing cells in APA; allowing for non-invasive characterisation by PET imaging. Given their high receptor affinity, the ligand compounds in accordance with the invention can be expected to provide a high sensitivity for the detection of CXCR4-expressing lesions greater than that of the current benchmark [68Ga]Ga-PentixaFor, especially in small adrenal lesions that might be missed by the other imaging techniques. Figure 5 illustrated the encouraging results that have been obtained for [68Ga]Ga-PentaxaFor.

[0293] Furthermore, higher contrast imaging of inflammatory diseases can be envisaged using the ligand compounds in accordance with the invention such as [68Ga]Ga-PentaxaFor as the high target affinity is expected to provide sufficient tracer accumulation even in areas of low CXCR4 expression. This concept is especially appealing in conditions such as vasculitis but also myocardial infarction or sarcoidosis.

[0294] Regarding potential therapeutic applications, the high bone marrow uptake the ligand according to the invention ([68Ga]Ga-PentaxaFor) as demonstrated in Figure 6 is further noteworthy, showing the high potential of the ligand compounds in accordance with the invention in the setting of a therapy for hematologic diseases such as acute leukemia, lymphoma or multiple myeloma. In all entities, CXCR4 represents an attractive target for radioligand therapy since the receptor is overexpressed on the tumor cell surface. Chemokine- receptor directed therapy using a ligand in accordance with the invention, such as [90Y]Y-PentaxaFor, could therefore address multiple rationales: First, endoradiotherapy can directly target and kill the respective tumor cell. Second, since the bone marrow niche plays an important role in disease progression of hematologic diseases and CXCR4 is also expressed on hematopoetic stem and progenitor cells present in high numbers in the bone marrow, it can eradicate the tumor-supporting bone marrow niche and thus, third, ameliorate the efficacy of “conventional” tumor therapies including chemotherapy and other targeted therapies. In all instances, the high receptor affinity of the ligand compounds in accordance with the invention suggest a significant improvement of the current therapeutic standard; e.g. in (CXCR4-positive) acute leukemia. Based on the results shown in Figure 6, it is conceivable that the use of a radioligand in accordance with the invention, such as well tolerated [90Y]Y-PentaxaFor, in combination with conditioning chemotherapy can achieve a deeper bone marrow response as compared to chemotherapy alone. If used therapeutically, the high receptor affinity of the compounds in accordance with the invention might result in a profound bone marrow ablation, a highly desirable effect in hematologic diseases scheduled for stem cell transplantation.

[0295] Brief Description of the Figures:

[0296] Figure 1 : A) IC50 values of different CXCR4-addressing ligands. Data is given as means ± SD (n=3), Affinities were determined against [125I]I-FC131 in a Jurkat cell-based assay; B) logD?.4 values. Data is given as means ± SD (n^6); Data for PentixaFor and PentixaTher is taken from literature except logD?.4Of [64Cu]Cu- and [177Lu]Lu-PentixaFor, respectively.

[0297] Figure 2: Dual tracer internalization of the respective radio labelled ligands and the reference compound [125I]I-FC131 (assay concentration for each peptide 0.2 nM) into stable hCXCR4 transfected Chem-1 cells (100,000 cells / well, 37°C). A: internalization efficiency is defined as the amount of internalized compound of the specific bound fraction; B: specific cellular uptake determined on stable CXCR4 transfected Chem-1 cells; values are referenced to I-FC131 and thus are given in [%I-FC131].

[0298] Figure 3: A) Time dependent stability studies of the respective radio labelled ligands in murine serum (ms) and human serum (hs), data is given as means ± SD (n=3); B) Stability studies in healthy CB17-SCID mice 1 h p.i., samples were pooled before analysis (n>3).

[0299] Figure 4: Example of a patient with newly diagnosed follicular lymphoma (FL) grade 1 / 2 undergoing CXCR4-directed imaging with [68Ga]Ga-PentaxaFor. Already 10 minutes after intravenous injection of [68Ga]Ga-PentaxaFor (152 MBq; 20 pg), a favourable biodistribution with excellent lymphoma-to-background contrast of the abdominal FL lesion can be acknowledged.

[0300] Figure 5: Example of a patient with primary aldosteronism and equivocal results in computed tomography as well as adrenal vein sampling undergoing CXCXR4-directed imaging for diagnostic work-up. Given are a maximum intensity projection (left) as well as transaxial slices of CT (middle) as well as positron emission tomography (PET ; right). One hour after injection of [88Ga]Ga-PentaxaFor (152 MBq; 20 pg), intense tracer uptake of the right adrenal gland can be noted, highly consistent with presence of an aldosterone-producing adenoma.

