Radiopharmaceutical somatostatin receptor ligands and their precursors.

Abstract

Novel SST receptor ligand compounds suitable for imaging and / or treating neuroendocrine tumors are provided. These SST receptor ligand compounds have an SST binding motif, 19 F 18 By isotopic exchange with F 18 may be labeled with F, or 18 It consists of a silicon fluoride acceptor group labeled with F, a chelating group suitable for forming a chelate with a radioactive or non-radioactive cation, and a hydrophilic amino acid unit or a sequence of such units.

Description

[Technical field]

[0001] This application relates to radiopharmaceutical somatostatin receptor ligands and their precursors. Summary of the Invention

[0002] Neuroendocrine tumors (NETs) are a heterogeneous group of malignant tumors that arise from the neuroendocrine system. This system is composed of neuroendocrine cells in a variety of different tissues, such as endocrine glands (pituitary gland, parathyroid gland, adrenal gland), pancreatic tissue, or endocrine cells located in the digestive and respiratory systems (diffuse endocrine system: lungs, gastrointestinal tract) [1]. NETs are rare entities with an incidence of 2–5 / 100,000 (0.5% of newly diagnosed malignancies per year), depending on the (ethnic) lineage of the patient. Tumors of the digestive tract are the most frequent, at 67%, followed by NETs of the respiratory system at 25%. Although the incidence may be low, the number of diagnosed entities has been increasing over the past three decades, as diagnostic methods have been optimized [1–4]. However, somatostatin receptor (SST) expression is not exclusive to neuroendocrine lung tumors, but is also a feature of some non-neuroendocrine carcinomas [5, 6].

[0003] Shortly after cloning, two classes or groups of SST receptors were identified based on their phylogeny, structural homology, and pharmacological properties: a) the first class was called SRIF1 and contained the receptor subtypes SST2, SST3, and SST5, and the other class was called SRIF2 and contained the other two recombinant receptor subtypes SST1 and SST4 [7]. G protein-coupled receptors SST 1~5SST2 is naturally expressed in neuroendocrine cells of various tissues, but is overexpressed in various types of NETs and other tumors as well as their metastases [8–10]. Therefore, SST receptors are attractive targets for clarifying the diagnosis, for example by applying positron emission tomography (PET)

[11] . The high density and frequency of SST2 expression has been found to play a major role in cancer diagnosis and treatment, which has led to the development of radiopharmaceuticals with high affinity for SST2 in general and various degrees of affinity for additional receptors [8, 11]. In addition, pan-ligands with high affinity for all five subtypes have been developed [6].

[0004] In the past decade, positron emission tomography (PET) has evolved as the primary imaging modality in nuclear medicine.

[12] Unlike computed tomography and magnetic resonance imaging, which provide detailed anatomical and morphological information, PET provides functional information, i.e., information about physiological and biochemical processes in the body, before the appearance of any gross or morphological abnormalities or potential clinical signs of disease.

[13]

[0005] In PET diagnosis, 68 Ga and 18 F is the currently most commonly used β + It is a (positron) emitting radionuclide. For complexation of gallium, chelators such as DOTA or NOTA are available. A novel method to introduce fluorine by isotope exchange using silicon fluoride acceptors (SiFA) can significantly improve the availability of 18F-labeled ligands

[14] . 68 Ga exhibits several beneficial properties. 68 Ga can also be produced by an on-site cyclotron, 68 The widespread availability of Ga is due to the availability of commercially available, easy-to-use 68 Ge / 68 Ga generator ( 68 Get;t 1 / 2= 270.8d). Such generators are often expensive and typically only provide up to 1.8 GBq per elution. 68 Provides Ga. Radioactive daughter nuclide 68 Ga is β + The positrons are highly abundant (89%) and highly energetically charged (E max (β + ) = 1.89 MeV), allowing good resolution in clinical scanners. The physical half-life of 68 min provides ample time for labeling, while labeling can be conveniently performed by complexation, with high radiochemical yields (RCY).

[0006] 18 F has always been the PET radionuclide of choice due to its nuclear properties. 68 Compared to Ga, 18 F has a higher positron abundance (97%β + ), β + The emitted energy is weaker (E max (β + )=0.64MeV), and has a longer half-life (t 1 / 2 = 109.8 min). This results in images with better resolution, especially when combined with small animal scanners, but also in clinical scanners. 68 Unlike Ga, 18 F production is from an on-site cyclotron or cyclotron site. 18 Current cyclotrons require a daily supply of F-fluoride at >10ci (370GBq). 18 Allows the generation of F-fluoride, thus 18 This allows for the large-scale production of F-radiopharmaceuticals and the treatment of large numbers of patients at significantly lower cost

[12] .

[0007] Towards tracers by the formation of carbon-fluorine bonds 18 In most cases, the introduction of F is achieved by using the leaving group [ 18Nucleophilic substitution of either aliphatic or aromatic groups with [F] fluoride takes place. Due to its low reactivity, activation of the fluoride anion in anhydrous polar aprotic solvents and high reaction temperatures are usually required. Elimination is therefore often observed, resulting in side reactions and undesired by-products, which require purification steps and reduce the RCY

[15] .

[0008] To circumvent the problems of traditional nucleophilic fluorination, novel methods for forming phosphorus-fluorine, silicon-fluorine, or boron-fluorine bonds have been developed. One promising method is the isotope exchange reaction of a silicon fluoride acceptor with 18 F labeling

[16] . Here, the focus was on silicon-fluorine compounds that have high stability under physiological conditions (plasma pH 7.4) and also allow rapid isotope exchange at room temperature. The compound di-tert-butylphenyl-fluorosilane and its derivatives were demonstrated to be particularly stable against defluorination in fluoride-free aqueous solutions. The stability was confirmed by the formation of a pentacoordinate intermediate, which eventually gives rise to S N It is based on the shielding effect of two sterically bulky tert-butyl substituents that efficiently inhibit the attack of the hydroxyl group at the Si position, which replaces the F in such compounds with OH in the base 2

[14] .

[0009] In contrast, the two tert-butyl groups are unable to prevent attack by small fluoride anions, resulting in the following SN2 base 19 F 18 Isotope exchange to F. 19 From F 18 Isotopic exchange to F is rapid even at room temperature, and high specific activity (>100 GBq / μmol) 18When F-fluoride is used, an RCY of 80–90% is obtained within 10–15 min at room temperature

[14] . Thus, di-tert-butylphenyl-fluorosilane and its analogues were named "silicone-based fluoride acceptors" (SiFAs). The first compounds containing the SiFA motif for effective coupling to peptides were para-(di-tert-butylfluorosilyl)benzoic acid (SiFA-benzoic acid) and para-(di-tert-butylfluorosilyl)benzaldehyde (SiFA-benzaldehyde). SiFA-benzaldehyde can be coupled to peptides via oxime ligation, while SiFA-benzoic acid can be converted to an active ester or activated in situ and act as an acylating agent at the N-terminus of peptides or at side chain amines of peptides to form peptide bonds

[17] . In a recent study by Niedermoser et al., the aldehyde moiety of SiFAlin is used to synthesize SiFAlinTATE. 18 F-labeled Tyr 3 The development of -octreotate analogues has been described [18, 19]. 18 F series SST tracer [ 18 F]SiFAlinTATE has attracted interest over the past few years [20, 21]. However, 68 Clinically established drugs such as Ga]DOTA-TATE 68 Compared to Ga-based ligands, their overall in vivo properties were less favorable [19, 20, 22].

[0010] One important drawback of oxime-based SiFA-radiopharmaceuticals generated via synthesized aldehydes is the equilibrium between the oxime product on the one hand and the extractables (free SiFA-aldehydes or SiFAlin-alhedydes and aminooxy conjugated peptides) on the other hand in aqueous solutions at pH 1.5-4.5. Thus, not surprisingly, the preactivated [ 18It was found that dissolving the SiFAlin precursor in a solution containing oxalic acid (necessary to adjust the alkaline pH) prior to isotope exchange with [F] fluoride resulted in the decomposition of the precursor

[23] .

[0011] [ka]

[0012] Thus, the present invention provides novel SiFA-based SST receptor ligand compounds suitable for imaging and / or treating neuroendocrine tumors. The SST receptor ligand compounds are composed of 1. SiFA-moieties, 2. chelators or chelates, and 3. hydrophilic amino acids / amino acid sequences. The latter two complement the high lipophilicity and partial binding of the SiFA components to human serum albumin (HSA) as relevant factors influencing in vivo parameters, such as blood clearance, extravasation and diffusion into tissues, such as tumor tissue, or routes of excretion, to name the most relevant. In addition, the amino acids / amino acid sequences modulate the net charge of the entire ligand, influencing the affinity of the ligand to the target. Through the adjustment of the SiFA components (e.g. addition of positive charges), the affinity of SiFA to HSA can be significantly lowered. All those parameters (lipophilicity, affinity to target and binding to HSA) affect the tumor uptake of such radiopharmaceuticals and therefore the diagnostic accuracy or therapeutic efficacy. In addition, the above design is 18 Not only does it allow the development of F-labeled diagnostic radiopharmaceuticals, but it also allows the development of therapeutic tracers labeled at the chelator moiety that forms a chelate with a radiometal (Lu-177, Y-90 or Ac-225, to name a few). In such therapeutic tracers, the SiFA moiety is not radioactive (···Si- 19 F) is the therapeutic tracer 18 F-labeled / non-radioactive chelates can be used for pre-treatment dosimetry by PET imaging, using tracers with identical chemical structures and therefore identical properties in vivo.

[0013] In addition, the combination of SiFA, chelator and additional hydrophilic components allows for tuning of pharmacokinetic properties optimal for imaging or treatment of tumors expressing SST. Thus, the compounds of the present invention are particularly suitable for medical applications such as preclinical and clinical imaging, therapeutic applications such as internal radiotherapy and pre-treatment dosimetry.

[0014] In particular, the present invention relates to a compound of formula (I):

[0015] [ka]

[0016] [In the formula, R B is a binding motif capable of binding to the somatostatin receptor, L D1 is a divalent linking group, m is an integer of 2 to 6, preferably 2 to 5, more preferably 2 or 3; A H1 is, independently at each occurrence, an amino acid unit derived from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to the -NH and -COOH functional groups of the hydrophilic amino acid; mUnit A H1 one of which may further have a hydrophilic unit other than an amino acid attached to its hydrophilic functional group; L T1 is a trivalent linking group, R CH is a chelating group which may contain a chelated radioactive or non-radioactive cation, R M1 is a hydrophilic modifying group, p is 0 or 1, L D2 is a divalent linking group, q is 0 or 1, R S is a silicon fluoride acceptor (SiFA) group having one of the following formulae, which contains a silicon atom and a fluorine atom:19 F 18 By isotopic exchange with F 18 may be labeled with F, or 18 It is labeled with F, If p is 1, then R S represents a group of formula (S-3) or a group of formula (S-4):

[0017] [ka]

[0018] (In the formula, r is 1, 2 or 3, preferably 1, -(CH2) s -s is an integer of 1 to 6, preferably 1; the R groups are independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably both are methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. and If p is 0, R S is a group of formula (S-4) as defined above. or a salt thereof.

[0019] As explained above, the compounds of the present invention include compounds of formula (I). In addition, salts of compounds of formula (I), typically pharma-ceutically acceptable salts, are included in the present invention. Thus, unless otherwise indicated, any reference to the compounds of the present invention herein includes compounds of formula (I) (and preferred embodiments of these formulas disclosed herein), and salts thereof. Similarly, any racemate, enantiomer, or diastereomer of any chiral compound of formula (I) and its salts are included, unless the specific stereochemistry of the compound under consideration is indicated by the specific context. The compounds of the present invention may also be referred to as the SST receptor ligand compounds of the present invention, or, for short, the ligand compounds of the present invention, due to their ability to bind to somatostatin (SST) receptors and act as ligands of such receptors.

[0020] Further description of the compounds of formula (I) and their salts and preferred embodiments thereof is provided below. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows the calibration plot of a Superdex75 Increase gel filtration column using a low molecular weight gel filtration calibration kit according to the table below. MW: molecular weight. tR: experimentally determined retention time. V: elution volume. Kav: partition. [Diagram 2] Figure 2 shows PET / CT MIP of [18F][natGa]19 at 10-30%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = kidney. [Diagram 3] Figure 3 shows PET / CT MIP of [18F][natGa]46 at 5-30%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = overlap between kidney and organs expressing the receptor at physiological levels (e.g. stomach and pancreas). [Figure 4]Figure 4 shows PET / CT MIP of [18F][natGa]50 at 5-40%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = overlap between kidney and organs expressing the receptor at physiological levels (e.g. stomach and pancreas). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] In order to be able to act as a ligand compound binding to the somatostatin (SST) receptor, the compound of the present invention has a binding motif R , which ensures a ligand / receptor interaction between the compound according to the present invention and the SST receptor, thereby serving as a basic affinity anchor for the compound to the SST receptor. B Includes: R B may also be referred to as a targeting group or targeting motif in the compounds of the invention. B can bind to at least somatostatin receptor 2 or SST2, or to more somatostatin receptor subtypes, or even to all somatostatin receptor subtypes, the latter being so-called SST pan-receptor ligands.

[0023] Binding motif R B can bind with high affinity to one or more SST receptors. In this context, high affinity binding preferably means that the ligand compound containing the binding motif exhibits an IC50 in the low nanomolar range, preferably 50 nM or less, more preferably 10 nM or less, even more preferably 5 nM or less. For clarity, in this specification, the half maximal inhibitory concentration (IC50) is defined as the concentration of the radioactive reference ligand, here [ 125 I]Tyr 3 -The binding motif R required to inhibit octreotide binding to the SST receptor by 50% in vitro B or a quantitative measure of the molar concentration of the ligand compound according to formula (I) or (II) [1].

[0024] As described herein, preferred binding motifs capable of high affinity binding to SST receptors may exhibit high affinity to more than one type of SST receptor. B exhibits the highest binding affinity to SST2 among the SST receptor subtypes.

[0025] Suitable binding motifs include agonists and antagonists of the SST receptor. The binding motif R 1 is a structural linker that ensures the binding interaction between the compound according to the invention and the SST receptor. B is usually a coupling group, i.e., R B Group and L D1 Group or L T2 R B is attached to the remainder of the compound of the invention. Coupling groups can consist of one or more atoms. Exemplary coupling groups are -NH-, -NR- (wherein R is a C1-C6 alkyl, preferably methyl), -C(O)-, -O-, -S-, a quaternary ammonium group, and a thiourea bridge or a linker such a thiourea bridge to R. B may be selected from groups that form together with the complementary group to which it is attached. In this connection, and in other instances in which reference is made herein to quaternary ammonium groups as possible coupling groups, the quaternary ammonium groups are preferably of the formula -N(R)2 + -, where the R groups are independently C1-C6 alkyl, preferably methyl. B The coupling group contained in L of the compound according to the invention D1 or L T2whereby the two coupling groups may combine to form a linking unit such as an amide bond (-C(O)-NH-), an alkylated amide bond (-C(O)-NR-) or a thiourea bridge (-NH-C(S)-NH-). As described herein and in further examples below, the substituent R of the alkylated amide bond -C(O)-NR- is a C1-C6 alkyl, preferably methyl. R B contains a coupling group -NH-, and that coupling group is L D1 or L T2 It is preferred to form an amide bond, -C(O)-NH-, with the -C(O)- group provided by each of the following:

[0026] Typically, the binding motif R B comprises a peptide structure capable of binding to SST, preferably a cyclic peptide structure or a peptide cyclized by a disulfide bridge. A variety of peptides capable of binding to SST are known and described in the literature. They can be used to provide binding motifs in the compounds of the invention, for example by using a carboxylic acid or amino group contained in the peptide to form an amide bond with the rest of the compound.

[0027] Thus, the binding motif is Tyr 3 -Octoleotate (or Tyr 3 ,Thr 8 -Octreotide, TATE, HD-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-OH), Thr 8 -Octreotide (ATE), Phe 1 ,Tyr 3 -Octreotide (TOC, HD-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), NaI 3-Octreotide (NOC, HD-Phe-cyclo(L-Cys-L-1-Nal-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-Nal 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8 -octreotide (BOCATE), JR11 (HL-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2), BASS (HL-Phe(4-NO2)-cyclo(D-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2) and KE121 (cyclo(D-Dab-L-Arg-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe)), more preferably from TATE or JR11, most preferably from TATE. As will be appreciated by the skilled reader, R B The group can be synthesized by using a functional group, such as a carboxylic acid or amino group, contained on the receptor agonist or antagonist, to form the R B The peptide receptor agonists or antagonists can be conveniently derived from the above-listed receptor agonists or antagonists by providing a coupling group that attaches the R group to the remainder of the compound. Preferably, these peptidic receptor agonists or antagonists can be linked to the remainder of the compound of the invention by forming an amide bond with the remainder of the compound of the invention using an amino group contained therein, for example, in an optionally substituted phenylalanine unit contained in the peptide. B In this case, R B and L D1 The covalent bond between (formula (I)) is R B The terminal -NH- group and L D1 is formed between the terminal -C(O)- group which may be present as a terminal coupling group.

[0028] Alternatively, as the experienced reader will understand, B The group is a group in which the chemical bond is L D1 Additional functional moieties, such as L, that provide functional groups that allow for the formation of D1 can be conveniently derived from the receptor agonists or receptor antagonists listed above by the introduction of an isothiocyanate-bearing moiety that can be linked to the amine of R to form a thiourea bridge. As the skilled reader will appreciate, other conjugation strategies, typically summarized as "bioconjugation strategies", can be used to incorporate R in the compounds according to the invention. B Group L D1 It can also be linked to.

[0029] Based on the above, the binding motif R B may include, for example, a group of formula (B-1) or a group of formula (B-2) shown below, and is preferably a group of formula (B-1) or a group of formula (B-2). Among them, the group of formula (B-1) is preferred.

[0030] The group of formula (B-1) has the following structure:

[0031] [ka]

[0032] [wherein the dashed line represents the bond connecting the group to the remainder of the compound]. As the skilled reader will appreciate, the dashed bond in formula (B-1) does not have a methyl group on the opposite end to the nitrogen atom, but rather a bond to the remainder of the compound of formula (I), i.e., in this case, R B R at the connection point of B Preferably, the bond shown by the dashed line in formula (B-1) represents a bond between the nitrogen atom of the -NH- group shown in formula (B-1) and L in the compound of the present invention. D1 This shows the covalent bond between the carbon atom of a carbonyl group which may be present as the terminal group of the aryl group, thus providing an amide bond.

[0033] The group of formula (B-2) has the following structure:

[0034] [ka]

[0035] [wherein the dashed line represents the bond connecting the group to the remainder of the compound]. As the skilled reader will appreciate, the dashed bond in formula (B-2) does not have a methyl group on the opposite end to the nitrogen atom, but rather a bond to the remainder of the compound of formula (I), i.e., in this case, R B R at the connection point of B Preferably, the bond shown by the dashed line in formula (B-2) represents a bond between the nitrogen atom of the -NH- group shown in formula (B-2) and L in the compound of the present invention. D1 This shows the covalent bond between the carbon atom of a carbonyl group which may be present as the terminal group of the aryl group, thus providing an amide bond.

[0036] More preferably, the binding motif R B represents a group of formula (B-1a) or (B-2a):

[0037] [ka]

[0038] wherein the dashed line indicates the bond attaching the group to the remainder of the compound, of which groups of formula (B-1a) are preferred. The chelating group R of the compounds of formula (I) and their salts CHis suitable for forming a chelate with a radioactive or non-radioactive cation. A variety of chelating agents from which suitable chelating groups can be derived are well known in the art and may be used in connection with the present invention. Metal or cation chelating agents suitable to act as chelating groups, e.g., macrocyclic or acyclic compounds, are available from a number of sources. It will be understood that many chelating agents may be used commercially without undue difficulty by those skilled in the art. It will be further understood that the suitability of a chelating group to form a chelate with a given cation requires that the chelating group is capable of providing a chelated ligand in a chelate complex with the cation under consideration, but does not require that the chelating group provide only the cation's ligand in the chelate complex. Thus, the chelating group R CH When contains a chelated radioactive or non-radioactive cation, the cation may be a complex cation, e.g., a metal ion having additional coordinating ligands other than the chelating group, e.g., an oxo ligand.

[0039] For example, the chelating group R CH teeth, (i) a macrocyclic structure having 8 to 20 ring atoms, of which 2 or more, preferably 3 or more, are selected from oxygen atoms and nitrogen atoms; and (ii) an acyclic open-chain chelating structure having 8 to 20 main chain atoms, of which at least two, preferably at least three, are heteroatoms selected from oxygen and nitrogen atoms; It may include at least one of the following:

[0040] Preferably, the chelating group R CH is a chelate comprising a cation selected from the cations Sc, Cr, Mn, Co, Fe, Ni, Cu, Ga, Zr, Y, Tc, Ru, Rh, Pd, Ag, In, Sn, Te, Pr, Nd, Gd, Pm, Tb, Sm, Eu, Gd, Tb, Ho, Dy, Er, Yb, Tm, Lu, Re, W, Pt, Ir, Hg, Au, Pb, At, Bi, Ra, Ac and Th, or 18 F or19 Chelates containing cationic molecules containing F, e.g. 18 F-[AlF] 2+ More preferably, the chelating group is suitable for forming a chelate with a cation selected from the cations Cu, Ga, Lu and Pb, even more preferably the cation Ga or Lu.