[0301] Figure 6: Example of a patient with newly diagnosed adenocarcinoma of unknown primary. Beyond lymph node metastases and focal skeletal lesions consistent with osseous metastases (arrows in the maximum intensity projection at 10 minutes after tracer injection) a diffuse up- regulation of physiologic CXCR4 expression as a result of reactive bone marrow activation can be noted ([68Ga]Ga-PentaxaFor (143 MBq; 18 pg).

[0302] References:

[0303] In this specification, a number of documents including not only scientific journal articles but also patent applications and manufacturer’s manuals were cited (cf, e.g., the following list of references in this respect). The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents were incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

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Claims

1. Claims1. A compound of formula (I) or a salt thereof:whereinRB1represents hydrogen or iodine;RB2represents hydrogen or methyl;RB3represents a group -(CH2)m- with m being selected from 1 , 2, 3 and 4;L represents a divalent linking group, or is absent; andRCHrepresents (i) a chelating group or (ii) a chelate group comprising a chelated radioactive or non-radioactive metal cation.

2. The compound or salt in accordance with claim 1 , wherein RB1represents hydrogen, RB2represents methyl, and RB3represents a group -(CH2)3-.

3. The compound or salt in accordance with claim 1 or 2, wherein L is a divalent linking group which is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2, 3, 4 or 5 amino acid subunits.

4. The compound or salt in accordance with claim 1 or 2, wherein the residue -L-RCHis a residue of the formula (L-1):wherein n is 0 or 1 ;L1is absent or is a divalent linking group;RCHis as defined in claim 1; and the bond marked with the waved line attaches the residue to the remainder of the compound of formula (I).

5. The compound or salt in accordance with claim 4, which is a compound of formula (IA) or a salt thereof:RB1and RB2are defined as in claim 1 or 2;RCHis defined as in claim 1 ; n is 0 or 1; andL1is absent or is a divalent linking group.

6. The compound or salt in accordance with claim 4 or 5, wherein L1is absent or is a divalent linking group which is selected from a divalent amino acid unit and a divalent oligopeptide unit comprising 2, 3 or 4 amino acid subunits.

7. The compound or salt in accordance with any of claims 1 to 6, wherein RCHin formula (I) or (IA) represents(i) a chelating group which is provided by a chelating agent selected from the group consisting of diethylenetriaminepentamethylenephosphonic acid (EDTMP), diethylenetriaminepentaacetic acid (DTPA), bis(carboxymethyl)-1 ,4,8,11-tetraaza- bicyclo[6.6.2] hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4- (1,4, 8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]-,pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]- amino]pentyl]-N-hydroxybutandiamide (DFO), 1 ,4,7, 10-tetraazacyclododecane-1 ,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecan-N,N',N",N,"-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acidj-pentanedioic acid (DOTAGA or DOTA-GA),1.4.7.10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), N,N'- dipyridoxylethylendiamine-N,N'-diacetate-5,5,-bis(phosphate) (DPDP), ethylenediamine-N,N'- tetraacetic acid (EDTA), ethyleneglykol-O,O-bis(2-aminoethyl)-N,N,N',N,-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), 3-[3-[4-[5-(2- carboxyethyl)-2-hydroxyphenyl]-1,4-bis(carboxymethylamino)butyl]-4-hydroxyphenyl]- propanoic acid (HBED-CC), hydroxyethyldiaminetriacetic acid (HEDTA), l-(p-nitrobenzyl)-1.4.7.10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7- triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 4,11- bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (TE2A), 1 ,4,8,11- tetraazacyclododecane-1, 4, 8, 11 -tetraacetic acid (TETA), terpyridine-bis(methyleneamine) tetraacetic acid (TMT), 1 ,4,7,10-tetraazacyclotridecan-N,N',N",N",-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridil)methyl]-4,13- diaza-18-crown-6 (l-hmacropa), 4-amino-4-{2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro- pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo- 1 ,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2- carboxyethyl)phosphinic acid (TRAP), 2-(4, 7,10-tris(2-amino-2-oxoethyl)-1, 4,7,10-tetraazacyclododecan-1-yl)acetic acid (D03AM), 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10- tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)- 1 ,4,7,10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4- aminobenzyl)-3,6, 10,13,16,19-hexaazabicyclo[6.6.6]-eicosan-1 ,8-diamine (SarAr), 6-Amino- 6-methylperhydro-1 ,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), (6-pentanoic acid)-6- (amino)methyl-1 ,4-diazepine triacetate (DATA), pentadeca-1 ,4,7,10,13-penta- aminopentaacetic acid (PEPA), hexadeca-1 ,4,7,10,13,16-hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl)) carbamoyl]methyl}-7,10-bis (carboxymethyl)-1,4,7,10- tetraazacyclododec-1-yl) acetic acid (BPAMD), N (4-{[bis (phosphonomethyl)) carbamoyl] methyl}-7,10-bis(carboxymethyl)-nona-1 ,4,7-triamine triacetic acid (BPAM), 1 ,2-[{6- (carboxylate) pyridin-2-yl} methylamine] ethane (DEDPA, H2DEDPA), deferoxamine (DFO), deferiprone, (4-acetylamino-4-yl) {2-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4-dihydro-pyridin-2- ylmethyl) -carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1 ,6-dimethyl-4-oxo-1 ,4- dihydro-pyridin-2-ylmethyl)-amide] (CP256), YM103, tetraazycyclodecane-phosphinic acid (TEAP), 6,6'-[{9-hydroxy-1 ,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7- diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa2), 1 ,2-[{6- (carboxylato)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2- pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N'-bis(2-hydroxy-5- sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (HeSbbpen), triethylenetetramine- N,N,N',N",N"',N"'-hexaacetic (TTHA), 2-aminomethylpiperidine triacetic acid (2-AMPTA), 2-(N- (2-Hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), 4-nitro-2-hydroxybenzyl-2-{[(6)- trans-2-[benzyl(carboxymethyl)amino] cyclohexyl] (carboxymethyl)amino}acetic acid (RESCA), 6-carboxy-1, 4, 8, 11 -tetraazaundecane (N4), S-acetylmercaptoacetyltriglycine (MAG3) and S-acetylmercaptoacetyltriserine (MAS3), or(ii) a chelate group wherein any one of these chelating groups forms a chelate complex comprising a chelated radioactive or non-radioactive metal cation.