[0041] Chelating group R CH In addition to structures suitable as chelating ligands for cations, R CH Group and L T1 R via the covalent bond formed between CH is attached to the remainder of the compound of the invention. The coupling group may consist of one or more atoms. Exemplary coupling groups are -NH-, -NR- (wherein the R group is a C1-C6 alkyl, preferably methyl), -C(O)-, -S-, -O-, a quaternary ammonium group, and a thiourea bridge or a combination of such a thiourea bridge with R. CH The coupling group may be selected from groups which form together with the complementary group to which L is attached. T1 whereby the two coupling groups may combine to form a linking unit such as an amide bond -C(O)-NH-, an alkylated amide bond -C(O)-NR- or a thiourea bridge. CH contains a coupling group -C(O)-, and that coupling group is L T1 It is preferred to form an amide bond, -C(O)-NH-, with the -NH- group provided by:

[0042] Chelating group R CHare diethylenetriaminepentamethylenephosphonic acid (EDTMP) and its derivatives, diethylenetriaminepentaacetic acid (DTPA) and its derivatives, 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]-(hydroxyphenyl)-1,2-diphenyl-1,2-diphenyl-2,3-diphenyl-2,4 ... )amino]-4-oxobutanoyl]-amino]pentyl]-N-hydroxybutanediamide (DFO) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecane-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 (DO TAM), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphato) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane -4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetate (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetate (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-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), as well as triethylenetetraminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa), 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), and 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid, hydrazinonicotinic acid (HYNIC), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA) and its derivatives, such as (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-triaminetriacetic acid (BPAM), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamine]ethane (DEDPA, H2DEDPA), deferoxamine (DFO) and its derivatives, 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) and its derivatives, such as YM103. Tetraadicyclodecane-phosphinic acid (TEAP), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr), 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 (H2Bispa, 2 (H2bispa 2), 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 (H6Sbbpen) and its derivatives, triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetic acid (TTHA), 2-aminomethylpiperidinetriacetic acid (2-AMPTA) and its derivatives, e.g. The chelating agent may contain, and preferably is, a group derivable from a chelating agent selected from 2-(N-(2-hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), a further functionalized derivative of 2-AMPTA, which has an additional functional group suitable for conjugation to a peptide structure, for example, 4-nitro-2-hydroxybenzyl-2-{[(6)-trans-2-[benzyl(carboxymethyl)amino]cyclohexyl](carboxymethyl)amino}acetic acid (RESCA) and its derivatives, and 6-carboxy-1,4,8,11-tetraazaundecane (N4) and its derivatives. Among these chelating agents, preference is given to CBTE2a, DOTA, DOTAGA, DOTAM, NODASA, NODAGA, NOTA, TE2A, DO3AM, SarAr, 2-AMPTA, 2-AMPTA-HB and RESCA. More preferred are DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA. Even more preferred are DOTA, DOTAGA and DOTAM. In accordance with the general definition above, the chelating groups derived from the exemplary chelators listed above may contain a chelated radioactive or non-radioactive cation.

[0043] As will be appreciated by the skilled reader, the chelating groups of the compounds according to the invention can be conveniently derived from the chelating agents listed above by using any of the functional groups contained in the chelating agent, such as a carboxylic acid group, an amide group, an amino group, a hydroxyl group, or a thiol functional group, to provide a coupling group, such as a group selected from -C(O)-, -NH-, -S-, and -O-, which bonds the chelating group to the remainder of the compound. Preferably, a carboxylic acid group is used to provide a coupling group -C(O)- (carbonyl) to form an amide. R CH The coupling group provided by L T1 Each of R may be covalently linked to a further complementary coupling group contained in R, whereby the two coupling groups may combine to form a linking unit such as an amide bond, -C(O)-NH-. CH contains a coupling group -C(O)-, and that coupling group is L T1 It is preferred to form an amide bond with the -NH- group provided by:

[0044] Alternatively, as will be appreciated by the skilled reader, the chelating groups of the compounds according to the invention can be modified by the introduction of additional functional groups or by the addition of L T1 Additional groups with functional groups capable of forming chemical bonds to L, e.g., by thiourea bridges T1 These can be conveniently derived from the chelators listed above by the introduction of a chelator modified with an additional residue having an isothiocyanate that can be linked to the amine of L. As the skilled reader will appreciate, other conjugation strategies, typically summarized as "bioconjugation strategies", can be used to attach the chelating group of the compounds according to the invention to L. T1 It can also be linked to.

[0045] R CH represents a group of formula (CH-1), (CH-2) or (CH-3):

[0046] [ka]

[0047] or a chelate formed by a group of formula (CH-1), (CH-2) or (CH-3) with a chelated radioactive or non-radioactive cation, i.e. a group of formula (CH-1), (CH-2) or (CH-3) which may contain a chelated radioactive or non-radioactive cation. Thus, as the skilled reader will appreciate, the bond at the carbonyl group shown in dashed lines in formulas (CH-1) to (CH-3) does not have a methyl group at the opposite end to the carbonyl group, but is connected to the remainder of the compound of formula (I), i.e. in this case R of formula (I). CH R at the connection point of CH Preferably, the bond shown by the dashed line in formulae (CH-1) to (CH-3) represents a bond between the carbon atom of the carbonyl group shown in formulae (CH-1) to (CH-3) and L in the compound of the present invention. T1 This shows the covalent bond existing between the nitrogen atom of an NH group that may be present as the terminal group of the aryl group, thus providing an amide bond.

[0048] Chelating group R CH The chelated radioactive or non-radioactive cations that may be contained in the 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 55 Co, 57 Co, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 86 Y, 94m Tc, 99m Tc, 97 Ru,105 Rh、 109 Pd、 111 Ag、 110m In、 111 In、 113m In、 114m In、 117m Sn、 121 Sn、 127 Tea, 142 Pr、 143 Pr、 147 Nd、 149 Gd、 149 Pm、 151 Pm、 149 Tb、 152 Tb、 155 Tb、 153 Sm、 156 Eu、 157 Gd、 155 Tb、 161 Tb、 164 Tb、 161 Your, 166 Your, 157 Dy、 165 Dy、 166 Dy、 160 Er、 165 Er、 169 Er、 171 Er、 166 Yb、 169 Yb、 175 Yb、 167 Tm、 172 Tm、 177 Ridiculous, 186 Too, 186g Too, 188 Too, 188 W、 191 Pt、 195m Pt、 194 They、 197 Hg、 198 I、 199 I、 212 Pb、 203 Pb、 211 And、 212 Bi、 213 Bi、 223 Does, 224 Does, 225 Ac、 226 Thおよび 227or comprising or consisting of a cation selected from the cations of Th and non-radioactive isotopes of any of these metals; 18 F or 19 Cationic molecules containing F, e.g. 18 F-[AlF] 2+ A chelated cation is a complex cation, e.g., a cation that has an additional coordinating ligand other than the chelating group, e.g. 99m It may also be a metal ion bearing oxo ligands in a chelate containing a Tc(V)-oxo core.

[0049] Particularly preferred as chelated cations are radioactive or non-radioactive cations of Ga, Lu or Pb, e.g. 177 Lu or 68 It's Ga. Furthermore, the compounds according to the invention may contain a silicon fluoride acceptor (SiFA) group R S Including R S contains a silicon atom and a fluorine atom, 19 F 18 By isotopic exchange with F 18 may be labeled with F, or 18 It is labeled with F.

[0050] When the variable p in formula (I) is 1, i.e. when the compound of formula (I) or a salt thereof is R M1 When it contains a group, R S represents a group of formula (S-3) or a group of formula (S-4):

[0051] [ka]

[0052] It is. In the group of formula (S-3), R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2Sis selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl. The dashed line indicates the bond attaching the group to the remainder of the compound.

[0053] In the group of formula (S-4), r is 1, 2 or 3, preferably 1, and -(CH2) s -s is an integer of 1 to 6, preferably 1; the R groups are independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably both are methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl. The dashed line indicates the bond attaching the group to the remainder of the compound.

[0054] When the variable p in formula (I) is 0, i.e. when the compound of formula (I) or a salt thereof is R M1 If it does not contain a group, R S is a group of formula (S-4) as defined above. Exemplary counterions for the positively charged quaternary ammonium group shown in formula (S-4) having two R substituents are anions as described herein with respect to salt forms of the compound of formula (I), including, for example, a trifluoroacetate anion or an acetate anion.

[0055] As will be appreciated by the skilled reader, the bond shown in dashed lines in formulas (S-3) and (S-4) does not have a methyl group on the end opposite the carbonyl group, but rather is connected to the remainder of the compound of formula (I), i.e., in this case, R SPreferably, the bond shown by the dashed line in formulas (S-3) and (S-4) represents a bond between the carbon atom of the carbonyl group shown in formulas (S-3) and (S-4) and R in the compounds of the present invention. S The end group of the unit having the formula (I) T1 , R M1 or L D2 ) represents the covalent bond between the nitrogen atom of the -NH group, which may be present as an amide bond.

[0056] The fluorine atoms shown in formulae (S-3) and (S-4) are 18 F atom, or 19 F 18 By isotopic exchange with F 18 can be exchanged to provide F 19 It may be an F atom.

[0057] Among the (S-3) and (S-4) groups, R S The most preferred group is the (S-4) group. Furthermore, the (S-3) group is preferably the (S-3a) group, and the (S-4) group is preferably the (S-4a) group;

[0058] [ka]

[0059] During the ceremony, t Bu represents a tert-butyl group and the dashed line represents the bond connecting the group to the remainder of the compound. As discussed above with respect to (S-4), exemplary counterions for the positively charged quaternary ammonium group shown in formula (S-4a) having two methyl substituents are anions as described herein with respect to salt forms of the compound of formula (I), including, for example, a trifluoroacetate anion or an acetate anion.

[0060] The above explanations regarding the SiFA groups of the formulae (S-3) and (S-3a) and (S-4) and (S-4a), respectively, apply not only to the formula (I) but also to preferred embodiments thereof, in which case the SiFA group R S1 , R S2 or R S3 defines a group of formula (S-3), preferably (S-3a), a group of formula (S-4), preferably (S-4a), or both.

[0061] R in formula (I) B Group, R CH Groups and R S The scaffold structure shown below has the following groups:

[0062] [ka]

[0063] comprises one or more amino acid units. As will be understood by those skilled in the art, an amino acid unit is a group that can be derived from an amino acid, i.e., from a compound that contains an amino group and a carboxylic acid group in the same molecule. Unless otherwise indicated in the particular context, one or more further functional groups in addition to the amino and carboxylic acid groups may be present in the amino acid from which the amino acid unit can be derived. A particular amino acid unit is usually identified by the name of the amino acid from which it can be derived, for example, a glycine unit, an asparagine unit, etc. Unless otherwise indicated in the particular context, the amino acid from which the amino acid unit can be derived is preferably an α-amino acid. When the amino acid unit contained in the scaffold structure can be derived from a chiral amino acid, the preference is for the D configuration.

[0064] Additionally, an amino acid unit may be derived from an amino acid by using one or more of the amino acid's functional groups to provide a coupling group that forms a bond to the adjacent atom or group to which the amino acid unit is attached. For example, the amino group of the amino acid may be used to provide a coupling group -NH-, where a bond to one hydrogen atom is replaced by a bond to another adjacent atom or group. The carboxylic acid group of the amino acid may be used to provide a coupling group -C(O)-, where a bond to an -OH group is replaced by a bond to another adjacent atom or group. Preferably, any coupling group provided by the amino acid is covalently linked to a further complementary coupling group in the compound according to the invention, whereby the two complementary coupling groups combine to form a linking unit such as an amide bond (-C(O)-NH-) or an alkylated amide bond -C(O)-NR-, preferably an amide bond. R is a C1-C6 alkyl, preferably methyl. If the amino acid providing the amino acid unit contains an additional functional group other than an amino or carboxylic acid group, then a coupling group other than the -NH- and -C(O)- coupling groups may be provided, such as -O- or -S-.

[0065] When the amino acid unit is a monovalent unit, it is preferred that the unit is linked in the compound of the present invention with one amide bond formed by either the amino group or the carboxylic acid group provided by the amino acid from which the amino acid unit is derived.When the amino acid unit is a divalent unit, it is preferred that the unit is linked in the compound of the present invention with two amide bonds formed by the amino group and the carboxylic acid group provided by the amino acid from which the amino acid unit is derived.When the amino acid unit is a trivalent unit, as may be provided by an amino acid that contains a further functional group in addition to the amino group and the carboxylic acid group required for the amino acid, it is preferred that the further functional group is also an amino group or a carboxylic acid group, and that the unit is linked in the compound of the present invention with three amide bonds formed by the amino group, the carboxylic acid group and the further functional group provided by the amino acid from which the amino acid unit is derived.

[0066] In the following, the formula (I)

[0067] [ka]

[0068] R in B , R CH and R S Further described is a structural element of the scaffold structure having: Divalent Linking Group L D1 is R B Group and Amino Acid Unit A H1 It provides a link between L D1 Typically, R B is attached to the end of the bond, a linking unit such as an amide bond (-C(O)-NH-), an alkylated amide bond -C(O)-NR- or a thiourea bridge, preferably an amide bond, B The R B In connection with the definition of L, reference is made to the description of the coupling groups. D1 The coupling group of L is a -C(O)- group. D1 typically represents the amino acid unit A H1 A bond unit such as an amide bond or an alkylated amide bond, preferably an amide bond, is attached to the end of the H1 Preferably, this L D1 The coupling group in is a -NH- group.

[0069] In a preferred embodiment, L D1typically contains, in addition to the above coupling groups, a divalent oligoethylene glycol group or polyethylene glycol group, preferably a divalent oligoethylene glycol group or polyethylene glycol group having 10 or less ethylene glycol units, more preferably a divalent oligoethylene glycol group or polyethylene glycol group having 2 to 5 ethylene glycol units.

[0070] According to this embodiment, L D1 is expressed by the formula (L-1a): -C(O)-(CH2) a -(O-CH2-CH2) b -NH- (L-1a) [In the formula, a is 1 or 2, preferably 1; b is an integer from 2 to 5, preferably 2 or 3. It can be a divalent group of the formula:

[0071] The C-terminal bond of the above formula is preferably R B is formed together with In another more preferred embodiment, the divalent linking group L D1 comprises a divalent amino acid unit or a divalent chain of amino acid units, more preferably a divalent chain of 2-5 amino acid units, and even more preferably a divalent chain of 2 or 3 amino acid units. Due to the functional groups contained in the amino acids, the amino acid unit / amino acid chain can be coupled to the above coupling groups R B Or A H1 Thus, the divalent linking group L D1 can consist of a divalent amino acid unit or a divalent chain of amino acid units, more preferably a divalent chain of 2 to 5 amino acid units, even more preferably a divalent chain of 2 or 3 amino acid units.

[0072] According to this embodiment, L D1 is expressed by the formula (L-1b): -[A L1 ] n - (L-1b) [In the formula, AL1 is, when n is greater than 1, each occurrence independently an amino acid unit, n is an integer of 1 to 5, preferably 2 to 5, more preferably 2 or 3. It can be expressed as:

[0073] Preferably, the (L-1b) group is R B The C-terminus forms a bond with, and A H1 provides the N-terminus that forms a bond with L D1 When L comprises or consists of one or more amino acid units, it is preferred that these amino acid units do not contain any free amino groups, free acid groups, or salts thereof. More preferably, the amino acid units do not contain any functional groups that are charged at pH 7.0. For example, L D1 The amino acid units contained in the formula (I) are independently selected from the amino acid units provided by glycine, β-alanine or γ-aminobutyric acid, as well as C1-C4 alkyl groups such as methyl, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, and -(CH2) v It may be selected from amino acid units containing a side chain selected from -OH (wherein v is 1-4, for example 1 or 2).

[0074] L D1 comprises or consists of one or more amino acid units, L D1 Each amino acid unit of is a unit of more than one amino acid unit of L D1More preferably, when present in, each occurrence is independently selected from a glycine (Gly) unit, a beta-alanine unit, an alanine (Ala) unit, an asparagine (Asn) unit, a glutamine (Gln) unit and a citrulline (Cit) unit. Even more preferred are amino acid units selected from a glycine unit and an asparagine unit. With regard to their stereochemistry, the amino acid units, with the exception of the glycine unit, are preferably D-amino acid units, thus, for example, the preferred -[A L1 ] n The - group can consist of (i) one Gly unit, (ii) two Gly units, (iii) three Gly units or (iv) two D-Asn units, with particularly preferred examples being -[A L1 ] n -based.

[0075] The variable m is an integer of 2 to 6, preferably 2 to 5, and more preferably 2 or 3. A H1 Each occurrence of m unit A is an amino acid unit derived from a hydrophilic amino acid that contains, in addition to the -NH2 and -COOH functional groups of the hydrophilic amino acid, an additional hydrophilic functional group. Such a unit may be referred to herein for short as a "hydrophilic amino acid unit." H1 One of the may optionally further have a hydrophilic unit other than an amino acid attached to its hydrophilic functional group.

[0076] For example, the amino acid unit A H1 can be independently selected at each occurrence from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, -NH-C(=O)-NH2, -OH and -P(=O)(OH). Among these, preferred are -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2 and -NH-C(=O)-NH2.

[0077] Preferably, m amino acid units A H1Each of the following independently at each occurrence, when m is greater than 1, is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, wherein v is 1 to 4, and m is an A H1 The functional group at the end of one of the above side chains may form a bond with an additional hydrophilic unit other than the amino acid unit. Based on the above, the side chain is more preferably -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2 and -(CH2) v -NH-C(=O)-NH2, where v is 1 to 4. As will be appreciated by the skilled reader, the amino acid unit A H1 The side chain of L D1 , L T1 A to or adjacent to H1 Based on the above, m unit A H1 One of the groups may optionally further have a hydrophilic unit other than an amino acid bonded to a hydrophilic functional group at the end of the side chain.

[0078] Therefore, the amino acid unit A H1are preferably independently selected at each occurrence from the 2,3-diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit, the lysine (Lys) unit, the arginine (Arg) unit, the glutamic acid (Glu) unit, the aspartic acid (Asp) unit, the asparagine (Asn) unit, the glutamine (Gln) unit, the serine (Ser) unit, the citrulline (Cit) unit, the thiocitrulline unit, the methylisothiocitrulline unit, the canavanine unit, the thiocanavanine unit, the α-amino-γ-(thioureaoxy)-n-butyric acid unit, the α-amino-γ-(thioureathio)-n-butyric acid unit and the phosphonomethylalanine (Pma) unit. They are preferably units that can be derived from amino acids of the D configuration. More preferred are units selected from the 2,3-diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit, the lysine (Lys) unit, the arginine (Arg) unit, the glutamic acid (Glu) unit, the aspartic acid (Asp) unit, the asparagine (Asn) unit, the glutamine (Gln) unit, the serine (Ser) unit, the citrulline (Cit) unit and the phosphonomethylalanine (Pma) unit. Even more preferred are units selected from the 2,3-diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit, the lysine (Lys) unit, the arginine (Arg) unit, the glutamic acid (Glu) unit, the aspartic acid (Asp) unit, the asparagine (Asn) unit, the glutamine (Gln) unit and the citrulline (Cit) unit. Based on the above, therefore, particularly preferred are units selected from the group consisting of [A H1 ] m The group is composed of two or three amino acid units independently selected from 2,3-diaminopropionic acid (Dap) units, 2,4-diaminobutanoic acid (Dab) units, ornithine (Orn) units, lysine (Lys) units, arginine (Arg) units, glutamic acid (Glu) units, aspartic acid (Asp) units, asparagine (Asn) units and glutamine (Gln) units. For example, the preferred [A H1 ] mThe group may consist of (i) two D-Asp units, (ii) two D-Orn units, (iii) two D-Asn units or (iv) two D-Asp units and a third unit selected from D-Lys, D-Cit and D-Glu.

[0079] A is selected accordingly H1 One of the units may optionally further comprise a hydrophilic unit other than an amino acid attached to the terminal hydrophilic functional group provided in the amino acid unit. H1 The optional hydrophilic unit other than an amino acid unit, optionally attached to one of the units, may be, for example, a carbohydrate group or a trimesic acid group.

[0080] Preferably, -[A H1 ] m The - group is L D1 and forms an amide bond (-C(O)-NH-) or an alkylated amide bond (-C(O)-NR-) with L T1 together with the linker to form an amide bond or an alkylated amide bond. More preferably, the bond is an amide bond.

[0081] Preferably, -[A H1 ] m The - group is L D1 The C-terminus forms a bond with, and L T1 provides the N-terminus that forms a bond with Trivalent Linking Group L T1 is the amino acid unit A H1 Between R CH Depending on p and q, R M1 , L D2 or R S It provides a link between L T1 Typically, A H1 A bond unit such as an amide bond (-C(O)-NH-) or an alkylated amide bond (-C(O)-NR-), preferably an amide bond, is attached to the end of the H1 Preferably, this LT1 The coupling group of L is a -C(O)- group. T1 Typically, R CH is attached to either its terminus or in a side chain, a linking unit such as an amide bond, an alkylated amide bond (-C(O)-NR-) or a thiourea bridge, preferably an amide bond, CH The R CH In the definition of L, reference is made to the description of the coupling groups. T1 The coupling group in is a -NH- group.

[0082] L T1 is R M1 , L D2 or R S At the end to which is bonded, the copolymer typically contains a coupling group selected from the following (i) and (ii), with (i) being preferred. (i) A linking unit such as an amide bond, an alkylated amide bond (—C(O)—NR—) or a thiourea bridge, preferably an amide bond, is provided by R M1 , L D2 or R S A coupling group suitable for forming with a complementary group contained in R S In the definition of L, reference is made to the description of the coupling groups. T1 The coupling group in is also typically an --NH-- group derived from an amino group.

[0083] (ii) Quaternary ammonium groups as coupling groups. As mentioned above, the quaternary ammonium groups are preferably of the formula -N(R)2 + - is a coupling group of -, and the R groups are independently C1-C6 alkyl, preferably methyl. This option can be extended, for example, when both p and q are 0 and R S L T1 When directly bonded to, for example, R S is the (S-5) group above, which may be suitably used when providing a substituent attached to the nitrogen atom of the quaternary ammonium group.

[0084] L T1 is preferably a trivalent amino acid unit. More preferably, L T1 is a trivalent amino acid unit selected from (i) and (ii) below, with (i) being more preferred: (i) a trivalent amino acid unit which can be derived from an amino acid which, in addition to a carboxylic acid group and an amino group, contains a further functional group selected from a carboxylic acid group and an amino group. More preferably, L T1 is selected from the 2,3-diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit and the lysine (Lys) unit, most preferably the Dap unit. With regard to their stereochemistry, these amino acid units are preferably D-amino acid units.

[0085] (ii) -N(R)2, which can be derived from a trifunctional amino acid containing a tertiary amino group as a third functional group in addition to the -NH2 group of the trifunctional amino acid and its -COOH group, preferably an amino acid selected from N-dialkylated 2,3-diaminopropionic acid (Dap), N-dialkylated 2,4-diaminobutanoic acid (Dab), N-dialkylated ornithine (Orn) and N-dialkylated lysine (Lys), most preferably an amino acid selected from N-dimethylated 2,3-diaminopropionic acid (Dap), N-dimethylated 2,4-diaminobutanoic acid (Dab), N-dimethylated ornithine (Orn) and N-dimethylated lysine (Lys). + - group. The tertiary amino group is R M1 , L D2 or R S with, preferably R S Through conjugation with the quaternary ammonium group -N(R)2 + -, preferably -N(CH3)2 + -. With regard to their stereochemistry, these amino acid units are preferably D-amino acid units.