8. The compound or salt in accordance with claim 7, wherein RCHin formula (I) or (IA) represents(I) a chelating group which is provided by a chelating agent selected from the group consisting of 1 ,4,7,10-tetraazacyclododecan-N,N,,N",N,"-tetraacetic acid (DOTA), 2-[1 ,4,7,10- tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA or DOTA-GA), 1 ,4,7,10-tetrakis(carbamoylmethyl)-1 ,4,7,10-tetraazacyclododecane (DOTAM), 2-(4,7,10- tris(2-amino-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1-yl)acetic acid (DO3AM), 1 ,4,7- triazacyclononanetriacetic acid (NOTA) and 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)- 1 ,4,7-triazacyclononane (NODAGA), or(ii) a chelate group wherein any one of these chelating groups forms a chelate complex comprising a chelated radioactive or non-radioactive metal cation.

9. The compound or salt in accordance with claim 8, wherein RCHin formula (I) or formula (IA) represents a chelating group of formula (CH-1), or a chelate group wherein the chelating group of formula (CH-1) forms a chelate complex comprising a chelated radioactive or nonradioactive metal cation:

10. The compound or salt in accordance with any of claims 1 to 8, wherein the chelated metal cation is selected from cations of62Cu,64Cu,67Cu,66Ga,68Ga,67Ga,90Y,86Y,99mTc,152Tb,155Tb,161Tb,149Tb,177Lu,212Bi,213Bi,212Pb and225Ac, and from cations of nonradioactive isotopes of any of these metals.

11. The compound or salt in accordance with claim 10, wherein the chelated metal cation is a radioactive metal cation selected from cations of67Ga,68Ga,64Cu,177Lu and90Y.

12. A pharmaceutical composition comprising or consisting of one or more compounds or salts in accordance with any of claims 1 to 11.

13. The compound or salt in accordance with any of claims 1 to 11 for use as a medicament.

14. The compound or salt in accordance with any of claims 1 to 11 or the pharmaceutical composition of claim 12 or 13 for use in a method of diagnosis in vivo of a disease or disorder.

15. A method for the synthesis of a compound or salt of any of claims 1 to 11 which comprises:(i) a step of reacting a compound of the formula (S-2)RS5represents an alkyl group, preferably a C1-C6 alkyl group, more preferably ethyl; andRS6represents a protective group for an amino group, preferably a fluorenylmethoxycarbonyl protecting group (Fmoc); with a tetrapeptide of the formula (S-3)whereinRS7represents a protective group for a phenolic hydroxy group, preferably a t-butyl group;RS8represents a protective group for an amino group, preferably a t-butoxycarbonyl (Boc) group;RS9represents a protective group for a guanidino group, preferably a 2, 2, 4,6,7- pentamethyl-2,3-dihydrobenzofuran-5-sulfonyl (Pbf) group; andRB1, RB2and RB3are defined as in claim 1 or 2; to provide a pentapeptide containing an amidine bond; (ii) a step of cyclizing the pentapeptide provided in step (i) after deprotection of its N- terminal amino group to obtain a cyclic peptide containing an amidine bond.

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