[0086] For the trivalent amino acid unit (i), it is preferred that this amino acid unit is linked by three amide bonds in the compounds of the invention. H1 and a -C(O)- coupling group bonded to R CH is preferably oriented to provide an --NH-- coupling group attached to

[0087] The variable p is 0 or 1, i.e., the hydrophilic modifying group R M1 may or may not be present. If p is 0, then R M1 If does not exist, L T1 L D2 (if q is 1) or R S (q is also 0, so L D2 (if neither is present) forms a bond with

[0088] Hydrophilic modification group R M1 is a divalent group that contains a hydrophilic moiety, i.e., typically a polar or charged moiety. Typically, R M1 L T1 A linking unit such as an amide bond (-C(O)-NH-) or an alkylated amide bond (-C(O)-NR-), preferably an amide bond, is attached to the end of L T1 Preferably, this R M1 The coupling group of R is a -C(O)- group. M1 is preferably L D2 or R S A linking unit such as an amide bond or an alkylated amide bond (-C(O)-NR-), preferably an amide bond, is attached to the end to which L D2 or R S Preferably, R M1 The coupling group in is a -NH group.

[0089] Preferably, the hydrophilic modifying group R M1is a group derivable from a hydrophilic amino acid which, if present, contains, in addition to the -NH2 and -COOH functional groups of the hydrophilic amino acid, a further hydrophilic functional group, preferably selected from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, -NH-C(=O)-NH2, -NH-C(=S)-NH2, -O-NH-C(=S)-NH2, -O-NH-C(=N)-NH2-OH and -P(=O)(OH), of which the -NH2 group is the further preferred hydrophilic functional group.

[0090] More preferably, the hydrophilic modifying group R M1 When present, is a divalent amino acid unit selected from the diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit and the lysine (Lys) unit, most preferably the diaminopropionic acid unit. In view of their stereochemistry, these amino acid units are preferably D-amino acid units.

[0091] The hydrophilic modifying group is L T1 forms an amide bond with L D2 together with, or if q is 0, R S It is preferred to form an amide bond together with The variable q is 0 or 1, i.e., the divalent linking group L D2 may or may not be present. If q is 0, then L D2 If does not exist, R S is R M1 (if p is 1) or L T1 (when p is also 0) forms a bond with either

[0092] an optional divalent linking group L D2 is R S and the remainder of the compound of the invention. Typically, L D2 L T1 or R M1A linking unit such as an amide bond (-C(O)-NH-) or an alkylated amide bond (-C(O)-NR-), preferably an amide bond, is attached to the end of L T1 or R M1 Preferably, this L D2 The coupling group of L is a -C(O)- group. D2 is preferably L D2 or R S A bond unit such as an amide bond or an alkylated amide bond, preferably an amide bond, is attached to the end to which L D2 or R S Preferably, L provides a coupling group suitable for forming with a complementary group contained in D2 The coupling group in is a -NH- group.

[0093] Divalent Linking Group L D2 When present, it is preferably represented by the formula (L-2): -[A L2 ] w - (L-2) [In the formula, A L2 is, independently for each occurrence when w is greater than 1, an amino acid unit; w is 1 to 5, preferably 1 to 3, more preferably 1 or 2. is the basis.

[0094] Preferably, the amino acid unit A L2 are independently selected from a glycine unit and an alanine unit. The alanine unit is preferably a D-alanine unit. A preferred type of compound of the present invention has formula (I.1):

[0095] [ka]

[0096] [In the formula, R B , L D1 , A H1 , m, LT1 , R CH , R M1 , L D2 and q are as defined hereinabove, including preferred embodiments thereof; R S2 has formula (S-3) as defined herein above, more preferably (S-3a), i.e.

[0097] [ka]

[0098] (In the formula, R 1S and R 2S are as defined hereinabove, including preferred embodiments thereof) is a SiFA group] or a salt thereof.

[0099] Among the compounds of formula (I.1) or salts thereof, further preference is given to the compounds of formula (I.2):

[0100] [ka]

[0101] [In the formula, R B , L D1 , A H1 , m, L T1 , R CH , R M1 and R S2 are as defined hereinabove, including preferred embodiments thereof. or a salt thereof.

[0102] An even more preferred type of compound of the present invention has formula (I.3):

[0103] [ka]

[0104] [In the formula, R B , L D1 , A H1 , m, L T1 , R CH , R M1 ,p,L D2 and q are as defined hereinabove, including preferred embodiments thereof; R S3 has formula (S-4) as defined herein above, more preferably (S-4a), i.e.

[0105] [ka]

[0106] (In the formula, r, s, R, R 1S and R 2S are as defined hereinabove, including preferred embodiments thereof) is a SiFA group] or a salt thereof.

[0107] Among the compounds of formula (I.3) or salts thereof, further preference is given to the compounds of formula (I.4) and (I.5):

[0108] [ka]

[0109] [In the formula, R B , L D1 , A H1 , m, L T1 , R CH , R M1 , L D2 , q and R S3 are as defined hereinabove, including preferred embodiments thereof. or a salt thereof.

[0110] Based on the above, for the compounds of formula (I) and their salts, and for the compounds of formulas (I.1) to (I.5) and their respective salts, R B Tyr 3 ,Thr 8 -Octreotide (TATE), Tyr 3 -Octreotide (TOC), Thr 8 -Octreotide (ATE), 1-NaI 3 -Octreotide (NOC), 1-Nal 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8 - comprising a group derivable from a receptor agonist or receptor antagonist selected from octreotide (BOCATE), JR11, BASS, and KE121; R CH comprises a group derivable from a chelating agent selected from DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, which chelating group may comprise a chelated radioactive or non-radioactive cation, A H1 is independently selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit, and a phosphonomethylalanine (Pma) unit at each occurrence. This is preferable.

[0111] For the compounds of formula (I) and their salts, and for the compounds of formulae (I.1) to (I.5) and their respective salts, R B Tyr 3 ,Thr 8 -Octreotide (TATE), Tyr 3 -Octreotide (TOC), Thr 8 -Octreotide (ATE), 1-NaI 3-Octreotide (NOC), 1-Nal 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8 - comprising a group derivable from a receptor agonist or receptor antagonist selected from octreotide (BOCATE), JR11, BASS, and KE121; R CH comprises a group derivable from a chelating agent selected from DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, which chelating group may comprise a chelated radioactive or non-radioactive cation, A H1 is independently selected at each occurrence from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit, and a phosphonomethylalanine (Pma) unit; R M1 is, if present, an amino acid unit selected from a diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, more preferably a diaminopropionic acid unit. This is even more preferable.

[0112] For the compounds of formula (I) and their salts, and for the compounds of formulae (I.1) to (I.5) and their respective salts, R B Tyr 3 ,Thr 8 - comprising a group derivable from a receptor agonist or receptor antagonist selected from octreotide (TATE) and JR11, R CHcomprises a group derivable from a chelating agent selected from DOTA, DOTAGA and DOTAM, which chelating group may comprise a chelated radioactive or non-radioactive cation; m is 2 or 3; A H1 is independently selected at each occurrence from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, and a citrulline (Cit) unit; R M1 is, if present, an amino acid unit selected from a diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, more preferably a diaminopropionic acid unit. This is even more preferred.

[0113] Based on the above description of the compounds of formula (I) and their salts, the preferred structure of these compounds is represented by the formula (Ia):

[0114] [ka]

[0115] [In the formula, R B and R CH is as defined herein above, including preferred embodiments thereof, n1 is 2 to 5, preferably 2 or 3; R L1 represents independently at each occurrence H, a C1-C4 alkyl group, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2 and -(CH2) v—OH, where v is 1 to 4; m1 is 2 to 5, more preferably 2 or 3; R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; d is an integer from 0 to 4; e is an integer from 0 to 4, Preferably, one of d and e is 0 and the other is an integer from 1 to 4, more preferably the other is 1; p1 is 0 or 1, R H2 is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; q1 is an integer of 0 to 2, R L2 is selected from H and CH3, and If p1 is 1, R S1 represents a group of formula (S-3) and a group of formula (S-4)

[0116] [ka]

[0117] (In the formula, r is 1, 2 or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. and If p1 is 0, R S1 is a group of formula (S-4) as defined above. and salts thereof. Groups of formula (S-3a) and (S-4a) remain even more preferred examples of these.

[0118] In formula (Ia), R B and R CH is as defined herein, including preferred embodiments thereof, and therefore (B-1) or (B-2) is still R B and the chelates formed with (CH-1) to (CH-3) or these chelating groups are still R CH This is a more preferred structure.

[0119] Square brackets [...] n1 In -C(O)-CH(R L1 )-NH- unit represents an amino acid unit, R L1 is H or the side chain of an amino acid unit. When the amino acid unit can be derived from a chiral amino acid, it is preferably in the D configuration. R L1 Each occurrence independently represents H, a C1-C4 alkyl group such as methyl, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v-C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, and -(CH2) v —OH, where v is 1 to 4, for example 1 or 2. L1 Each of the amino acid units having the formula -C(O)-CH(R L1 )-NH] n1 The - group can consist of (i) one Gly unit, (ii) two Gly units, (iii) three Gly units or (iv) two D-Asn units, and particularly preferred examples include -[C(O)-CH(R L1 )-NH] n1 -based.

[0120] Square brackets [...] m1 In -C(O)-CH(R H1 )-NH- unit represents an amino acid unit as well, R H1 is the side chain of the amino acid unit. The amino acid from which the amino acid unit is derived is preferably in the D configuration. R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v —P(═O)(OH)2, where v is 1-4.

[0121] R H1 is preferably -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v-C(=O)NH2 and -(CH2) v —NH—C(═O)—NH2, where v is 1 to 4.

[0122] Preferably, R H1 are independently selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit and a phosphonomethylalanine (Pma) unit, more preferably a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit , ornithine (Orn), lysine (Lys), arginine (Arg), glutamic acid (Glu), aspartic acid (Asp), asparagine (Asn), glutamine (Gln) and citrulline (Cit) units, and even more preferably D-2,3-diaminopropionic acid, D-2,4-diaminobutanoic acid, D-ornithine, D-lysine, D-arginine, D-glutamic acid, D-aspartic acid, D-asparagine, D-glutamine and D-citrulline units. Thus, for example, preferred -[C(O)-CH(R H1 )-NH] m1 The - group can consist of (i) two D-Asp units, (ii) two D-Orn units, (iii) two Asn units or (iv) two D-Asp units and a third unit selected from D-Lys, D-Cit and D-Glu.

[0123] The variable d is an integer from 0 to 4, and e is an integer from 0 to 4. More preferably, one of d and e is 0 and the other is 1 to 4, and even more preferably the other is 1. Thus, the most preferred combinations are d is 1 and e is 0, or d is 0 and e is 1.

[0124] Trivalent units in the above formula

[0125] [ka]

[0126] is likewise an amino acid unit. Preferably, it is selected from the 2,3-diaminopropionic acid (Dap) unit, the 2,4-diaminobutanoic acid (Dab) unit, the ornithine (Orn) unit and the lysine (Lys) unit, more preferably the Dap unit. Even more preferred are the D-2,3-diaminopropionic acid (Dap) unit, the D-2,4-diaminobutanoic acid (Dab) unit, the D-ornithine (Orn) unit and the D-lysine (Lys) unit, most preferably the D-Dap unit.

[0127] In the above formula, the square brackets [···] p1 In -C(O)-CH(R H2 )-NH- unit represents an amino acid unit as well, R H2 is the side chain of the amino acid unit. The amino acid from which the amino acid unit is derived is preferably in the D configuration. R H2 is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4. Preferably, R H2is selected from 2,3-diaminopropionic acid (Dap) unit, 2,4-diaminobutanoic acid (Dab) unit, ornithine (Orn) unit, lysine (Lys) unit, arginine (Arg) unit, glutamic acid (Glu) unit, aspartic acid (Asp) unit, asparagine (Asn) unit, glutamine (Gln) unit, serine (Ser) unit, citrulline (Cit) unit and phosphonomethylalanine (Pma) unit. Among them, Dap unit is particularly preferred. More preferably, the unit is selected from a D-2,3-diaminopropionic acid unit, a D-2,4-diaminobutanoic acid unit, a D-ornithine unit, a D-lysine unit, a D-arginine unit, a D-glutamic acid unit, a D-aspartic acid unit, a D-asparagine unit, a D-glutamine unit, a D-serine unit, a D-citrulline unit and a D-phosphonomethylalanine unit, most preferably the D-Dap unit.

[0128] Square brackets [...] q1 In -C(O)-CH(R L2 )-NH- unit represents an amino acid unit as well, R L2 is H or the side chain of an amino acid unit. R L2 When R is not H, the amino acid from which the amino acid unit is derived is preferably in the D configuration. H2 is selected from H and CH3, preferably H.

[0129] R S1 represents a group of formula (S-3) and a group of formula (S-4) as defined herein:

[0130] [ka]

[0131] [In the formula, r is 1, 2 or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. and more preferably group (S-4).

[0132] As mentioned above, among the (S-3) groups, the (S-3a) groups are more preferred, and among the (S-4) groups, the (S-4a) groups are more preferred. A preferred type of compound of formula (Ia) or a salt thereof is represented by the formula (Ia.1):

[0133] [ka]

[0134] [In the formula, R B , R L1 , n1, R H1 , m1, d, e, R CH , R H2 , R L2 and q1 are as defined herein above, including preferred embodiments thereof; R S2 has formula (S-3) as defined herein above, more preferably (S-3a), i.e.

[0135] [ka]

[0136] (In the formula, R 1S and R 2S are as defined hereinabove, including preferred embodiments thereof) is a SiFA group] or a salt thereof.

[0137] Among the compounds of formula (Ia.1) or salts thereof, further preference is given to the compounds of formula (Ia.2):

[0138] [ka]

[0139] [In the formula, R B , R L1 , n1, R H1 , m1, d, e, R CH , R H2 and R S2 are as defined hereinabove, including preferred embodiments thereof. or a salt thereof.

[0140] An even more preferred type of compound of formula (Ia) or a salt thereof is represented by formula (Ia.3):

[0141] [ka]

[0142] [In the formula, R B , R L1 , n1, R H1 , m1, d, e, R CH , R H2 , p1, R L2 and q1 are as defined herein above, including preferred embodiments thereof; R S3 has formula (S-4) as defined herein above, more preferably (S-4a), i.e.

[0143] [ka]

[0144] (In the formula, r, s, R, R 1S and R 2S are as defined herein, including preferred embodiments thereof. is a SiFA group] or a salt thereof.

[0145] Among the compounds of formula (Ia.3) or salts thereof, further preference is given to the compounds of formula (Ia.4) and (Ia.5):

[0146] [ka]

[0147] [In the formula, R B , R L1 , n1, R H1 , m1, d, e, R CH , R H2 , R L2 , q1 and R S3 are as defined hereinabove, including preferred embodiments thereof. or a salt thereof.

[0148] As mentioned above, the compounds according to the present invention include compounds of formula (I) and their salts. The salts are preferably pharmaceutically acceptable salts, i.e. salts formed with pharmaceutically acceptable anions or cations. Salts can be formed by protonating an atom with an unshared pair of electrons that is easily protonated, such as nitrogen atoms, with inorganic or organic acids, or by removing a proton from an acidic group, such as a carboxylic acid group, for example, by neutralizing with a base. Other charged groups that may be present in the compounds according to the present invention and provide the compounds in the form of salts include permanently charged groups, such as quaternary ammonium groups, which include an ammonium cation with nitrogen substituted with four organyl groups, or charged chelate complexes.

[0149] When the salt forms of the compounds of the present invention comprise a positively charged form of the compound of formula (I), exemplary anions that may be present as counterions in the salt forms include, for example, chloride, bromide, iodide, sulfate, nitrate, phosphate (such as phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, or perchlorate, acetate, trifluoroacetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanepropionate, and the like. The anion may be selected from the group consisting of acid, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate, sulfonate (e.g., methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate or camphorsulfonate). Trifluoroacetic acid is frequently used during the synthesis of peptides, so trifluoroacetate is a typical salt provided when a compound containing a peptide structure is formed. Such trifluoroacetate may be converted to acetate, for example, during post-treatment of the salt.

[0150] When the salt forms of the compounds of the invention include negatively charged forms of the compounds of formula (I), exemplary cations that may be present as counterions in the salt forms may include, for example, cations selected from alkali metal cations such as lithium, sodium or potassium ions, alkaline earth metal cations such as calcium or magnesium ions, and ammonium ions (including ammonium ions substituted with organic groups).

[0151] The compounds according to the invention have an IC50 activity at SST receptors, preferably at SST2, of 50 nM or less, more preferably 10 nM or less, even more preferably 5 nM or less. 50The antibody can preferably bind with an affinity reflected by the value of

[0152] The compounds according to the invention preferably have an octanol-water partition coefficient (logD) of less than or equal to -1.0, more preferably less than or equal to -2.0. 7.4 or logP value), which is generally not lower than -4.0.

[0153] This partition coefficient is determined by measuring the equilibrium partition of the compound according to the invention in a two-phase system containing equal amounts of n-octanol and PBS (pH=7.4), e.g., 1.00 ml of each, at room temperature (20° C.), and calculating the logD 7.4 Log the value 10 (concentration in octanol / concentration in PBS). Parameters proportional to the concentration of the compound in each phase, rather than the (absolute) concentration of the compound according to the invention in octanol and PBS, can also be used to calculate radioactivity etc., if the compound contains a radioactive moiety, e.g. a radioactive chelate.

[0154] The compounds of the present invention can provide advantageous binding properties to human serum albumin (HSA). Moderate to low HSA binding values, expressed as apparent molecular weight in kDa and determined by radio inversed affinity chromatography (RIAC) as described in the Examples section below, can be achieved. Preferably, the HSA binding value is less than 22 kDa, more preferably less than 10 kDa.

[0155] Exemplary compounds according to the invention further include the following: Compound 23 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0156] Compound 19 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0157] Compound 39 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0158] Compound 40 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0159] Compound 20 having the formula shown in the Examples section below, a compound in which the DOTAGA chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0160] Compound 41 having the formula shown in the Examples section below, a compound in which the DOTAGA chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0161] Compound 42 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0162] Compound 42 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0163] Compound 36 having the formula shown in the Examples section below, a compound in which the DO3AM chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0164] Compound 37 having the formula shown in the Examples section below, a compound in which the DOTAGA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0165] Compound 24 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0166] Compound 38 having the formula shown in the Examples section below, a compound in which the DO3AM chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0167] Compound 48 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0168] Compound 49 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0169] Compound 50 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0170] Compound 54 having the formula shown in the Examples section below, a compound in which the DOTAM (or DO3AM) chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0171] Compound 55 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0172] Compound 56 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0173] Compound 57 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0174] Compound 58 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0175] Compound 59 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0176] Compound 61 having the formula shown in the Examples section below, a compound in which the DOTAM (or DO3AM) chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0177] Compound 44 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0178] Compound 45 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0179] Compound 46 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0180] Compound 47 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0181] Compound 51 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in that formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0182] Compound 60 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0183] Compound 52 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0184] Compound 53 having the formula shown in the Examples section below, a compound in which the DOTA chelating group shown in the formula forms a chelate with a chelated radioactive or non-radioactive cation, or any salt thereof.

[0185] In that these exemplary compounds or salts include a chelated radioactive or non-radioactive cation, the cation is preferably a Ga, Lu or Pb cation. In a further aspect, the present invention provides a pharmaceutical composition (also called a therapeutic composition) comprising or consisting of one or more types, preferably one type, of the ligand compounds according to the present invention, i.e. the compounds of formula (I) (including any preferred embodiments thereof) described herein, or salts thereof. In a related aspect, the ligand compounds according to the present invention are provided for use in therapy or as a medicament. Thus, the ligand compounds of the present invention can be used in a therapeutic method, which may include administering the ligand compounds to a subject. The subject may be a human or an animal, preferably a human.

[0186] The above-mentioned treatment or method of treatment is aimed at treating or preventing a disease or disorder of the human or animal body, generally a disease or disorder associated with increased or abnormal expression of somatostatin receptors, preferably a disease or disorder associated with increased or abnormal expression of SST2. The disease or disorder to be treated or prevented can be cancer, preferably a neuroendocrine tumor.

[0187] For example, chelated radioactive cations, e.g. 177 Lu cation or 68 Compounds according to the invention which contain a Ga cation can advantageously be used in radiotherapy, for example in the radiotherapy of the above mentioned diseases or disorders.

[0188] In another aspect, the present invention provides a diagnostic composition comprising or consisting of the ligand compound according to the present invention, i.e. one or more types, preferably one type, of the compounds of formula (I) (including any preferred embodiments thereof) described herein, or salts thereof. In a related aspect, the ligand compound according to the present invention is provided for use in an in vivo method of diagnosis of a disease or disorder. Thus, the ligand compound according to the present invention can be used in a diagnostic method that may include administering the ligand compound to a subject, detecting the ligand compound in the subject, or monitoring the distribution of the ligand compound in the subject, thereby detecting or monitoring the disease to be diagnosed. For example, nuclear imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT), respectively, can be used to detect or monitor the ligand compound according to the present invention. The subject can be a human or an animal, preferably a human. Alternatively, the diagnostic method may also include adding the ligand compound to a sample, for example a physiological sample obtained from a subject, in vitro or ex vivo, and detecting the ligand compound in the sample.

[0189] The above diagnostic method aims at identifying diseases or disorders of the human or animal body, generally diseases or disorders associated with increased or abnormal expression of somatostatin receptors, preferably diseases or disorders associated with increased or abnormal expression of SST2. Thus, in terms of diagnostic applications, the compounds of the present invention are preferably provided for use in an in vivo method for the diagnosis of cancer, more preferably neuroendocrine tumors.

[0190] For example, the SiFA group 18 The compounds of the invention containing F fluoride or a radioactive cation to which the chelating group is chelated, e.g. 68The compounds of the invention containing a Ga cation can advantageously be used in nuclear imaging, for example by positron emission tomography (PET) or by single photon emission computed tomography (SPECT).

[0191] Suitability for therapeutic and diagnostic applications is not mutually exclusive; i.e., the compounds according to the invention may be suitable for both applications. For example, chelated 177 Compounds containing the Lu cation can be used for both therapeutic and diagnostic imaging applications. Furthermore, due to the presence of a chelating group and a SiFA group, the compounds of the present invention are suitable as emissive hybrid (rh) ligands. Such rh ligands are [ 18 F]fluoride (e.g. for PET) or radioactive metals (e.g. for PET) 68 Ga cations, or for radiation therapy 177 Alternatively, the rh ligand can be labeled with [ 18 When the rh ligand is labeled with the corresponding radioactive metal cation, the cold metal cation can, but does not have to, be complexed elsewhere in the molecule; when the rh ligand is labeled with the corresponding radioactive metal cation, the cold metal cation can, but does not have to be complexed elsewhere in the molecule; when the rh ligand is labeled with the corresponding radioactive metal cation, the cold metal cation can be complexed elsewhere in the molecule; 19 F] fluorine may be included. 18 F-labeled peptides and the corresponding radioactive metal-labeled analogs have the same chemical structure and therefore identical in vitro and in vivo properties, thereby enabling the generation of structurally identical theranostic tracers with the exact same in vivo properties of diagnostic and therapeutic tracers (e.g. 18 F / 177 Lu analogues)

[24] .

[0192] Based on this approach, the ligand compounds of the present invention are therefore 18 A non-radioactive cation labeled with F and chelated by the chelating group ( nat Lu or natCompounds containing a radioactive cation (e.g., Ga) and a chelating group that is chelated to the radioactive cation (e.g., 177 Lu or 68 Ga, etc.) and has a silicon fluoride acceptor group 18 Not labeled with F (hence 19 The invention likewise provides compounds of the invention for use in a hybrid method of in vivo diagnosis and treatment of a disease or disorder associated with increased or abnormal expression of the above-mentioned somatostatin receptors, the method comprising first reacting a compound having a silicon fluoride acceptor group 18 A non-radioactive cation labeled with F and chelated by the chelating group ( nat Lu or nat Ga, etc.), followed by administration of a compound of the invention in which the chelating group contains a chelated radioactive cation and the silicon fluoride acceptor group is 18 Requires administration of a compound that is not labeled with F.

[0193] Thus, in another aspect, the present invention provides a dedicated composition comprising or consisting of the ligand compound according to the present invention, i.e. one or more types, preferably one type, of the compound of formula (I) described herein (including any preferred embodiment thereof), or their salts. In a related aspect, the ligand compound according to the present invention is provided for use in an in vivo imaging method of disease or disorder. Thus, the ligand compound according to the present invention can be used in an imaging method, which can include administering the ligand compound to a subject, detecting the ligand compound in the subject, and monitoring the distribution of the ligand compound in vivo at various times after injection, for the purpose of calculating dosimetry before or during a therapeutic treatment. The subject can be a human or an animal, preferably a human.

[0194] Said imaging method is aimed at calculating the dosimetry before or during therapeutic treatment of diseases or disorders of human or animal body, generally diseases or disorders associated with increased or abnormal expression of somatostatin receptors, preferably diseases or disorders associated with increased or abnormal expression of SST2.Therefore, in view of such application, the compound of the present invention is preferably provided for use in in vivo imaging method of cancer, more preferably neuroendocrine tumors.

[0195] For example, the SiFA group 18 F fluoride and non-radioactive nat The compounds of the invention comprising Lu or a radioactive cation to which the chelating group is chelated, e.g. 177 The compounds of the invention, which contain the Lu cation but whose SiFA is non-radioactive, can advantageously be used for nuclear imaging by positron emission tomography (PET) or single photon emission computed tomography (SPECT), respectively, to monitor the distribution of the applied compound and subsequently calculate individual dosimetry with quantitative distribution kinetics.

[0196] The pharmaceutical or diagnostic composition may further comprise one or more pharma- ceutically acceptable carriers, excipients and / or diluents. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline, amino acid buffer (with or without saline), water for injection, emulsions, such as oil / water emulsions, various types of wetting agents, sterile solutions, and the like. Compositions comprising such carriers may be formulated by well-known conventional methods. These compositions may be administered to subjects in appropriate doses. Administration of suitable compositions may be achieved in various ways, for example, by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchial administration. It is particularly preferred that said administration is performed by intravenous injection and / or intravenous delivery. The composition may be administered directly to the target site. The administration schedule will be determined by the attending physician and clinical factors. As is well known in the medical art, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the particular compound being administered, dosimetry, sex, time and route of administration, general health, and other drugs being co-administered. The compound may be administered in an amount between, for example, 0.1 ng and 10 μg / kg body weight. For example, in diagnostic applications, typical dosages of the compounds of the invention or salts thereof range from <100 μg / patient, for example 0.1 to 30 μg / patient, although higher or lower dosages may be envisaged where appropriate. Typical dosages of the compounds of the invention or salts thereof in radiotherapy applications range from 50 to 200 μg / patient, preferably 75 to 150 μg / patient, although higher or lower dosages may be envisaged where appropriate.

[0197] The following items are summaries of aspects of the present invention, it being understood that these items are closely related to the above description, and that the information provided in these items can supplement the above description, and vice versa.

[0198] 1. Formula (I):

[0199] [ka]

[0200] [In the formula, R B is a binding motif capable of binding to the somatostatin receptor, L D1 is a divalent linking group, m is an integer of 2 to 6, preferably 2 to 5, more preferably 2 or 3; A H1 is, independently at each occurrence, an amino acid unit derived from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to the -NH and -COOH functional groups of the hydrophilic amino acid; mUnit A H1 one of which may further have a hydrophilic unit other than an amino acid attached to its hydrophilic functional group; L T1 is a trivalent linking group, R CH is a chelating group which may contain a chelated radioactive or non-radioactive cation, R M1 is a hydrophilic modifying group, p is 0 or 1, L D2 is a divalent linking group, q is 0 or 1, R S is a silicon fluoride acceptor (SiFA) group having one of the following formulae, which contains a silicon atom and a fluorine atom: 19 F 18 By isotopic exchange with F 18 may be labeled with F, or 18 It is labeled with F, If p is 1, then R S represents a group of formula (S-3) or a group of formula (S-4):

[0201] [ka]

[0202] (In the formula, r is 1, 2 or 3, preferably 1, -(CH2) s -s is an integer of 1 to 6, preferably 1; the R groups are independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably both are methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. and If p is 0, R S is a group of formula (S-4) as defined above. or a salt thereof.

[0203] 2. The compound or salt of item 1, wherein the binding motif is capable of binding to somatostatin receptor 2. 3. Binding motif R B Tyr 3 ,Thr 8 -Octreotide (TATE), Tyr 3 -Octreotide (TOC), Thr 8 -Octreotide (ATE), 1-NaI 3 -Octreotide (NOC), 1-Nal 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8 - The compound or salt of item 1 or 2, which is a group derivable from a receptor agonist or receptor antagonist selected from octreotide (BOCATE), JR11, BASS and KE121.

[0204] 4. Binding motif R Bis a group of formula (B-1) or (B-2):

[0205] [ka]

[0206] where the dashed line represents the bond attaching the group to the remainder of the compound. 3. The compound or salt of item 1 or 2, 5. Chelating group R CH teeth, (i) a macrocyclic structure having 8 to 20 ring atoms, of which 2 or more, preferably 3 or more, are selected from oxygen atoms and nitrogen atoms; and (ii) an acyclic open-chain chelating structure having 8 to 20 main chain atoms, of which at least two, preferably at least three, are heteroatoms selected from oxygen and nitrogen atoms; 5. The compound or salt according to any one of items 1 to 4, comprising at least one of:

[0207] 6. Chelating group R CHare diethylenetriaminepentamethylenephosphonic acid (EDTMP) and its derivatives, diethylenetriaminepentaacetic acid (DTPA) and its derivatives, 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- ... Amino]-4-oxobutanoyl]-amino]pentyl]-N-hydroxybutanediamide (DFO) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecane-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 (DO TAM), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphato) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane -4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetate (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetate (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-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), as well as triethylenetetraminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2 macropa), 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), and 1,4,7 ,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid, hydrazinonicotinic acid (HYNIC), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA) and its derivatives, such as (6-pentanoic acid)-6-(amino)methyl-1,4-diazepine triacetate (DATA), etc. , 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-triaminetriacetic acid (BPAM), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamine]ethane (DEDPA, H2DEDPA), deferoxamine (DFO) and its derivatives, 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) and its derivatives, such as YM103. Tetraadicyclodecane-phosphinic acid (TEAP), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr), 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 (H2Bispa, 2), 1,2-[{6-(carboxylato)pyridin-2-yl}methylamino]-ethane (H2 dedopa), N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4 octapa), N,N'-bis(2-hydroxy-5-sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (H6 subpen) and its derivatives, triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetic acid (TTHA), 2-aminomethylpiperidinetriacetic acid (2-AMPTA) and its derivatives, e.g. with additional functional groups suitable for conjugation to peptide structures, 2-AM 6. The compound or salt according to any of items 1 to 5, wherein the group can be derived from a chelating agent selected from 2-(N-(2-hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB), a further functionalized derivative of PTA, 4-nitro-2-hydroxybenzyl-2-{[(6)-trans-2-[benzyl(carboxymethyl)amino]cyclohexyl](carboxymethyl)amino}acetic acid (RESCA) and its derivatives, and 6-carboxy-1,4,8,11-tetraazaundecane (N4) and its derivatives, which chelating group may comprise a chelated radioactive or non-radioactive cation.

[0208] 7. Chelating group R CH is a group derivable from a chelating agent selected from CBTE2a, DOTA, DOTAGA, DOTAM, NODASA, NODAGA, NOTA, TE2A, DO3AM, SarAr, 2-AMPTA, 2-AMPTA-HB and RESCA, the chelating group optionally comprising a chelated radioactive or non-radioactive cation.

[0209] 8. Chelating group R CH is a group derivable from a chelating agent selected from DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, the chelating group may comprise a chelated radioactive or non-radioactive cation.

[0210] 9.R CH is a group of the formula (CH-1), (CH-2) or (CH-3), which may contain a chelated radioactive or non-radioactive cation:

[0211] [ka]

[0212] where the dashed line represents the bond attaching the group to the remainder of the compound. 9. The compound or salt according to any one of items 1 to 8, 10. Chelated cations, if present, 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 55 Co, 57 Co, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 86 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 147 Nd, 149 Gd, 149 Pm, 151 Pm, 149 Tb, 152Tb, 155 Tb, 153 Sm, 156 EU, 157 Gd, 155 Tb, 161 Tb, 164 Tb, 161 Ho, 166 Ho, 157 Dy, 165 Dy, 166 Dy, 160 Er, 165 Er, 169 Er, 171 Er, 166 Yb, 169 Yb, 175 Yb, 167 Tm, 172 Tm, 177 Lu, 186 Re, 186g Re, 188 Re, 188 W, 191 Pt, 195m Pt, 194 Ir, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb, 211 At, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, 226 Th and 227 or comprising or consisting of a cation selected from the cations of Th and non-radioactive isotopes of any of these metals; 18 F or 19 Cationic molecules containing F, e.g. 18 F-[AlF] 2+ 10. The compound or salt according to any one of items 1 to 9,

[0213] 11. Divalent Linking Group L D111. The compound or salt according to any one of items 1 to 10, comprising a divalent oligoethylene glycol group or polyethylene glycol group, preferably a divalent oligoethylene glycol group or polyethylene glycol group having 10 or less ethylene glycol units, more preferably a divalent oligoethylene glycol group or polyethylene glycol group having 2 to 5 ethylene glycol units.

[0214] 12.L D1 is expressed by the formula (L-1a): -C(O)-(CH2) a -(O-CH2-CH2) b -NH- (L-1a) [In the formula, a is 1 or 2, preferably 1; b is an integer from 2 to 5, preferably 2 or 3. The compound or salt of item 11, wherein

[0215] 13. Divalent Linking Group L D1 11. The compound or salt of any of items 1 to 10, comprising a divalent amino acid unit or a divalent chain of amino acid units, more preferably a divalent chain of 2 to 5 amino acid units, even more preferably a divalent chain of 2 or 3 amino acid units.

[0216] 14.L D1 is expressed by the formula (L-1b): -[A L1 ] n - (L-1b) [In the formula, A L1 is, independently for each occurrence when n is greater than 1, an amino acid unit; n is an integer of 1 to 5, preferably 2 to 5, more preferably 2 or 3. The compound or salt of item 13 represented by the formula:

[0217] 15.L D1 15. The compound or salt of item 13 or 14, wherein the amino acid unit of does not contain a free amino group, a free acid group, or a salt thereof. 16.LD1 Each amino acid unit of is a unit of more than one amino acid unit of L D1 16. The compound or salt of any of items 13 to 15, wherein, if present, each occurrence is independently selected from a glycine (Gly) unit, an alanine (Ala) unit, a β-alanine unit, an asparagine (Asn) unit, a glutamine (Gln) unit and a citrulline (Cit) unit.

[0218] 17. Amino acid unit A H1 17. The compound or salt of any of items 1 to 16, wherein each additional hydrophilic functional group is independently selected from -NH, -COOH, -NH-C(=NH)-NH, -C(=O)NH, -NH-C(=O)-NH, -OH and -P(=O)(OH).

[0219] 18. Amino acid unit A H1 Each of v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, wherein v is 1 to 4, and m is an A H1 18. The compound or salt of any of items 1 to 17, wherein the functional group at the end of one of the above side chains is capable of forming a bond with an additional hydrophilic unit other than an amino acid unit.

[0220] 19. Amino acid unit A H1 Each of v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2 and -(CH2) v-NH-C(=O)-NH2, wherein v is 1 to 4, and m is an A H1 19. The compound or salt of item 18, wherein the functional group at the end of one of the above side chains is capable of forming a bond with an additional hydrophilic unit other than an amino acid unit.

[0221] 20. Amino acid unit A H1 is independently selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit and a phosphonomethylalanine (Pma) unit.

[0222] 21. Amino acid unit A H1 is independently selected at each occurrence from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit and a citrulline (Cit) unit.

[0223] 22.A H1 22. The compound or salt of any of items 1 to 21, wherein the hydrophilic unit other than an amino acid unit, optionally attached to, is a carbohydrate group or a trimesic acid group. 23.L T1 teeth, (i) a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, or (ii) -N(R)2, which can be derived from a trifunctional amino acid containing a tertiary amino group selected from N-dialkylated 2,3-diaminopropionic acid (Dap), N-dialkylated 2,4-diaminobutanoic acid (Dab), N-dialkylated ornithine (Orn) and N-dialkylated lysine (Lys). + - group, where the R groups are independently C1-C6 alkyl, preferably methyl. 23. The compound or salt of any of items 1 to 22, wherein the trivalent amino acid unit is selected from:

[0224] 24. p is 1, and the hydrophilic modifying group R M1 24. The compound or salt of any of items 1 to 23, wherein p is a group derivable from a hydrophilic amino acid which contains, in addition to the -NH2 and -COOH functional groups of the hydrophilic amino acid, a further hydrophilic functional group, preferably a hydrophilic functional group selected from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2, -NH-C(=O)-NH2, -OH and -P(=O)(OH)2, or p is 0.

[0225] 25. p is 1, and the hydrophilic modifying group R M1 is an amino acid unit selected from a diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, more preferably a diaminopropionic acid unit, or p is 0.

[0226] 26.q is 1 and a divalent linking group L D2 is expressed as (L-2): -[A L2 ] w - (L-2) [In the formula, A L2 is, independently for each occurrence when w is greater than 1, an amino acid unit; w is 1 to 5, preferably 1 to 3, more preferably 1 or 2. 26. The compound or salt of any one of items 1 to 25, wherein q is a group represented by the formula:

[0227] 27.q is 1 and the amino acid unit A L2 27. The compound or salt of item 26, wherein: is independently selected from a glycine unit and an alanine unit; or q is 0. 28. Formula (I.2):

[0228] [ka]

[0229] [In the formula, R B , L D1 , A H1 , m, L T1 , R CH and R M1 is defined as described in items 1 to 27, R S2 is a group of formula (S-3):

[0230] [ka]

[0231] (In the formula, R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. is] 28. The compound or salt of any one of items 1 to 27,

[0232] 29. Formula (I.4) or (I.5):

[0233] [ka]

[0234] [In the formula, R B , L D1 , A H1 , m, L T1 , R M1 , L D2 , q and R CH is defined as described in items 1 to 27, R S3 is a group of formula (S-4):

[0235] [ka]

[0236] (In the formula, r is 1, 2 or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. is] 28. The compound or salt of any one of items 1 to 27,

[0237] 30. Formula (Ia):

[0238] [ka]

[0239] [In the formula, R B and R CH is defined as described in items 1 to 27, n1 is 2 to 5, preferably 2 or 3; R L1 represents independently at each occurrence H, a C1-C4 alkyl group, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2 and -(CH2) v —OH, where v is 1 to 4; m1 is 2 to 5, more preferably 2 or 3; R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; d is an integer of 0 to 4, preferably 0 or 1; e is an integer of 0 to 4, preferably 0 or 1, more preferably one of d and e is 1 and the other is 0; p1 is 0 or 1, R H2 is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; q1 is an integer of 0 to 2, R L2 is selected from H and CH3, and If p1 is 1, R S1 represents a group of formula (S-3) and a group of formula (S-4)

[0240] [ka]

[0241] (In the formula, r is 1, 2 or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. and If p1 is 0, R S1 is a group of formula (S-4) as defined above. 28. The compound or salt of any one of items 1 to 27,

[0242] 31. Formula (Ia.2):

[0243] [ka]

[0244] [In the formula, R B and R CH is defined as described in items 1 to 27 and 30, n1 is 2 to 5, preferably 2 or 3; R L1 represents independently at each occurrence H, a C1-C4 alkyl group, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2 and -(CH2) v —OH, where v is 1 to 4; m1 is 2 to 5, more preferably 2 or 3; R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; d is an integer from 0 to 4; e is an integer of 0 to 4, preferably one of d and e is 0 and the other is an integer of 1 to 4, more preferably the other is 1; R H2 is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; R S2 is a group of formula (S-3):

[0245] [ka]

[0246] (In the formula, R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound. is] 31. The compound or salt of item 30, which is a compound or salt thereof.

[0247] 32. A compound of formula (Ia.4) or a salt thereof or a compound of formula (Ia.5) or a salt thereof:

[0248] [ka]

[0249] [In the formula, R B and R CH is defined as described in items 1 to 27 and 30, n1 is 2 to 5, preferably 2 or 3; R L1 represents independently at each occurrence H, a C1-C4 alkyl group, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2 and -(CH2) v —OH, where v is 1 to 4; m1 is 2 to 5, more preferably 2 or 3; R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2)v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; d is an integer from 0 to 4; e is an integer of 0 to 4, preferably one of d and e is 0 and the other is an integer of 1 to 4, more preferably the other is 1; R H2 is -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2, -(CH2) v -NH-C(=O)-NH2, -(CH2) v -OH and -(CH2) v -P(=O)(OH)2, where v is 1 to 4; q1 is 0 or an integer from 0 to 2; R L2 is selected from H and CH3, and R S3 is a group of formula (S-4):

[0250] [ka]

[0251] (In the formula, r is 1, 2 or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently H or C1-C6 alkyl, preferably H or C1-C2 alkyl, more preferably methyl; R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1S and R 2Sis selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, and the dashed line attaches the group to the remainder of the compound. is] 31. The compound or salt of item 30,

[0252] 33.R H1 Each occurrence is independently -(CH2) v -NH2, -(CH2) v -COOH, -(CH2) v -NH-C(=NH)-NH2, -(CH2) v -C(=O)NH2 and -(CH2) v 34. The compound or salt of any of items 30 to 33, wherein v is 1 to 4, and is selected from the group consisting of —NH—C(═O)—NH2.

[0253] 34. The chelating group contains a chelated radioactive cation and the silicon fluoride acceptor group is 18 A compound or salt of any of items 1 to 33 not labeled with F.

[0254] 35. A chelated radioactive cation is 177 Lu cation or 68 The compound or salt of item 34, which is a cation of Ga. 36. The silicon fluoride acceptor group is 18 34. The compound or salt of any of items 1 to 33, which is labeled with F and the chelating group contains a chelated non-radioactive cation or does not contain a chelated cation.

[0255] 37. A pharmaceutical composition comprising or consisting of one or more compounds or salts of any of items 1 to 36. 38. A compound or salt of any of items 1 to 36 for use as a medicament.

[0256] 39. A compound or salt of any of items 1 to 36 or a pharmaceutical composition of item 37 for use in the treatment or prevention of cancer, preferably a neuroendocrine tumor. 40. A diagnostic composition comprising or consisting of a compound or salt according to any one of items 1 to 36.

[0257] 41. A compound or salt of any of items 1 to 36 or a diagnostic composition of item 40 for use in an in vivo method for the diagnosis of a disease or disorder. 42. The compound or salt or diagnostic composition for use according to item 41, wherein the disease or disorder is cancer, and the cancer is preferably a neuroendocrine tumor.

[0258] 43. The compound or salt or diagnostic composition for use according to item 41 or 42, wherein the diagnostic method requires nuclear imaging, which is preferably positron emission tomography or single photon emission computed tomography.

[0259] In this specification, several documents are cited, including not only scientific journal articles, but also patent applications and manufacturer's manuals (see, for example, the list of references in this regard below). The disclosures of these documents are not considered relevant to the patentability of the present invention, but are incorporated herein by reference in their entirety. More specifically, all references are incorporated by reference to the same extent as if each document was specifically and individually designated as being incorporated by reference. Abbreviation 2-CTC 2-Chlorotrityl chloride Acm Acetamidomethyl AR42J rat pancreatic exocrine tumor Arg - Arginine Asp·Aspartic acid BA·benzoic acid Boc tert-butoxycarbonyl BSA · Bovine serum albumin CHO Chinese hamster ovary CT - Computed Tomography Cys·Cysteine d·D-isomer, doublet DCM dichloromethane Dde·2-acetyldimedone DIPEA·N,N-Diisopropylethylamine DMEM / F-12 · Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 DMF (Dimethylformamide) DMSO Dimethyl sulfoxide eq・equivalent Electrospray ionization mass spectrometry (ESI-MS) FCS·Fetal calf serum, Fetal calf serum Fmoc Fluorenylmethyloxycarbonyl GBq Gigabecquerel Gly·Glycine GP General Procedures HATU·Hexafluorophosphate azabenzotriazole tetramethyluronium Hanks' Balanced Salt Solution (HBSS) HBSS-B HBSS containing 1% BSA HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HFIP Hexafluoro-2-propanol HOAt·1-Hydroxy-7-azabenzotriazole HOBt Hydroxybenzotriazole HPLC HSA - human serum albumin I C 50 Half-maximal inhibitory concentration J spin-spin coupling K av Partition coefficient l L-isomer, loading density Lys·Lysine M・Molecular weight m / z·mass-to-charge ratio MBq Megabecquerel m exact ·Calculation accurate mass mfound Experimentally determined mass MHz · Megahertz n = number of experimental replicates nm = nanomole, nanometer NMP N-Methylpyrrolidone OI / Optical Imaging Ornithine p·para PBS (phosphate buffered saline) PCC Pyridinium Chlorochromate PEG (Polyethylene glycol) PET / Positron Emission Tomography PG・protecting group Phe·Phenylalanine PLL Poly-L-lysine Pma·phosphonomethylalanine ppm・parts per million Rf・retention factor RP / Reverse Phase RT / room temperature s Single line SiFA: Silicon Fluoride Acceptor SPECT / Single-Photon Emission Computed Tomography SST2 - somatostatin receptor type 2 TATE Tyr 3 -Octoleotate TBDMS tert-butyldimethylsilyl TBq terabecquerel TBTU hexafluorophosphate benzotriazole tetramethyluronium tBu tert-Butyl TFA trifluoroacetic acid THF Tetrahydrofuran Thr Threonine TIPS Triisopropylsilane TLC Thin Layer Chromatography TOC·Octreotide t R ·Retention time TRIS (Tris(hydroxymethyl)aminomethane) Trp - Tryptophan Tyr - Tyrosine UV / VIS・Ultraviolet / Visible v / v volume percentage V0 Void volume V e Dissolution volume Vol-% Volume Percentage Xaa Amino Acid Gamma δ Chemical shift, in ppm EXAMPLES

[0260] I. Materials and Methods 1.General method 1.1 Reagents, solvents and radioisotopes Reagents and solvents were used without further purification. Solvents used were purchased from VWR International (Buchsal, Germany) or Sigma Aldrich (Munich, Germany). Water for HPLC-solvents was obtained from an in-house Millipore system at Thermo Fischer Scientific Inc. (Waltham MA, USA) and Tracepure water was obtained from Merck Millipore (Darmstadt, Germany). Amino acids were purchased from IRIS Biotech GmbH (Marktredewitz, Germany), Sigma-Aldrich (Munich, Germany), Carbolution Chemicals GmbH (St. Ingbert, Germany), and Merck Millipore (Darmstadt, Germany). Resins were purchased from IRIS Biotech GmbH (Marktredewitz, Germany) or CEM (Matthews, USA). Coupling reagents and other chemicals were obtained from Sigma-Aldrich (Munich, Germany), Molekula GmbH (Garching, Germany), CEM (Matthews, USA) and Macrocyclics Inc. (Dallas, USA). Chemicals for synthesis were purchased from Sigma-Aldrich (Munich, Germany) and Merck KGaA (Darmstadt, Germany). The chelators used were obtained from CheMatech (Dijon, France). 125 Radiolabeling with I was performed using 100 mM NaOH in 40 mM NaOH at HARTMANN ANALYTIC GmbH (Braunschweig, Germany). 125 The experiment was carried out using a [I]NaI solution (74 TBq / mmol) for radiolabeling. 18 F was received from Klinikum Rechts der Isar (Technische Universitat Munchen, Munchen, Germany). Biochemicals such as cell culture medium, PBS, and trypsin were purchased from Biochrom GmbH (Berlin) and Sigma-Aldrich (Munchen, Germany). 1.2 Instrumentation and Analysis 1.2.1 RP-HPLC system Reaction control and quality control were performed by analytical RP-HPLC. For this purpose, a linear gradient of MeCN (0.1% TFA, 2% H2O; v / v) in H2O (0.1% TFA; v / v) was performed. The respective gradient can be obtained from the synthesis instructions. Detection was performed by a UV / VIS detector at λ=220 nm or λ=254 nm. All RP-HPLC chromatograms were evaluated using LabSolutions software from Shimadzu Corporation (Kyoto, Japan). For analytical tests, the following systems were used: Shimadzu Corporation (Kyoto, Japan): two LC-20AD gradient pumps, a CBM-20A communication module, a CTO-20A column oven, an SPD-20A UV / VIS detector, and a MultoKrom 100-5C 18 -column (5 μm, 125 × 4.6 mm, CS Chromatographie GmbH, Langerwehe, Germany), flow rate 1 mL / min.

[0261] Complete purification of intermediates and final products was carried out by semi-preparative RP-HPLC. Here again a linear gradient of MeCN (0.1% TFA, 5% H2O; v / v) in H2O (0.1% TFA; v / v) was carried out. The respective gradient can be obtained from the synthesis instructions. Detection was performed by UV / VIS detector at λ=220 nm or λ=254 nm. All RP-HPLC chromatograms were evaluated using LabSolution software from Shimadzu Corporation (Kyoto, Japan). For preparative purification, two systems from Shimadzu Corporation (Kyoto, Japan) were used. Shimadzu Corporation (Kyoto, Japan): two LC-20AP gradient pumps, a DGU-20A degassing unit, a CBM-20A communication module, a CTO-20A column oven, an SPD-20A UV / VIS detector, and a MultoKrom 100-5 C 18 -column (5 μm, 250 × 10 mm, CS Chromatographie GmbH, Langerwehe, Germany), flow rate 5 mL / min. Shimadzu Corporation (Kyoto, Japan): two LC-20AT gradient pumps, a DGU-20A degassing unit, a CBM-20A communication module, an SPD-20A UV / VIS detector, and a MultoKrom 100-5 C 18 -column (5 μm, 250 × 10 mm, CS Chromatographie GmbH, Langerwehe, Germany), flow rate 5 mL / min. 1.2.2 ESI-MS spectroscopy Mass spectrometry was performed using an Expression CMS quadrupole device from Advion Inc. (Ithaca, USA). 1.2.3 Flash Chromatography Flash chromatography purification was performed on an Isolera™ Prime System from Biotage (Uppsala, Sweden) using a Biotage 09474 Rev.E Bio pump from Biotage. For purification, a linear gradient of MeCN (0.1% TFA, 2% H2O; v / v) in H2O (0.1% TFA; v / v) was performed. In addition, a Biotage™ SNAP KP-C pump from Biotage (Uppsala, Sweden) was used. 18 Cartridge (12g cartridge material, pore size: 93Å, surface area: 382m 2 / g was used. 1.2.4 Lyophilization Freeze-drying of intermediates and final products was performed in an Alpha1-2 freeze-dryer from Christ (Osterode am Harz, Germany) using an RZ-2 vacuum pump from Vacubrand GmbH. The substances to be dried were previously dissolved in HO and tBuOH (1 / 1; v / v) and the solution was frozen at -80 °C. 1.2.5 NMR 1 H- and 13 C-NMR spectra were recorded at 300 K on a Bruker (Billerica, Massachusetts, USA) AVHD-300 or AVHD-400. 1 H and 13C chemical shifts are reported in ppm and are referenced to residual protons of the solvent. Deuterated solvents were obtained from Sigma Aldrich. 2.Organic synthesis 2.1 Synthesis of SiFA-Br and SiFA-BA

[0262] [ka]

[0263] ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane (B2)

[0264] [ka]

[0265] In a round-bottom flask, 4.68 g of 4-bromobenzyl alcohol (B1, 25.0 mmol, 1.00 equiv.) are dissolved in 70 mL of anhydrous DMF and stirred. 2.04 g of imidazole (30.0 mmol, 1.20 equiv.) and 4.52 g of TBDMS-chloride (30.0 mmol, 1.20 equiv.) are added with stirring. The mixture is allowed to react for 20 h at room temperature. The reaction product is then poured into 250 mL of ice-cold H2O and the organic phase is extracted with Et2O (5 x 50 mL). The combined organic phase is washed with a saturated aqueous solution of NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. The solvent is evaporated under reduced pressure and the crude product is purified by column chromatography (5% EtOAc in petroleum ether). After evaporating the solvent under reduced pressure, 7.24 g of product B2 (24.1 mmol, 96%) is obtained as a colorless oil. TLC (SiO2, 5% EtOAc / petroleum ether): R f =0.97[UV] 1 H-NMR (300 MHz, CDCl3): δ[ppm] = 7.45 (d, 3 J = 8 Hz, 2 H, H Ar ), 7.20 (d, 3 J = 8 Hz, 2 H, HAr ), 4.68 (s, 2 H, Ar-CH2), 0.94 (s, 9 H, C-CH3), 0.10 (s, 6 H, Si-CH3). 13 C-NMR (75 MHz, CDCl3): δ [ppm] = 140.3 (s, C i ), 130.1 (s, C m ), 127.5 (s, C o ) 120.4 (s, C p ), 64.2, (s, CH2), 25.8 (s, C-CH3), 18.2, (s, C-CH3) 5.4 (s, Si-CH3). Di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane (B3)

[0266] [ka]

[0267] In an argon atmosphere, 7.24 g of B2 (24.1 mmol, 1.00 equiv.) is dissolved in 67 mL of anhydrous THF and cooled to -78°C (dry ice and acetone). Over a period of 1.5 hours, 32.6 mL of a 1.7 M solution of tBuLi in pentane (55.4 mmol, 2.30 equiv.) is slowly added dropwise to the solution of B2 in THF. This mixture is stirred at -78°C for an additional 30 minutes. In a separate round-bottom flask, 5.00 g of di-tert-butyldifluorosilane (27.7 mmol, 1.10 equiv.) is dissolved in 44 mL of anhydrous THF and also cooled to -78°C. With continuous stirring over a period of 2 hours, the mixture of B2 and tBuLi in THF is slowly added dropwise to the solution of di-tert-butyldifluorosilane. The reaction product is allowed to warm to room temperature and stirred for an additional 15 hours. The reaction is quenched by the addition of 120 mL of brine and the organic phase is separated. The aqueous phase is extracted with Et2O (3 x 100 mL), the combined organic phases are dried over MgSO4 and the solvent is evaporated under reduced pressure. The product B3 is obtained as a yellowish oil (9.14 g, 23.9 mmol, 99%). 13 C-NMR (75 MHz, CDCl3): δ [ppm] = 143.0 (s, C i ), 134.1 (d, 3 J ( 13 C, 19 F) = 12 Hz, C m ), 132.0 (d, 2 J ( 13 C, 19 F) = 56 Hz, C p ), 125.3 (s, C o ), 65.0 (s, CH2), 27.5 (s, CH3), 26.8 (s, C-CH3), 26.1 (s, CH3), 20.4 (d, 2 J ( 13 C, 19 F) = 8 Hz, C-CH3), 5.11 (s, Si-CH3). (4-(di-tert-butylfluorosilyl)phenyl)methanol (B4)

[0268] [ka]

[0269] Compound B3 (9.14 g, 23.9 mmol, 1.00 equiv.) is dissolved in 50 mL MeOH. After adding 3.00 mL concentrated HCl (97.9 mmol, 4.10 equiv.), the solution is reacted at room temperature for 18 h. The mixture is concentrated under reduced pressure, the precipitate is dissolved in 50 mL Et2O and the organic phase is washed with 50 mL of a saturated aqueous solution of NaHCO3. The aqueous phase is extracted with Et2O (3 x 50 mL) and the combined organic phases are combined and dried over MgSO4. The solvent is evaporated under reduced pressure to give product B4 (5.90 g, 22.0 mmol, 92%) as a yellowish oil. 1 H-NMR (CDCl3): δ [ppm] = 7.61 (d, 2 H, 3 J = 8 Hz, H Ar ), 7.38 (d, 2 H, 3 J = 8 Hz, H Ar), 4.72 (s, 2 H, Ar-CH2), 1.06 (s, 18 H, C-CH3). 13 C-NMR (CDCl3): δ [ppm] = 142.3 (s, C i ), 134.4 (d, 3 J ( 13 C, 19 F) = 12 Hz, C m ), 133.1 (d, 2 J ( 13 C, 19 F) = 56 Hz, C p ), 125.6 (s, C o ), 65.4 (s, CH2), 27.4 (s, CH3), 20.4 (d, 2 J ( 13 C, 19 F) = 8 Hz, C-CH3). HPLC (50-100% B in 15 min) R =10.7 minutes. 4-(Di-tert-butylfluorosilyl)benzaldehyde (B5)

[0270] [ka]

[0271] Alcohol B4 (5.90 g, 55.0 mmol, 2.5 equiv.) is dissolved in 60 mL of anhydrous DCM and slowly added dropwise to an ice-cold solution of 11.9 g of PCC (55.0 mmol, 2.5 equiv.) in 180 mL of DCM. The solution is stirred for 30 min at 0 °C and for another 4 h at room temperature. The reaction is stopped by the addition of 60 mL of Et2O and the supernatant is decanted. The insoluble black residue is washed thoroughly with Et2O and the combined organic phases are filtered through a short silica plug. After evaporation of the solvent under reduced pressure, purification is performed by column chromatography (2.5% EtOAc in petroleum ether). The product B5 is obtained as a yellowish oil that slowly crystallizes to a yellowish solid (2.22 g, 8.33 mmol, 36%). 1H-NMR (CDCl3): δ [ppm] = 10.1 (s, 1 H, CHO), 7.88 (d, 3 J = 6 Hz, 2 H, H Ar ), 7.79 (d, 3 J = 9 Hz, 2 H, H Ar ), 1.07 (s, 18 H, C-CH3). 13 C-NMR (CDCl3): δ [ppm] = 192.7 (s, CHO), 142.5 (s, C i ), 137.2 (s, C p ), 134.7 (d, 3J ( 13 C, 19 F) = 12 Hz, C m ), 128.6 (s, C o ), 27.4 (s, CH3), 20.5 (s, C-CH3). 18 F-NMR (CDCl3) = δ [ppm] = 188.4 (s, F). HPLC (50-100% B in 15 min) R =15.9 minutes. 4-(Di-tert-butylfluorosilyl)benzoic acid (SiFA-BA)

[0272] [ka]

[0273] Aldehyde B5 (1.0 equiv.) is dissolved in tBuOH (23 mL / g starting material), DCM (2.5 mL / g starting material) and NaH2PO4×H2O (1.25 M, pH=4.0-4.5, 15 mL / g extract) and aqueous KMnO4 (1 M, 23 mL / g starting material) are added. After stirring for 25 min, the mixture is cooled to 5 °C. The reaction is quenched by adding KMnO4 (1.0 equiv.) followed immediately by the addition of a saturated aqueous solution of NaHCO3. The mixture is dried over MgSO4 and the solvent is evaporated under reduced pressure. The crude product is purified by recrystallization from Et2O / n-hexane (1 / 3 v / v) to give SiFA-BA as a colorless solid (60% yield). 1 H-NMR (300 MHz, CDCl3): δ [ppm] = 8.10 (d, 3 J = 8.1 Hz, 2 H, H m ), 7.74 (d, 3 J = 8.1 Hz, 2 H, H o ), 1.07 (s, 18H, CCH3). 13 C-NMR (75 MHz, CDCl3): δ [ppm] = 171.0 (s, COOH), 141.4 (d, C p ), 134.2 (d, C m ), 129.0 (d, C i;o ), 27.4 (s, CCH3), 20.4 (d, CCH3). RP-HPLC (50-100% in 15 min) R =8.4 minutes. (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (SiFA-Br)

[0274] [ka]

[0275] To a solution of B4 (3.08 g, 11.5 mmol, 1.0 equiv.) and tetrabromomethane (4.18 g, 12.6 mmol, 1.1 equiv.) in 100 mL of DCM cooled to 0° C., triphenylphosphine (3.30 g, 12.6 mmol, 1.1 equiv.) was added in portions over 30 min. The solution was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was washed with cold n-hexane (3×50 mL). The white precipitate was removed by filtration and the solution was concentrated in vacuo. Purification was carried out by flash column chromatography (silica, 5% EtOAc in petroleum, v / v). Compound SiFA-Br was isolated as a colorless oil (3.06 g, 9.20 mmol, 80%). RP-HPLC (50-100% B in 15 min): R =9.2 minutes, K'=3.73. 1 H-NMR (400 MHz, CDCl3): δ [ppm] = 7.58 (2 H, d, C6H4), 7.40 (2 H, d, C6H4), 4.49 (2 H, s, CH2OSi), 1.05 (18 H, s, Si(tBu)2). 3. Peptide Synthesis 3.1 General Procedures (GP) 3.1.1 General Procedure for Solid Phase Peptide Synthesis (SPPS) Peptides are synthesized on resin using solid phase peptide synthesis with the Fmoc strategy, using Fmoc as a temporary protecting group. The resin is loaded with an amino acid (Xaa) protected with Fmoc, which is then Fmoc deprotected and reacted with the next amino acid. After completion of the desired peptide, it is separated from the resin. Before peptide elongation, cleavage of the protecting group or any other type of chemical modification, the already loaded resin must be swollen in an appropriate solvent (DMF, DCM, NMP) for 30 minutes. After each reaction step, the resin must be washed thoroughly with the solvent used for the reaction. If no further reaction steps are performed, the resin must be washed with DCM and dried in vacuum. GP1:2-CTC-resin loading Loading of Fmoc-protected amino acids (Fmoc-Xaa-OH) onto 2-chlorotrityl chloride resin (2-CTC) is carried out by stirring a suspension of 2-CTC-resin (1.60 mmol / g) and Fmoc-Xaa-OH (0.70 equiv.) in DMF with DIPEA (4.5 equiv.) for 4 h at room temperature. The remaining trityl chloride is capped for 15 min by adding methanol (2 mL / g resin). The resin is then filtered, washed with DMF (5 x 5 mL / g resin), methanol (3 x 5 mL / g resin) and dried in vacuum. The final loading of Fmoc-Xaa-OH is determined by the following equation:

[0276]

number

[0277] GP2: Peptide formation on resin The respective side chain protected Fmoc-Xaa-OH (1.5 equiv.) is dissolved in DMF (8 mL / g resin) and preactivated by adding TBTU or HATU (1.5 equiv.), HOBt or HOAt (1.5 equiv.), and DIPEA (4.5 equiv.) or 2,4,6-collidine (5.5 equiv.). The solution is preactivated for 10 min and then the resin-bound peptide NH2-(Xaa) x Add -2-CT and shake for 2 hours at room temperature. For amino acids prone to racemization (e.g. Dap, Cys), the preactivation time is strictly limited to 2 minutes and 2,4,6-collidine is used as base. The resin is then washed with DMF (6 x 5 mL / g resin) and, after Fmoc deprotection, the next amino acid is coupled in the same way. Coupling of non-amino acid building blocks (e.g. SiFA-BA) is performed following the same protocol. GP3: Chelator conjugation on resin The chelator (1.5 equiv.) (e.g. DOTA(tBu)3, R / S-DOTAGA(tBu)4) is dissolved in DMF (8 mL / g resin) and preactivated by adding HATU (1.5 equiv.), HOAT (1.5 equiv.) and DIPEA (4.5 equiv.). After 10 min of preactivation, the solution is mixed with the resin-bound peptide H2N-(Xaa) x Add to -2-CT and shake for 6-18 h. Completion of the reaction should be confirmed by RP-HPLC and ESI-MS. The resin is then washed with DMF (6 x 5 mL / g resin). GP4: On-resin Fmoc deprotection The resin-bound Fmoc-peptide is treated with 20% piperidine in DMF (v / v, 8 mL / g resin) for 5 min followed by 15 min. The resin is then washed extensively with DMF (8 x 5 mL / g resin). GP5: On-resin Dde deprotection Dde deprotection is carried out by adding a solution of imidazole (0.46 g), hydroxylamine hydrochloride (0.63 g) in NMP (2.5 mL) and DCM (0.5 mL) for 3 h at room temperature. After deprotection, the resin is washed with DMF (6 x 5 mL / g resin). GP6: Cleavage of peptides from resin (preservation of acid-labile groups) The resin-bound peptide is cleaved, dissolved in a mixture of HFIP / DCM (v / v; 4 / 1, 8 mL / g resin) and shaken for 45 min. The solution containing the fully protected peptide is filtered off and the resin is treated with another portion of the cleavage solution for 45 min. Both fractions are combined and the solvent is removed in vacuo. After lyophilization in tBuOH / H2O, the crude fully protected peptide is obtained. GP7: Cleavage of peptides from the resin (deprotection of all acid labile groups) The fully protected, resin-bound peptide is dissolved in a mixture of TFA / TIPS / H2O (v / v / v; 90 / 2.5 / 7.5) and shaken for 45 min. The solution is filtered off and the resin is treated similarly for another 45 min. Complete deprotection is achieved by combining both filtrates and incubating at 40°C for 1 h and at room temperature for 2 h (no chelator with obvious tBu-protecting group in peptide) or 12 h (chelator with obvious tBu-protecting group in peptide, e.g. DOTA(tBu)3). After concentration under a stream of nitrogen, the crude product is dissolved in a mixture of tert-butanol and water and subsequently lyophilized to obtain the crude peptide. GP8: Reaction control by test cutting To verify the completion of amino acid coupling or any other type of chemical modification, a small portion of the resin is transferred into a 1.5 mL reaction tube and treated with the solutions described in GP6 and GP7 to obtain either protected (described below as gentle test cleavage) or unprotected (described below as harsh test cleavage) peptides. After concentration under a stream of nitrogen, the residue is dissolved in RP-HPLC solvents and is therefore suitable for RP-HPLC and ESI-MS investigations. 3.1.2 General procedure for synthesis in solution GP9: [ nat Formation of Ga complexes The ligand is dissolved in DMSO at a concentration of 2 mM. The solvent for purification by semi-preparative RP-HPLC is acidified with TFA, so the formation of a TFA salt is assumed and included in the molecular weight. For complex formation, a given volume of peptide solution is dissolved in 1.5 equivalents of [ nat Mix with Ga]Ga(NO3)3. Add DMSO to produce a final concentration of 1 mM. Leave the solution at 70°C for 40 min and check the stoichiometric conversion of the chelator by RP-HPLC and ESI-MS. GP10: [ nat Formation of [Lu] complexes The ligand is dissolved in DMSO at a concentration of 2 mM. The solvent for purification by semi-preparative RP-HPLC is acidified with TFA, so the formation of a TFA salt is assumed and included in the molecular weight. For complex formation, a given volume of peptide solution is dissolved in 1.5 equivalents of [ nat Mix with [Lu]LuCl3. Add DMSO to produce a final concentration of 1 mM. Leave the solution at 70° C. for 40 min and check the stoichiometric conversion of the chelator by RP-HPLC and ESI-MS. GP11: [ nat Pb] complex formation The ligand is dissolved in DMSO at a concentration of 2 mM. The solvent for purification by semi-preparative RP-HPLC is acidified with TFA, so the formation of a TFA salt is assumed and included in the molecular weight. For complex formation, a given volume of peptide solution is dissolved in 1.1 equivalents of [ nat Mix with [Pb]PbCl2. Add DMSO to produce a final concentration of 1 mM. Leave the solution at 70° C. for 40 min and check the stoichiometric conversion of the chelator by RP-HPLC and ESI-MS. 3.2 Composition of Components Synthesis of SiFA-BA-D-Asp-OtBu (B6)

[0278] [ka]

[0279] The on-resin synthesis of SiFA-BA-D-Asp-OtBu (B6) is carried out applying general procedures GP1, GP2, GP4 and GP6. Briefly, Fmoc-D-Asp-OtBu (0.7 eq.) is loaded onto 2-CTC resin (1.0 eq.; loading capacity 1.6 mmol / g). After Fmoc deprotection, HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.) are applied to conjugate SiFA-BA (1.5 eq.). To separate the peptide from the resin while preserving the tBu-protecting group, the resin is treated with HFIP / DCM (v / v; 4 / 1, 8 mL / g resin) as described in GP6. After final lyophilization, the crude product B6 is obtained as a colorless solid. Correct product formation is confirmed by RP-HPLC and ESI-MS. RP-HPLC (10-90% in 15 min): R =17.1 minutes. ESI-MS: exact (C 19 H 28 FNO5Si):397.2;m found : m / z=398.2[M+H] + .

[0280] [ka]

[0281] Synthesis of Boc-D-Orn(Boc)-D-Orn(Boc)-OH (B7)

[0282] [ka]

[0283] The on-resin synthesis of Boc-D-Orn(Boc)-D-Orn(Boc)-OH (B7) is carried out applying general procedures GP1, GP2, GP4 and GP6. Briefly, Fmoc-D-Orn(Boc)-OH (0.7 eq.) is loaded onto 2-CTC resin (1.0 eq.; loading capacity 1.6 mmol / g). After Fmoc deprotection, Boc-D-Orn(Boc)-OH (1.5 eq.) is conjugated applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). Mild peptide cleavage from the resin is carried out according to GP6. After final lyophilization, the crude product B7 is obtained as a colorless solid. Correct product formation is confirmed by RP-HPLC and ESI-MS.

[0284] [ka]

[0285] 3.3 Synthesis of binding motifs 3.3.1 Tyr 3 -Octoleotate (TATE or X1)

[0286] [ka]

[0287] Peptide sequence The on-resin synthesis of fully protected TATE is performed similarly to published protocols [19, 25], applying general procedures GP1, GP2 and GP4. Briefly, Fmoc-L-Thr(tBu)-OH (0.7 equiv.) is loaded onto 2-CTC resin (1.0 equiv.; loading capacity 1.6 mmol / g), followed by Fmoc deprotection and subsequent coupling of Fmoc-L-Cys(Acm)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Cys(Acm)-OH and Fmoc-D-Phe-OH. For the conjugation of all amino acids the following protocol is applied: Fmoc-Xaa-OH (1.5 eq.), HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). The Fmoc protecting group of the last amino acid remains until the formation of the disulfide bridge. Formation of disulfide bridges [19, 25-27] Fmoc-D-Phe-L-Cys(Acm)-L-Tyr(tBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(tBu)-L-Cys(Acm)-L-Thr(tBu)-2-CT (1.0 equiv.) is treated with Tl(TFA)3 (4.0 equiv.) in DMF for 45 min. After discarding the first solution, the procedure is repeated with a new portion of Tl(TFA)3 for another 45 min. The resin is washed with DMF (6 × 5 mL / g resin) and the completion of the cyclization is verified by RP-HPLC and ESI-MS (test cleavage: TFA / HO / TIPS 90 / 2.5 / 7.5), confirming the synthesis of Fmoc-D-Phe-cyclo[L-Cys-L-Tyr(tBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(tBu)-L-Cys]-L-Thr(tBu)-2-CT. Finally, the peptide is Fmoc-deprotected to obtain H-TATE(PG)-2-CT(X1). RP-HPLC (10-90% in 15 min): R =10.8 minutes. ESI-MS: exact (C 64 H 74 N10 O 14 S2):1270.5;m found :m / z=1273.4[M+H] + .

[0288]

change

[0289] 3.3.2 JR11(X25)

[0290]

change

[0291] The synthesis on resin of the fully protected JR11 (X25) is carried out similarly to that described for X1, applying general procedures GP2 and GP4. Unlike the synthesis described for TATE-based peptides, the resin applied here is Rink-amide resin. No specific loading protocol is required for this type of resin, therefore the first amino acid (Fmoc-D-Tyr(tBu)-OH, 1.5 eq.) is directly conjugated, applying HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.0 eq.). Then Fmoc deprotection is followed by coupling of Fmoc-L-Cys(Acm)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-D-Aph(Cbm)-OH, Fmoc-L-Aph(Hor)-OH, Fmoc-D-Cys(Acm)-OH and Fmoc-L-Phe(4-Cl)-OH. For the conjugation of all amino acids, the following protocol is applied: Fmoc-Xaa-OH (1.5 eq.), HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.0 eq.). The Fmoc protecting group of the last amino acid remains until the disulfide bridge is formed. The formation of the disulfide bridge is carried out similarly to the synthesis described for X1. The completion of the cyclization is verified by RP-HPLC and ESI-MS (test cleavage: TFA / HO / TIPS 90 / 2.5 / 7.5), confirming the synthesis of Fmoc-L-Phe(4-Cl)-cyclo[D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys(Boc)-L-Thr(tBu)-L-Cys]-D-Tyr(tBu)-rink-amide. Finally, the peptide is Fmoc-deprotected to give H-JR11(PG)-2-CT(X25). RP-HPLC (10-90% in 15 min): R =9.90 minutes. ESI-MS: exact (C 77 H 90 ClN 15 O 16 S2): 1522.5;m found : m / z=763.7[M+2H] 2+ , 1524.2[M+H]+ . 3.4 Synthesis of ligands 3.4.1 Precursor synthesis Synthesis of H-PEG1-TATE(PG)-2-CT(X4)

[0292] [ka]

[0293] The synthesis of H-PEG1-TATE(PG)-2-CT (X4) is carried out by applying GP2 and GP4. Briefly, resin-bound X1 (1.0 equiv.) is conjugated with Fmoc-O2Oc-OH (Fmoc-PEG1-OH, 1.50 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). Final Fmoc deprotection gives compound X4. H-[Gly] 1~3 Synthesis of -TATE(PG)-2-CT (X12, X5, X13)

[0294] [ka]

[0295] The synthesis of H-Gly-TATE(PG)-2-CT(X12), H-Gly-Gly-TATE(PG)-2-CT(X5) and H-Gly-Gly-Gly-TATE(PG)-2-CT(X13) is carried out similarly, applying GP2 and GP4. Briefly, resin-bound X1 (1.0 equiv.) is conjugated once, twice or three times with Fmoc-Gly-OH (1.5 equiv.) applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). Final Fmoc deprotection gives compounds X12, X5 and X13. Synthesis of HL / D-Asn(Trt)-L / D-Asn(Trt)-TATE(PG)-2-CT (X6 and X16)

[0296] [ka]

[0297] The synthesis of HL-Asn(Trt)-L-Asn(Trt)-TATE(PG)-2-CT (X6) and HD-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT (X16) is carried out by applying GP2 and GP4. Briefly, resin-bound X1 (1.0 equiv.) is conjugated twice with Fmoc-L-Asn(Trt)-OH (1.5 equiv.) or Fmoc-D-Asn(Trt)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). Final Fmoc deprotection gives compounds X6 and X16. Synthesis of H-Gly-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT(X17)

[0298] [ka]

[0299] The synthesis of H-Gly-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT (X17) is carried out by applying GP2 and GP4. Briefly, resin-bound X1 (1.0 equiv.) is conjugated twice with Fmoc-D-Asn(Trt)-OH (1.5 equiv.) and once with Fmoc-Gly-OH by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). Final Fmoc deprotection gives compound X17. HD-Asp(tBu)-D-Asp(tBu)-PEG1-TATE(PG)-2-CT(X7)

[0300] [ka]

[0301] The synthesis of HD-Asp(tBu)-D-Asp(tBu)-PEG1-TATE(PG)-2-CT (X7) is carried out by applying GP2 and GP4. Briefly, resin-bound X4 (1.0 equiv.) is conjugated twice with Fmoc-D-Asp(tBu)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). Final Fmoc deprotection gives compound X7. HD-Asp(tBu)-D-Asp(tBu)-Gly-TATE(PG)-2-CT(X14)

[0302] [ka]

[0303] Starting from resin-bound X12, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-Gly-TATE(PG)-2-CT (X14) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-TATE(PG)-2-CT(X8)

[0304] [ka]

[0305] Starting from resin-bound X5, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-TATE(PG)-2-CT (X8) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-Gly-TATE(PG)-2-CT(X15)

[0306] [ka]

[0307] Starting from resin-bound X13, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-Gly-TATE(PG)2-CT (X15) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. HD-Asp(tBu)-D-Asp(tBu)-L-Asn(Trt)-L-Asn(Trt)-TATE(PG)-2-CT(X9)

[0308] [ka]

[0309] Starting from resin-bound X6, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-L-Asn(Trt)-L-Asn(Trt)-TATE(PG)-2-CT (X9) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. HD-Asp(tBu)-D-Asp(tBu)-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT(X18)

[0310] [ka]

[0311] Starting from resin-bound X16, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT (X18) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. HD-Asp(tBu)-D-Asp(tBu)-Gly-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT(X19)

[0312] [ka]

[0313] Starting from resin-bound X17, the synthesis of HD-Asp(tBu)-D-Asp(tBu)-D-Asn(Trt)-D-Asn(Trt)-TATE(PG)-2-CT (X19) is carried out analogously to the synthesis of X7. All synthetic steps are transferable. Synthesis of HD-Orn(Boc)-D-Orn(Boc)-Gly-Gly-TATE(PG)-2-CT(X10)

[0314] [ka]

[0315] Starting from resin-bound X5, the synthesis of HD-Orn(Boc)-D-Orn(Boc)-Gly-Gly-TATE(PG)-2-CT (X10) is carried out similarly to the synthesis of X7. Unlike X7, Fmoc-D-Orn(Boc)-OH is used as the amino acid instead of Fmoc-D-Asp(tBu)-OH. All other steps are transferable. Synthesis of HD-Orn(Boc)-D-Orn(Boc)-Gly-Gly-Gly-TATE(PG)-2-CT(X23)

[0316] [ka]

[0317] Starting from resin-bound X13, the synthesis of HD-Orn(Boc)-D-Orn(Boc)-Gly-Gly-Gly-TATE(PG)-2-CT (X23) is carried out analogously to the synthesis of X10. All synthetic steps are transferable. Synthesis of HD-Asn(Trt)-D-Asn(Trt)-Gly-Gly-TATE(PG)-2-CT(X11)

[0318] [ka]

[0319] Starting from resin-bound X5, the synthesis of HD-Asn(Trt)-D-Asn(Trt)-Gly-Gly-TATE(PG)-2-CT (X11) is carried out similarly to the synthesis of X7. Unlike X7, Fmoc-D-Asn(Trt)-OH is used as the amino acid instead of Fmoc-D-Asp(tBu)-OH. All other steps are transferable. Synthesis of HD-Asn(Trt)-D-Asn(Trt)-Gly-Gly-Gly-TATE(PG)-2-CT(X24)

[0320] [ka]

[0321] Starting from resin-bound X13, the synthesis of HD-Asn(Trt)-D-Asn(Trt)-Gly-Gly-Gly-TATE(PG)-2-CT (X24) is carried out analogously to the synthesis of X11. All synthetic steps are transferable. Synthesis of HD-Lys(Boc)-D-Asp(tBu)-D-Asp(tBu)-Gly-Gly-TATE(PG)-2-CT(X20), HD-Cit-D-Asp(tBu)-D-Asp(tBu)-Gly-Gly-TATE(PG)-2-CT(X21) and HD-Glu(tBu)-D-Asp(tBu)-D-Asp(tBu)-Gly-Gly-TATE(PG)-2-CT(X22)

[0322] [ka]

[0323] The synthesis of X20, X21 and X22 is carried out by applying GP2 and GP4. Briefly, X15 (1.0 eq.) bound to resin is conjugated with either Fmoc-D-Lys(Boc)-OH (1.5 eq.) or Fmoc-D-Cit-OH (1.5 eq.) or Fmoc-D-Glu(tBu)-OH (1.5 eq.) by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). Final Fmoc deprotection gives compounds X20, X21 and X22. HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-Gly-JR11(PG)-rink-amide (X26)

[0324] [ka]

[0325] The synthesis of HD-Asp(tBu)-D-Asp(tBu)-Gly-Gly-Gly-JR11(PG)-rink-amide (X26) is carried out by applying GP2 and GP4. Briefly, resin-bound X25 (1.0 equiv.) is conjugated three times with Fmoc-Gly-OH and then twice with Fmoc-D-Asp(tBu)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and DIPEA (4.0 equiv.). Final Fmoc deprotection gives compound X26. 3.4.2 Ligand synthesis: simple SiFA-moieties Synthesis of 1 (reference ligand)

[0326] [ka]

[0327] The synthesis of ligand 1 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X7 (1.0 eq.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 eq.) by applying HOBt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). After Dde deprotection, SiFA-BA (1.5 eq.) is conjugated by applying HOBt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.5 eq.). After Fmoc deprotection, the N-terminus (1.0 eq.) is conjugated with the chelator rac-DOTAGA-anhydride (2.5 eq.) by applying DIPEA (10.0 eq.) in DMF (8 mL / g resin) for 24 h at room temperature. The resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80 °C and finally lyophilized to give peptide 1 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =11.8 minutes. RP-HPLC (10-90% in 15 min): R =10.9 minutes. ESI-MS: exact (C 100 H 142 FN 19 O 32 S2Si):2231.9;m found : m / z=745.3[M+3H] 3+ , 1117.2[M+2H] 2+ , 1489.4[2M+3H] 3+ . Synthesis of 3 (reference ligand)

[0328] [ka]

[0329] Starting from precursor X7, the synthesis of ligand 3 is carried out similarly to that described for 1. Unlike the synthesis of 1, HOBt (1.2 eq.), TBTU (1.2 eq.) and DIPEA (3.6 eq.) are applied and DOTA-(tBu)3 (1.2 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 3 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =10.7 minutes. RP-HPLC (10-90% in 15 min): R =8.84 minutes. ESI-MS: exact (C 97 H 138 FN 19 O 30 S2Si):2159.9;m found : m / z=721.1[M+3H] 3+ , 1081.1[M+2H] 2+ , 1441.1[2M+3H] 3+ . Synthesis of 6 (reference ligand)

[0330] [ka]

[0331] Starting from precursor X8, the synthesis of ligand 6 is carried out analogously to that described for 1. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 6 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =10.5 minutes. RP-HPLC (10-90% in 15 min): R =8.67 minutes. ESI-MS: exact (C 98 H 137 FN 20 O 31S2Si):2200.9;m found : m / z=735.2[M+3H] 3+ , 1101.9[M+2H] 2+ , 1468.4[2M+3H] 3+ . Synthesis of 8 (reference ligand)

[0332] [ka]

[0333] Starting from precursor X8, the synthesis of ligand 8 is carried out similarly to that described for 1. Unlike the synthesis of 1, HOBt (1.2 eq.), TBTU (1.2 eq.) and DIPEA (3.6 eq.) are applied and DOTA(tBu)3 (1.2 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 8 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =10.7 minutes. RP-HPLC (10-90% in 15 min): R =8.74 minutes. ESI-MS: exact (C 95 H 133 FN 20 O 29 S2Si):2128.9;m found : m / z=711.3[M+3H] 3+ , 1065.7[M+2H] 2+ . Synthesis of 2 (reference ligand)

[0334] [ka]

[0335] The synthesis of ligand 2 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X7 (1.0 eq.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 eq.) by applying HOBt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). After Fmoc deprotection, SiFA-BA (1.5 eq.) is conjugated by applying HOBt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.5 eq.). After Dde deprotection, the N-terminus (1.0 eq.) is conjugated to the chelator rac-DOTAGA-anhydride (2.5 eq.) by applying DIPEA (10.0 eq.) in DMF (8 mL / g resin) for 24 h at room temperature. The resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80 °C and finally lyophilized to give peptide 1 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =11.5 minutes. RP-HPLC (10-90% in 15 min): R =10.7 minutes. ESI-MS: exact (C 100 H 142 FN 19 O 32 S2Si):2231.9;m found : m / z=745.3[M+3H] 3+ , 1117.2[M+2H] 2+ , 1489.4[2M+3H] 3+ . Synthesis of 4 (reference ligand)

[0336] [ka]

[0337] Starting from precursor X7, the synthesis of ligand 4 is carried out similarly to that described for 2. Unlike the synthesis of 2, HOBt (1.2 eq.), TBTU (1.2 eq.) and DIPEA (3.6 eq.) are applied and DOTA(tBu)3 (1.2 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 4 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =10.6 minutes. RP-HPLC (10-90% in 15 min): R =8.83 minutes. ESI-MS: exact (C 97 H 138 FN 19 O 30 S2Si):2159.9;m found : m / z=721.1[M+3H] 3+ , 1081.1[M+2H] 2+ , 1441.1[2M+3H] 3+ . Synthesis of 7 (reference ligand)

[0338] [ka]

[0339] Starting from precursor X8, the synthesis of ligand 7 is carried out analogously to that described for 2. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 7 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =10.5 minutes. RP-HPLC (10-90% in 15 min): R =8.64 minutes. ESI-MS: exact (C 98 H 137 FN 20 O 31S2Si):2200.9;m found : m / z=735.2[M+3H] 3+ , 1101.9[M+2H] 2+ , 1468.4[2M+3H] 3+ . Synthesis of 9 (reference ligand)

[0340] [ka]

[0341] Starting from precursor X8, the synthesis of ligand 9 is carried out similarly to that described for 2. Unlike the synthesis of 2, HOBt (1.2 eq.), TBTU (1.2 eq.) and DIPEA (3.6 eq.) are applied and DOTA(tBu)3 (1.2 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 9 as a colorless solid. RP-HPLC semi-preparative (38-55% in 20 min): R =11.0 minutes. RP-HPLC (10-90% in 15 min): R =8.89 minutes. ESI-MS: exact (C 95 H 133 FN 20 O 29 S2Si):2128.9;m found : m / z=711.3[M+3H] 3+ , 1065.7[M+2H] 2+ , 1420.7[2M+3H] 3+ . Synthesis of 18 (reference ligand)

[0342] [ka]

[0343] The synthesis of ligand 18 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X10 (1.0 eq.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 eq.) by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). After Dde deprotection, SiFA-BA (1.5 eq.) is conjugated by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.) and the N-terminus is Fmoc deprotected. R-DOTAGA(tBu)4 is conjugated by applying HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.5 eq.). The resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80°C and final lyophilization gives peptide 18 as a colorless solid. RP-HPLC semi-preparative (30-50% in 20 min): R =16.1 minutes. RP-HPLC (10-60% in 15 min): R =11.2 minutes. ESI-MS: exact (C 100 H 147 FN 22 O 27 S2Si):2199.0;m found : m / z=550.7[M+4H] 4+ , 733.8[M+3H] 3+ , 1099.9[M+2H] 2+ , 1466.1[2M+3H] 3+ . 3.4.3 Ligand synthesis: positive charge via additional Dap at SiFA Synthesis of 23

[0344] [ka]

[0345] The synthesis of ligand 23 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X7 (1.0 equiv.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). After Dde deprotection, DOTA(tBu)3 (1.5 equiv.) is conjugated by applying HOAt (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (4.5 equiv.). The N-terminus is Fmoc-deprotected and conjugated with Fmoc-D-Dap(Boc)-OH (1.5 eq.) by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.), followed by Fmoc-deprotection. SiFA-BA (1.5 eq.) is conjugated by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). The resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80°C and final lyophilization gives peptide 23 as a colorless solid. RP-HPLC semi-preparative (37-45% in 20 min): R =14.0 minutes. RP-HPLC (10-60% in 15 min): R =12.2 minutes. ESI-MS: exact (C 100 H 144 FN 21 O 31 S2Si):2246.0;m found : m / z=749.6[M+3H] 3+ , 1123.8[M+2H] 2+ , 1499.0[2M+3H] 3+ , 1685.7[3M+4H] 4+ . Synthesis of 19

[0346] [ka]

[0347] Starting from precursor X8, the synthesis of ligand 19 is carried out analogously to that described for 23. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 19 as a colorless solid. RP-HPLC semi-preparative (33-45% in 20 min): R =17.6 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 98 H 139 FN 22 O 30 S2Si):2214.9;m found : m / z=739.7[M+3H] 3+ , 1108.5[M+2H] 2+ , 1477.8[2M+3H] 3+ , 1662.5[3M+4H] 4+ . Synthesis of 39

[0348] [ka]

[0349] Starting from precursor X14, the synthesis of ligand 39 is carried out similarly to that described for 23. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 39 as a colorless solid. RP-HPLC semi-preparative (34-44% in 20 min): R =15.5 minutes. RP-HPLC (10-60% in 15 min): R =12.3 minutes. ESI-MS: exact (C 96 H 136 FN 21O 29 S2Si):2157.9;m found : m / z=720.6[M+3H] 3+ , 1080.5[M+2H] 2+ , 1440.9[2M+3H] 3+ , 1620.3[3M+4H] 4+ . Synthesis of 40

[0350] [ka]

[0351] Starting from precursor X15, the synthesis of ligand 40 is carried out similarly to that described for 23. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 40 as a colorless solid. RP-HPLC semi-preparative (37-44% in 20 min): R =14.8 minutes. RP-HPLC (10-60% in 15 min): R =12.0 minutes. ESI-MS: exact (C 100 H 142 FN 23 O 31 S2Si):2271.9;m found : m / z=758.7[M+3H] 3+ , 1137.6[M+2H] 2+ , 1517.2[2M+3H] 3+ , 1706.5[3M+4H] 4+ . Synthesis of 20

[0352] [ka]

[0353] Starting from precursor X8, the synthesis of ligand 20 is carried out similarly to that described for 23. Unlike the synthesis of 23, HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.5 eq.) are applied and R-DOTAGA(tBu)4 (1.5 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 20 as a colorless solid. RP-HPLC semi-preparative (34-42% in 20 min): R =17.1 minutes. RP-HPLC (10-60% in 15 min): R =11.7 minutes. ESI-MS: exact (C 101 H 143 FN 22 O 32 S2Si):2286.9;m found : m / z=572.9[M+4H] 4+ , 763.7[M+3H] 3+ , 1144.5[M+2H] 2+ . Synthesis of 41

[0354] [ka]

[0355] Starting from precursor X11, the synthesis of ligand 41 is carried out similarly to that described for 23. Unlike the synthesis of 23, HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.5 eq.) are applied and R-DOTAGA(tBu)4 (1.5 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 41 as a colorless solid. RP-HPLC semi-preparative (35-44% in 20 min): R =13.5 minutes. RP-HPLC (10-60% in 15 min): R=11.7 minutes. ESI-MS: exact (C 101 H 145 FN 24 O 30 S2Si):2285.0;m found : m / z=763.1[M+3H] 3+ , 1143.7[M+2H] 2+ , 1525.4[2M+3H] 3+ . Synthesis of 42

[0356] [ka]

[0357] Starting from precursor X9, the synthesis of ligand 42 is carried out analogously to that described for 23. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 42 as a colorless solid. RP-HPLC semi-preparative (35-45% in 20 min): R =14.6 minutes. RP-HPLC (10-60% in 15 min): R =11.8 minutes. ESI-MS: exact (C 102 H 145 FN 24 O 32 S2Si):2329.0;m found : m / z=778.0[M+3H] 3+ , 1166.9[M+2H] 2+ , 1555.6[2M+3H] 3+ . Synthesis of 43

[0358] [ka]

[0359] Starting from precursor X18, the synthesis of ligand 43 is carried out similarly to that described for 23. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 43 as a colorless solid. RP-HPLC semi-preparative (35-45% in 20 min): R =15.4 minutes. RP-HPLC (10-60% in 15 min): R =12.0 minutes. ESI-MS: exact (C 102 H 145 FN 24 O 32 S2Si):2329.0;m found : m / z=777.7[M+3H] 3+ , 1165.8[M+2H] 2+ , 1554.5[2M+3H] 3+ . Synthesis of 36

[0360] [ka]

[0361] Starting from precursor X8, the synthesis of ligand 36 is carried out similarly to that described for 23. Unlike the synthesis of 23, HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (5.5 eq.) in DMF / NMP (1 / 1 v / v; 8 mL / g resin) are applied at room temperature for 3 h and DO3AM-acetic acid (1.8 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, giving peptide 36 as a colorless solid. RP-HPLC semi-preparative (34-43% in 20 min): R =14.7 minutes. RP-HPLC (10-60% in 15 min): R =11.3 minutes. ESI-MS: exact (C 98 H 142FN 25 O 27 S2Si):2212.0;m found : m / z=728.4[M+3H] 3+ , 1106.7[M+2H] 2+ , 1475.9[2M+3H] 3+ . Synthesis of 37

[0362] [ka]

[0363] Starting from precursor X11, the synthesis of ligand 37 is carried out similarly to that described for 23. Unlike the synthesis of 23, HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.5 eq.) are applied and R-DOTAGA(tBu)4 (1.5 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 37 as a colorless solid. RP-HPLC semi-preparative (35-45% in 20 min): R =10.5 minutes. RP-HPLC (10-60% in 15 min): R =10.8 minutes. ESI-MS: exact (C 103 H 153 FN 24 O 28 S2Si):2285.1;m found : m / z=573.1[M+4H] 4+ , 763.9[M+3H] 3+ . 3.4.4 Ligand synthesis: positive charge via SiFAlin-building block Synthesis of 24

[0364] [ka]

[0365] The synthesis of ligand 24 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X8 (1.0 equiv.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). After Dde deprotection, DOTA(tBu)3 (1.5 equiv.) is conjugated by applying HOAt (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (4.5 equiv.). The N-terminus is Fmoc-deprotected and conjugated with Me2-Gly-OH (3.0 equiv.) by applying HOAt (3.0 equiv.), TBTU (3.0 equiv.) and 2,4,6-collidine (9.0 equiv.) in DMF (8 mL / g resin) for 4 h at room temperature. The SiFA-moiety is formed by incubating with SiFA-Br (3.0 equiv.) and 2,4,6-collidine (6.0 equiv.) in DCM (8 mL / g resin) for 24 h at room temperature. Reaction control by test cleavage (GP8; mild test cleavage) confirms the formation of the correct but incomplete product. However, the resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80°C and finally lyophilized to give peptide 24 as a colourless solid. Due to the presence of a quaternary amine in the peptide, formation of a TFA salt is expected. RP-HPLC semi-preparative (37-53% in 20 min): R =11.9 minutes. RP-HPLC (10-60% in 15 min): R =12.2 minutes. ESI-MS: exact (C 99 H 143 FN 21 O 29 S2Si + ):2201.0;m found : m / z=1101.0[M+2H] 2+ , 1467.6[2M+3H] 3+ , 1650.4[3M+4H]4+ . Synthesis of 38

[0366] [ka]

[0367] Starting from precursor X8, the synthesis of ligand 38 is carried out similarly to that described for 24. Unlike the synthesis of 24, HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (5.5 eq.) in DMF / NMP (1 / 1 v / v; 8 mL / g resin) are applied at room temperature for 3 h and DO3AM-acetic acid (1.8 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, giving peptide 38 as a colorless solid. RP-HPLC semi-preparative (35-43% in 20 min): R =14.6 minutes. RP-HPLC (10-60% in 15 min): R =11.7 minutes. ESI-MS: exact (C 99 H 146 FN 24 O 26 S2Si + ):2198.0;m found : m / z=734.5[M+3H] 3+ , 1101.3[M+2H] 2+ . Synthesis of 48

[0368] [ka]

[0369] Starting from precursor X18, the synthesis of ligand 48 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 48 as a colorless solid. RP-HPLC semi-preparative (40-48% in 20 min): R =16.0 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 103 H 149 FN 23 O 31 S2Si + ):2315.0;m found : m / z=772.3[M+3H] 3+ , 1032.7[M-CH2-C6H4-SitBu2F+2H] 2+ , 1157.8[M+2H] 2+ . Synthesis of 49

[0370] [ka]

[0371] Starting from precursor X19, the synthesis of ligand 49 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 49 as a colorless solid. RP-HPLC semi-preparative (40-45% in 20 min): R =17.0 minutes. RP-HPLC (10-60% in 15 min): R =11.8 minutes. ESI-MS: exact (C 105 H 152 FN 24 O 32 S2Si + ):2372.0;m found : m / z=791.3[M+3H] 3+ , 1061.2[M-CH2-C6H4-SitBu2F+2H] 2+ , 1186.4[M+2H] 2+ . 50 Synthesis

[0372] [ka]

[0373] Starting from precursor X15, the synthesis of ligand 50 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 50 as a colorless solid. RP-HPLC semi-preparative (42-47% in 20 min): R =14.1 minutes. RP-HPLC (10-60% in 15 min): R =12.0 minutes. ESI-MS: exact (C 101 H 146 FN 22 O 30 S2Si + ):2258.0;m found : m / z=753.3[M+3H] 3+ , 1004.2[M-CH2-C6H4-SitBu2F+2H] 2+ , 1129.4[M+2H] 2+ . Synthesis of 54

[0374] [ka]

[0375] Starting from precursor X15, the synthesis of ligand 54 is carried out similarly to that described for 24. Unlike the synthesis of 24, HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (5.5 eq.) in DMF (8 mL / g resin) are applied at room temperature for 3 h and DO3AM-acetic acid (1.8 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 54 as a colorless solid. RP-HPLC semi-preparative (36-42% in 20 min): R=11.8 minutes. RP-HPLC (10-60% in 15 min): R =11.6 minutes. ESI-MS: exact (C 101 H 149 FN 25 O 27 S2Si + ):2255.0;m found : m / z=564.8[M+4H] 4+ , 752.7[M+3H] 3+ , 1128.6[M+2H] 2+ , 1504.8[2M+3H] 3+ . Synthesis of 55

[0376] [ka]

[0377] Starting from precursor X23, the synthesis of ligand 55 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 55 as a colorless solid. RP-HPLC semi-preparative (34-45% in 20 min): R =11.9 minutes. RP-HPLC (10-60% in 15 min): R =11.0 minutes. ESI-MS: exact (C 103 H 156 FN 24 O 26 S2Si + ):2256.1;m found : m / z=565.1[M+4H] 4+ , 753.2[M+3H] 3+ , 1129.2[M+2H] 2+ , 1505.1[2M+3H] 3+ , 1693.8[3M+4H] 4+ . Synthesis of 56

[0378] [ka]

[0379] Starting from precursor X24, the synthesis of ligand 56 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified applying semi-preparative RP-HPLC to give peptide 56 as a colorless solid. RP-HPLC semi-preparative (36-48% in 20 min): R =12.6 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 101 H 148 FN 24 O 28 S2Si + ):2256.0;m found : m / z=753.0[M+3H] 3+ , 1129.2[M+2H] 2+ , 1505.3[2M+3H] 3+ , 1694.0[3M+4H] 4+ . Synthesis of 57

[0380] [ka]

[0381] Starting from precursor X20, the synthesis of ligand 57 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 57 as a colorless solid. RP-HPLC semi-preparative (35-42% in 20 min): R =12.3 minutes. RP-HPLC (10-60% in 15 min): R =11.4 minutes. ESI-MS: exact(C 107 H 158 FN 24 O 31 S2Si + ):2386.1;m found :m / z=2256.0;m found : m / z=597.7[M+4H] 4+ , 796.4[M+3H] 3+ , 1194.2[M+2H] 2+ , 1592.3[2M+3H] 3+ , 1791.3[3M+4H] 4+ , 1910.7[4M+5H] 5+ . Synthesis of 58

[0382] [ka]

[0383] Starting from precursor X21, the synthesis of ligand 58 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 58 as a colorless solid. RP-HPLC semi-preparative (38-42% in 20 min): R =11.3 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 107 H 157 FN 25 O 32 S2Si + ):2415.1;m found : m / z=806.1[M+3H] 3+ , 1208.8[M+2H] 2+ . Synthesis of 59

[0384] [ka]

[0385] Starting from precursor X26, the synthesis of ligand 59 is carried out similarly to that described for 24. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 59 as a colorless solid. RP-HPLC semi-preparative (37-45% in 20 min): R =14.1 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 110 H 154 ClFN 27 O 32 S2Si + ):2511.0;m found : m / z=629.0[M+4H] 4+ , 838.3[M+3H] 3+ , 1257.0[M+2H] 2+ , 1676.1[2M+3H] 3+ , 1885.3[3M+4H] 4+ . Synthesis of 61

[0386] [ka]

[0387] Starting from precursor X23, the synthesis of ligand 61 is carried out similarly to that described for 24. Unlike the synthesis of 24, HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (5.5 eq.) in DMF (8 mL / g resin) are applied at room temperature for 3 h and DO3AM-acetic acid (1.8 eq.) is used as chelator. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 61 as a colorless solid. RP-HPLC semi-preparative (33-45% in 20 min): R =11.6 minutes. RP-HPLC (10-60% in 15 min): R=10.6 points. ESI-MS:m exact (C 103 H 159 FN 27 O 23 S2S + ):2253.1;m found :m / z=564.5[M+4H] 4+ 、752.2[M+3H] 3+ 、1127.4[M+2H] 2+ . 44のSynthesis

[0388]

change

[0389] The synthesis of ligand 44 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X15 (1.0 equiv.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). After Dde deprotection, Me2-Gly-OH (3.0 equiv.) is conjugated by applying HOAt (3.0 equiv.), TBTU (3.0 equiv.) and 2,4,6-collidine (9.0 equiv.) in DMF (8 mL / g resin) at room temperature for 4 h. The N-terminus is Fmoc-deprotected and conjugated with DOTA(tBu)3 (1.5 eq.) by applying HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.5 eq.). The SiFA-moiety is then formed by incubation with SiFA-Br (3.0 eq.) and 2,4,6-collidine (6.0 eq.) in DCM (8 mL / g resin) for 24 h at room temperature. Reaction control by test cleavage (GP8; mild test cleavage) confirms the correct but incomplete formation of the product. Nevertheless, the resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. The crude product is purified by applying semi-preparative RP-HPLC and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80 °C and a final lyophilization gives peptide 44 as a colorless solid. Due to the presence of quaternary amines in the peptides, formation of TFA salts is expected. RP-HPLC semi-preparative (35-45% in 20 min): R =13.2 minutes. RP-HPLC (10-60% in 15 min): R =12.0 minutes. ESI-MS: exact (C 101 H 146 FN 22 O 30 S2Si + ):2258.0;m found : m / z=753.2[M+3H] 3+ , 1129.2[M+2H] 2+ , 1505.0[2M+3H]3+ . Synthesis of 45

[0390] [ka]

[0391] Starting from precursor X20, the synthesis of ligand 45 is carried out similarly to that described for 44. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 45 as a colorless solid. RP-HPLC semi-preparative (32-42% in 20 min): R =15.0 minutes. RP-HPLC (10-60% in 15 min): R =11.3 minutes. ESI-MS: exact (C 107 H 158 FN 24 O 31 S2Si + ):2386.1;m found : m / z=597.4[M+4H] 4+ , 795.8[M+3H] 3+ , 1193.2[M+2H] 2+ , 1590.7[2M+3H] 3+ . Synthesis of 46

[0392] [ka]

[0393] Starting from precursor X21, the synthesis of ligand 46 is carried out similarly to that described for 44. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 46 as a colorless solid. RP-HPLC semi-preparative (35-42% in 20 min): R =12.1 minutes. RP-HPLC (10-60% in 15 min): R =11.8 minutes. ESI-MS: exact (C 107 H 157 FN 25 O 32 S2Si + ):2415.1;m found : m / z=805.4[M+3H] 3+ , 1207.7[M+2H] 2+ , 1610.0[2M+3H] 3+ . Synthesis of 47

[0394] [ka]

[0395] Starting from precursor X22, the synthesis of ligand 47 is carried out similarly to that described for 44. All synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 47 as a colorless solid. RP-HPLC semi-preparative (40-50% in 20 min): R =15.5 minutes. RP-HPLC (10-60% in 15 min): R =11.9 minutes. ESI-MS: exact (C 106 H 153 FN 23 O 33 S2Si + ):2387.0;m found : m / z=796.3[M+3H] 3+ , 1068.7[M-CH2-C6H4-SitBu2F+2H] 2+ , 1193.8[M+2H] 2+ . Synthesis of 51

[0396] [ka]

[0397] The synthesis of ligand 51 is carried out by applying GP2, GP3, GP4, GP5 and GP7. Briefly, resin-bound precursor X15 (1.0 equiv.) is conjugated with Fmoc-D-Dap(Dde)-OH (1.5 equiv.) by applying HOAt (1.5 equiv.), TBTU (1.5 equiv.) and 2,4,6-collidine (5.5 equiv.). After Dde deprotection, DOTA(tBu)3 (1.5 equiv.) is conjugated by applying HOAt (1.5 equiv.), HATU (1.5 equiv.) and DIPEA (4.5 equiv.). The N-terminus is Fmoc-deprotected and conjugated with Fmoc-D-Dap(Boc)-OH (1.5 eq.) by applying HOAt (1.5 eq.), TBTU (1.5 eq.) and 2,4,6-collidine (5.5 eq.). After Fmoc-deprotection, Me2-Gly-OH (3.0 eq.) is conjugated by applying HOAt (3.0 eq.), TBTU (3.0 eq.) and 2,4,6-collidine (9.0 eq.) in DMF (8 mL / g resin) for 4 h at room temperature. The SiFA-moiety is formed by incubating SiFA-Br (3.0 eq.) and 2,4,6-collidine (6.0 eq.) in DCM (8 mL / g resin) for 24 h at room temperature. Reaction control by test cleavage (GP8; mild test cleavage) confirms the formation of the correct but incomplete product. Nevertheless, the resin-bound peptide is deprotected and cleaved from the resin by treatment with TFA / TIPS / H2O as described in GP7. Semi-preparative RP-HPLC is applied to purify the crude product and the solvent is evaporated under reduced pressure. The precipitate is dissolved in tBuOH / H2O, frozen at -80 °C and finally lyophilized to give peptide 51 as a colorless solid. Due to the presence of a quaternary amine in the peptide, the formation of a TFA salt is expected. RP-HPLC semi-preparative (40-45% in 20 min): R =14.5 minutes. RP-HPLC (10-60% in 15 min): R =11.6 minutes. ESI-MS: exact (C 104 H 152 FN 24 O31 S2Si + ):2344.0;m found : m / z=781.3[M+3H] 3+ , 1171.4[M+2H] 2+ , 1156.9[2M+3H] 3+ , 1757.1[3M+4H] 4+ . 60 Synthesis

[0398] [ka]

[0399] Starting from precursor X15, the synthesis of ligand 60 is carried out similarly to that described for 51. Unlike the synthesis of 51, HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (4.5 eq.) are applied to conjugate Fmoc-Gly-OH instead of Fmoc-D-Dap(Boc)-OH. All other synthesis steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 60 as a colorless solid. RP-HPLC semi-preparative (37-43% in 20 min): R =15.8 minutes. RP-HPLC (10-60% in 15 min): R =12.2 minutes. ESI-MS: exact (C 103 H 149 FN 23 O 31 S2Si + ):2315.0;m found : m / z=579.8[M+4H] 4+ , 772.8[M+3H] 3+ , 1158.5[M+2H] 2+ , 1544.9[2M+3H] 3+ . Synthesis of 52

[0400] [ka]

[0401] Starting from precursor X15, the synthesis of ligand 52 is carried out similarly to that described for 51. Unlike the synthesis of 51, Fmoc-Gly-OH is ligated before the conjugation of Me2-Gly-OH. All other synthetic steps are transferable. After deprotection and cleavage from the resin, the crude product is purified by applying semi-preparative RP-HPLC to give peptide 52 as a colorless solid. RP-HPLC semi-preparative (45-48% in 20 min): R =11.3 minutes. RP-HPLC (10-60% in 15 min): R =11.7 minutes. ESI-MS: exact (C 106 H 155 FN 25 O 32 S2Si + ):2401.1;m found : m / z=800.2[M+3H] 3+ , 1199.9[M+2H] 2+ , 1599.9[2M+3H] 3+ , 1800.2[3M+4H] 4+ . Synthesis of 53

[0402] [ka]

[0403] Starting from precursor X15, the synthesis of ligand 53 is carried out similarly to that described for 51. Unlike the synthesis of 51, Fmoc-Gly-OH is linked twice before the conjugation of Me2-Gly-OH. All other synthetic steps are transferable. After deprotection and cleavage from the resin, semi-preparative RP-HPLC is applied to purify the crude product, yielding peptide 53 as a colorless solid. RP-HPLC semi-preparative (42-45% in 20 min): R =13.5 minutes. RP-HPLC (10-60% in 15 min):R =11.8 minutes. ESI-MS: exact (C 108 H 158 FN 26 O 33 S2Si + ):2458.1;m found : m / z=819.2[M+3H] 3+ , 1228.3[M+2H] 2+ , 1637.4[2M+3H] 3+ , 1841.8[3M+4H] 4+ . 3.4.5 Metal complexation for biological evaluation nat Ga III - Chelate, nat Lu III -Chelate and nat Pb II - The formation of the chelates was achieved by applying general procedures GP9, GP10 and GP11. The analytical data obtained (analytical RP-HPLC and ESI-MS) are listed below. nat Ga III -Complex [ nat Ga]1 RP-HPLC (10-90% in 15 min): R =10.9 minutes. ESI-MS: exact (C 100 H 139 FN 19 O 32 S2SiGa):2298.7;m found : m / z=767.6[M+3H] 3+ , 1150.7[M+2H] 2+ , 1533.9[2M+3H] 3+ . [ nat Ga]2 RP-HPLC (10-90% in 15 min): R =10.4 minutes. ESI-MS: exact (C 100 H 139 FN 19 O 32S2SiGa):2298.7;m found :m / z=767.6[M+3H] 3+ 、1150.7[M+2H] 2+ 、1533.9[2M+3H] 3+ . [ nat Ga]3 RP-HPLC (15 minutes, 10~90%):t R =11.1 points. ESI-MS:m exact (C 97 H 135 FN 19 O 30 S2SiGa):2226.7;m found :m / z=743.3[M+3H] 3+ 、1114.6[M+2H] 2+ 、1485.9[2M+3H] 3+ . [ nat Ga]4 RP-HPLC (15 minutes, 10~90%):t R =11.4 points. ESI-MS:m exact (C 97 H 135 FN 19 O 30 S2SiGa):2226.7;m found :m / z=743.3[M+3H] 3+ 、1114.6[M+2H] 2+ 、1485.9[2M+3H] 3+ . [ nat Ga]5 RP-HPLC (15 minutes, 10~90%):t R =8.87 points. ESI-MS:m exact (C 109 H 145 FN 21 O 36 S2SiGa):2504.7;m found :m / z=836.2[M+3H] 3+ 、1253.5[M+2H] 2+ 、1671.4[2M+3H] 3+ . [nat Ga]6 RP-HPLC (15 minutes, 10~90%):t R =8.81 points. ESI-MS:m exact (C 98 H 134 FN 20 O 31 S2SiGa):2267.6;m found :m / z=1135.6[M+2H] 2+ 、1513.6[2M+3H] 3+ . [ nat 7 RP-HPLC (15 minutes, 10~90%):t R =8.77 points. ESI-MS:m exact (C 98 H 134 FN 20 O 31 S2SiGa):2267.66;m found :m / z=1135.6[M+2H] 2+ 、1513.6[2M+3H] 3+ . [ nat 8 RP-HPLC (15 minutes, 10~90%):t R =8.80 points. ESI-MS:m exact (C 95 H 130 FN 20 O 29 S2SiGa):2195.6;m found :m / z=1099.6[M+2H] 2+ 、1466.4[2M+3H] 3+ . [ nat Ga]9 RP-HPLC (15 minutes, 10~90%):t R =8.81 points. ESI-MS:m exact (C 95 H 130 FN 20 O 29 S2SiGa):2195.6;m found :m / z=1099.6[M+2H]2+ 、1466.4[2M+3H] 3+ . [ nat Ga]18 RP-HPLC (15 minutes, 10~60%):t R =11.6 points. ESI-MS:m exact (C 100 H 145 FGaN 22 O 27 S2Si):2265.9;m found :m / z=1134.6[M+2H] 2+ 、757.0[M+3H] 3+ . [ nat Ga]19 RP-HPLC (15 minutes, 10~60%):t R =11.7 points. ESI-MS:m exact (C 98 H 138 FGaN 22 O 30 S2Si):2282.8;m found :m / z=1142.1[M+2H] 2+ 、1522.5[2M+3H] 3+ 、1712.1[3M+4H] 4+ . [ nat Ga]20 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 101 H 141 FGaN 22 O 32 S2Si):2353.9;m found :m / z=1178.2[M+2H] 2+ 、1570.5[2M+3H] 3+ 、1766.4[3M+4H] 4+ . [ nat Ga]23 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:mexact (C 100 H 142 FGaN 21 O 31 S2Si):2312.9;m found :m / z=771.9[M+3H] 3+ 、1157.6[M+2H] 2+ 、1542.9[2M+3H] 3+ . [ nat Ga]24 RP-HPLC (15 minutes, 10~60%):t R =12.4 points. ESI-MS:m exact (C 99 H 141 FGaN 21 O 29 S2S + ):2267.9;m found :m / z=756.6[M+3H] 3+ 、1134.4[M+2H] 2+ 、1512.6[2M+3H] 3+ . [ nat Ga]37 RP-HPLC (15 minutes, 10~60%):t R =11.1 points. ESI-MS:m exact (C 103 H 151 FGaN 24 O 28 S2Si):2352.0;m found :m / z=589.2[M+4H] 4+ 、785.4[M+3H] 3+ 、1177.6[M+2H] 2+ . [ nat Ga]39 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 96 H 134 FGaN 21 O 29 S2Si):2224.8;m found :m / z=743.0 1114.1. [ nat Ga]40 RP-HPLC (15 minutes, 10~60%):t R =11.8 points. ESI-MS:m exact (C 100 H 140 FGaN 23 O 31 S2Si):2338.9;m found :m / z=781.1[M+3H] 3+ 、1171.1[M+2H] 2+ 、1561.3[2M+3H] 3+ . [ nat Ga]41 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 101 H 143 FGaN 24 O 30 S2Si):2351.9;m found :m / z=785.2[M+3H] 3+ 、1177.7[M+2H] 2+ 、1571.0[2M+3H] 3+ . [ nat Ga]42 RP-HPLC (15 minutes, 10~60%):t R =11.7 points. ESI-MS:m exact (C 102 H 143 FGaN 24 O 32 S2Si):2395.9;m found :m / z=800.2[M+3H] 3+ 、1200.3[M+2H] 2+ 、1599.2[2M+3H] 3+ . [ nat Ga]43 RP-HPLC (15 minutes, 10~60%):t R = points. ESI-MS:m exact (C 102 H143 FGaN 24 O 32 S2Si):2395.9;m found :m / z=799.8[M+3H] 3+ 、1199.5[M+2H] 2+ 、1599.8[2M+3H] 3+ . [ nat Ga]44 RP-HPLC (15 minutes, 10~60%):t R =12.1 points. ESI-MS:m exact (C 101 H 144 FGaN 22 O 30 S2S + ):2324.9;m found :m / z=775.4[M+3H] 3+ 、1162.4[M+2H] 2+ 、1549.6[2M+3H] 3+ . [ nat Ga]45 RP-HPLC (15 minutes, 10~60%):t R =11.4 points. ESI-MS:m exact (C 107 H 156 FGaN 24 O 31 S2S + ):2453.0;m found :m / z=817.9[M+3H] 3+ 、1226.0[M+2H] 2+ 、1634.6[2M+3H] 3+ . [ nat Ga]46 RP-HPLC (15 minutes, 10~60%):t R =11.9 points. ESI-MS:m exact (C 107 H 155 FGaN 25 O 32 S2S + ):2482.0;m found :m / z=827.6[M+3H]3+ 、1240.8[M+2H] 2+ 、1653.3[2M+3H] 3+ . [ nat Ga]47 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 106 H 151 FGaN 23 O 33 S2S + ):2453.9;m found :m / z=817.9[M+3H] 3+ 、1226.6[M+2H] 2+ 、1635.3[2M+3H] 3+ . [ nat Ga]48 RP-HPLC (15 minutes, 10~60%):t R =12.1 points. ESI-MS:m exact (C 103 H 147 FGaN 23 O 31 S2S + ):2381.9;m found :m / z=794.1[M+3H] 3+ 、1190.3[M+2H] 2+ 、1587.6[2M+3H] 3+ . [ nat Ga]49 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 105 H 150 FGaN 24 O 32 S2S + ):2438.9;m found :m / z=813.1[M+3H] 3+ 、1218.8[M+2H] 2+ 、1625.1[2M+3H] 3+ 、1829.4[3M+4H] 4+ . [ nat Ga]50 RP-HPLC (15 minutes, 10~60%):t R =12.2 points. ESI-MS:m exact (C 101 H 144 FGaN 22 O 30 S2S + ):2324.9;m found :m / z=775.1[M+3H] 3+ 、1162.1[M+2H] 2+ 、1549.1[2M+3H] 3+ 、1742.3[3M+4H] 4+ . [ nat Ga]51 RP-HPLC (15 minutes, 10~60%):t R =11.4 points. ESI-MS:m exact (C 104 H 150 FGaN 24 O 31 S2S + ):2410.9;m found :m / z=803.5[M+3H] 3+ 、1204.6[M+2H] 2+ 、1605.6[2M+3H] 3+ . [ nat Ga]52 RP-HPLC (15 minutes, 10~60%):t R =11.5 points. ESI-MS:m exact (C 106 H 153 FGaN 25 O 32 S2S + ):2468.0;m found :m / z=822.3[M+3H] 3+ 、1232.8[M+2H] 2+ 、1643.7[2M+3H] 3+ . [ nat Ga]53 RP-HPLC (15 minutes, 10~60%):tR =11.9 points. ESI-MS:m exact (C 108 H 156 FGaN 26 O 33 S2S + ):2525.0;m found :m / z=841.4[M+3H] 3+ 、1261.3[M+2H] 2+ 、1680.8[2M+3H] 3+ . [ nat Ga]55 RP-HPLC (15 minutes, 10~60%):t R =11.1 points. ESI-MS:m exact (C 103 H 154 FGaN 24 O 26 S2S + ):2323.0;m found :m / z=581.8[M+4H] 4+ 、775.3[M+3H] 3+ 、1163.2[M+2H] 2+ . [ nat Ga]56 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 101 H 146 FGaN 24 O 28 S2S + ):2322.9;m found :m / z=775.3[M+3H] 3+ 、1161.9[M+2H] 2+ 、1549.4[2M+3H] 3+ . [ nat Ga]57 RP-HPLC (15 minutes, 10~60%):t R =11.4 points. ESI-MS:m exact (C 107 H 156 FGaN24 O 31 S2S + ):2453.0;m found :m / z=818.8[M+3H] 3+ 、1227.9[M+2H] 2+ . [ nat Ga]58 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 107 H 155 FGaN 25 O 32 S2S + ):2482.0;m found :m / z=828.2[M+3H] 3+ 、1242.2[M+2H] 2+ 、1655.7[2M+3H] 3+ . [ nat Ga]59 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 110 H 152 ClFGaN 27 O 32 S2S + ):2577.9;m found :m / z=860.6[M+3H] 3+ 、1290.4[M+2H] 2+ 、1720.9[2M+3H] 3+ 、1935.3[3M+4H] 4+ . [ nat Ga]60 RP-HPLC (15 minutes, 10~60%):t R =12.2 points. ESI-MS:m exact (C 103 H 147 FGaN 23 O 31 S2S + ):2381.9;m found :m / z=795.0[M+3H]3+ 、1192.0[M+2H] 2+ 、1588.6[2M+3H] 3+ . nat Lu III -Wrong body [ nat Lu]19 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 98 H 136 FWf 22 O 30 S2Si):2386.8;m found :m / z=796.9[M+3H] 3+ 、1194.6[M+2H] 2+ 、1593.2[2M+3H] 3+ . [ nat Lu]20 RP-HPLC (15 minutes, 10~60%):t R =12.3 points. ESI-MS:m exact (C 101 H 140 FWf 22 O 32 S2Si):2458.9;m found :m / z=820.8[M+3H] 3+ 、1230.9[M+2H] 2+ 、1641.4[2M+3H] 3+ . [ nat Lu]24 RP-HPLC (15 minutes, 10~60%):t R =12.4 points. ESI-MS:m exact (C 99 H 140 FWf 21 O 29 S2S + ):2372.9;m found :m / z=790.7[M+3H] 3+ 、1185.8[M+2H] 2+ 、1581.2[2M+3H] 3+ . [ nat Lu]44 RP-HPLC (15 minutes, 10~60%):t R =12.2 points. ESI-MS:m exact (C 101 H 143 FWf 22 O 30 S2S + ):2429.9;m found :m / z=809.9[M+3H] 3+ 、1214.2[M+2H] 2+ 、1618.7[2M+3H] 3+ . [ nat Lu]45 RP-HPLC (15 minutes, 10~60%):t R =11.6 points. ESI-MS:m exact (C 107 H 155 FWf 24 O 31 S2S + ):2558.0;m found :m / z=852.6[M+3H] 3+ 、1278.3[M+2H] 2+ 、1703.4[2M+3H] 3+ . [ nat Lu]46 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 107 H 154 FWf 25 O 32 S2S + ):2587.0;m found :m / z=862.2[M+3H] 3+ 、1292.8[M+2H] 2+ 、1722.8[2M+3H] 3+ . [ nat Lu]47 RP-HPLC (15 minutes, 10~60%):t R =12.1 points. ESI-MS:m exact (C 106 H 150 FWf 23 O 33 S2S + ):2558.9;m found :m / z=853.0[M+3H] 3+ 、1278.7[M+2H] 2+ 、1704.1[2M+3H] 3+ . [ nat Lu]48 RP-HPLC (15 minutes, 10~60%):t R =12.1 points. ESI-MS:m exact (C 103 H 146 FWf 23 O 31 S2S + ):2486.9;m found :m / z=829.0[M+3H] 3+ 、1242.7[M+2H] 2+ 、1656.3[2M+3H] 3+ . [ nat Lu]49 RP-HPLC (15 minutes, 10~60%):t R =12.0 points. ESI-MS:m exact (C 105 H 149 FWf 24 O 32 S2S + ):2543.9;m found :m / z=847.9[M+3H] 3+ 、1271.2[M+2H] 2+ 、1694.7[2M+3H] 3+ 、1907.3[3M+4H] 4+ . [ nat Lu]50 RP-HPLC (15 minutes, 10~60%):t R =12.3 points. ESI-MS:m exact (C 101 H 143 FWf22 O 30 S2S + ):2429.9;m found :m / z=810.0[M+3H] 3+ 、1214.0[M+2H] 2+ 、1618.3[2M+3H] 3+ . [ nat Lu]51 RP-HPLC (15 minutes, 10~60%):t R =11.9 points. ESI-MS:m exact (C 104 H 149 FWf 24 O 31 S2S + ):2515.9;m found :m / z=838.4[M+3H] 3+ 、1257.5[M+2H] 2+ 、1676.2[2M+3H] 3+ . [ nat Lu]52 RP-HPLC (15 minutes, 10~60%):t R =11.9 points. ESI-MS:m exact (C 106 H 152 FWf 25 O 32 S2S + ):2573.0;m found :m / z=857.3[M+3H] 3+ 、1285.0[M+2H] 2+ 、1714.6[2M+3H] 3+ . [ nat Lu]53 RP-HPLC (15 minutes, 10~60%):t R =12.3 points. ESI-MS:m exact (C 108 H 155 FWf 26 O 33 S2S + ):2630.0;m found :m / z=876.4[M+3H] 3+、1314.2[M+2H] 2+ 、1751.9[2M+3H] 3+ . nat Pb II -Wrong body [ nat Pb]36 RP-HPLC (15 minutes, 10~60%):t R =11.4 points. ESI-MS:m exact (C 98 H 140 FN 25 O 27 PbS2Si):2417.9;m found :m / z=807.2[M+3H] 3+ 、1210.8[M+2H] 2+ 、1613.5[2M+3H] 3+ . [ nat Pb]38 RP-HPLC (15 minutes, 10~60%):t R =11.8 points. ESI-MS:m exact (C 99 H 144 FN 24 O 26 PbS2Si + ):2404.0;m found :m / z=801.7[M+3H] 3+ 、1202.0[M+2H] 2+ 、1603.4[2M+3H] 3+ . [ nat Pb]54 RP-HPLC (15 minutes, 10~60%):t R =11.6 points. ESI-MS:m exact (C 101 H 147 FN 25 O 27 PbS2Si + ):2461.0;m found :m / z=616.2[M+4H] 4+ 、821.2[M+3H] 3+ 、1231.5[M+2H] 2+, 1641.7[2M+3H] 3+ . [ nat Pb]61 RP-HPLC (10-60% in 15 min): R =10.6 minutes. ESI-MS: exact (C 103 H 157 FN 27 O 23 PbS2Si + ):2459.1;m found : m / z=615.7[M+4H] 4+ , 820.7[M+3H] 3+ , 1230.5[M+2H] 2+ . 4. Radiolabeling 4.1 68 Ga-labeling 68 Ga-labeling was performed using an automated system (GallElut) as previously described. + This was done using a 3D scanner (Scintomics, Germany)

[28] . Briefly, a SnO2 matrix was used. 68 Ge / 68 A Ga-generator (IThemba LABS) was eluted with 1.0 M aqueous HCl from which fractions (1.25 mL) of approximately 80% activity (500-700 MBq) were transferred into reaction vials (ALLTECH, 5 mL). Before elution, the reactor was charged with 2-5 nmol of the respective chelator conjugate in 2.7 M aqueous HEPES (900 μL). After elution, the vials were heated at 95 °C for 5 min. Purification was performed by passing the reaction mixture through a solid-phase extraction cartridge (C8 Light, SepPak), which was purged with water (10 mL) and the product was eluted with 50% aqueous ethanol (2 mL), phosphate buffered saline (PBS, 1 mL) and again with water (1 mL). After evaporating the ethanol in vacuo, the purity of the radiolabeled compound was determined by radio-TLC (ITLC-SG chromatography paper, mobile phase: 1:1 mixture (v / v) of 0.1 M trisodium citrate and 1 M ammonium acetate with methanol). 4.2 18 F sign 18 For F labeling, we applied a previously published procedure

[29] . 4.3 TOC 125 I-label

[0404] [ka]

[0405] Reference ligand for in vitro studies [ 125 [I]TOC was prepared according to a previously published procedure

[30] . Briefly, 50–150 μg of non-iodized precursor TOC was dissolved in 20 μL of DMSO and 280 μL of Tris iodination buffer (25 mM Tris-HCl, 0.4 mM NaCl, pH = 7.5). 5.00 μL (15–20 MBq) [I]TOC was added to the 500 μL iodized solution. 125 After addition of [I]NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany), the solution was transferred to a reaction vial coated with 150 μg of IodoGen®. The reaction was stopped by incubating at room temperature for 15 min and separating the solution from the oxidizing agent. 125 The crude product of [I]I-TOC was analyzed by RP-HPLC [(20%-50% B in 15 min):t R = 9.4 min] and the final lysed product was treated with a 100 mM solution of 10 Vol-% Na ascorbate in H2O to prevent radiolysis. 5. In vitro experiments 5.1 IC 50 Decision SST2-transfected CHO cells were cultured in Dulbecco's modified Eagle's medium / nutrient mixture F-12 (DMEM / F-12) and Glutamax-I (1:1) (Gibco) supplemented with 10% fetal calf serum (FCS) and maintained at 37°C in a humidified 5% CO2 atmosphere. Half-maximal inhibitory concentrations (IC 50 For the determination of ), cells were harvested 24 ± 2 h before the experiment and seeded (1.0 × 10 5Cells were incubated in 1 mL / well of culture medium. After removing the culture medium, cells were treated once with 300 μL of HBSS-B (Hank's Balanced Salt Solution, Biochrom, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA)) and left with 200 μL of HBSS-B. Then, cells were treated with HBSS-B (control) or increasing concentrations (10% in HBSS-B) of 100 μL of HBSS-B. -10 ~10 -4 Addition of 25 μL of solution per well containing either of the respective ligands for M was followed by addition of [ 125 I]TOC([ 125 I]Tyr 3 25 μL of 1.0 nM octreotide was added. Each concentration was investigated in triplicate. After 60 min incubation at room temperature, the experiment was terminated by removing the assay medium followed by rinsing with 300 μL cold PBS. The medium from both steps was combined into one fraction, which represents the amount of unbound radioligand. Afterwards, the cells were lysed with 300 μL 1M NaOH and combined with 300 μL 1M NaOH from the next washing step. Quantification of bound and unbound radioligand was achieved in a gamma counter. 5.2 Internalization AR42J cells were cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum (FCS) and 2 mM L-Glu and maintained at 37°C in a humidified 5% CO2 atmosphere. For internalization studies, AR42J cells were harvested 24±2 h before the experiment and seeded into 24-well PLL-plates (2 × 10 in 1 mL / well). 5 After removing the culture medium, the cells were washed once with 300 μL RPMI (5% BSA, 2 mM L-Glu) and left to equilibrate in 200 μL RPMI (5% BSA, 2 mM L-Glu) at 37° C. for at least 15 minutes. Each well was treated with 25 μL of either RPMI (5% BSA, 2 mM L-Glu) or 10 μM TOC solution (1 μM assay concentration) for blocking. Then, 18 F-labeled SST ligand at 20 nM concentration and the reference ligand [ 12525 μL of a solution also containing [I]TOC at 1 nM concentration was added and the cells were incubated at 37°C for 15, 30 and 60 min. For each investigated time point, a separate well plate was prepared. The experiment was terminated by placing the 24-well plate on ice and subsequently removing the medium. Each well was rinsed with 300 μL of RPMI (2 mM L-Glu) and the fractions from these first two steps were combined. This represents the amount of free radioligand. Removal of surface-bound activity was achieved by incubating the cells with 300 μL of ice-cold acid wash solution for 15 min and rinsing again with another 300 μL of ice-cold acid wash. Internalized activity was determined by incubating the cells in 300 μL of 1 M NaOH and combining the fractions from the next wash step with 300 μL of 1.0 M NaOH. Each experiment (control and blocked) was performed in triplicate. Free, surface-bound and internalized activity were quantified in a gamma counter. Data were corrected for non-specific internalization and normalized relative to the specific internalization observed for a radioiodinated reference compound. 5.3 Octanol-water partition coefficient Approximately 1 MBq of labeled tracer was dissolved in 1 mL of a 1:1 mixture (by volume) of phosphate-buffered saline (PBS, pH 7.4) and n-octanol in an Eppendorf tube. After vigorously mixing the suspension for 3 min at room temperature, the vial was centrifuged at 15000 g for 5 min (Biofuge15, Heraus Sepatech, Osterode, Germany) and 100 μL aliquots of both layers were measured in a gamma counter. Experiments were repeated at least six times. 5.4 HSA binding RIAC method The gel filtration column Superdex75 Increase10 / 300 GL (GE Healthcare, Uppsala, Sweden) was pre-calibrated according to the manufacturer's recommendations using a commercial gel filtration calibration kit (GE Healthcare, Buckinghamshire, UK) containing conalbumin (MW: 75 kDa), ovalbumin (44 kDa), carbonic anhydrase (29 kDa), ribonuclease A (13.7 kDa) and aprotinin (6.5 kDa) as reference proteins with known molecular weights. AMSEC experiments were performed using a constant flow rate of 0.8 mL / min at room temperature. A physiological concentration (700 μM) of HSA in PBS was used as the mobile phase. The SST2 ligand was labeled as described, with a molar activity of 10–20 GBq / μmol. 1.0 MBq of the radioactive ligand probe was injected directly from the labeling solution. HSA binding was expressed as apparent molecular weight MW calculated from the retention time of the radioligand using a defined calibration curve.

[0406] FIG. 1 shows the calibration plot of the Superdex75 Increase gel filtration column using the low molecular weight gel filtration calibration kit according to the table below. MW: molecular weight. R : experimentally determined retention time. V: elution volume. K av :Distribution.

[0407] For the evaluation, the experimentally determined retention time t R First, multiply the elution volume V by the flow rate. e and then the formula

[0408]

number

[0409] [Wherein, V0 is the column void volume (8.027 mL), V c is the geometric column volume (24 mL). av The equation given by the trend line plot of the column calibration is K av=-0.18ln(MW)+2.0967 The apparent molecular weight MW is calculated using

[0410]

number

[0411] It is calculated as: 6. In vivo Experiments 6.1 Mouse and tumor models All animal experiments were performed in accordance with the general German animal protection regulations and the institutional guidelines for the care and use of animals. To establish tumor xenografts, AR42J cells (5 × 10 6 Cells (100 μL) were suspended in Dulbecco's modified Eagle's medium / nutrient mixture F-12 and Glutamax-I (1:1) and inoculated subcutaneously into the right shoulder of 8-week-old female CD1 nu / nu mice (Charles River, Sulzfeld, Germany). Mice were used for experiments when tumors had grown to 5–9 mm in diameter (7–15 days after inoculation). 6.2 μPET / CT Imaging Imaging experiments were performed using the MILabs VECTor 4 Small animal SPECT / PET / OI / CT was used. The data were analyzed using the associated PMOD (version 4.0) software. Mice were anesthetized with isoflurane. 18F-labeled compounds were injected via the tail vein (0.05–0.25 nmol; 1–20 MBq). Mice were euthanized 1 h after injection and blood samples for later biodistribution studies were collected by cardiac puncture, after which images were acquired. Static images were acquired using a HE-UHR-M collimator and stepwise spiral bed movement with an imaging time of 45 min. All images were reconstructed using MILabs-Rec software (version 10.02) and a pixel-based Similarity-Regulated Ordered Subsets Expectation Maximization (SROSEM) algorithm with window-based scatter correction (<20% and >20% of the photopeak, respectively). Voxel size CT: 80 μm, 1.6 mm Gaussian blur, with calibration factor (in kBq / mL) and attenuation correction. For blockade, 20 μg TOC was administered directly before tracer injection. 6.3 Biodistribution Approximately 0.5-2.0MBq (0.05-0.25nmol) 18 F-labeled SST2 ligand was injected into the tail vein of AR42J tumor-bearing female CD1 nu / nu mice, and the mice were sacrificed 1 h after injection (n=3-5). Selected organs were removed, weighed, and measured in a γ-counter. II. Results Tables 1, 2 and 3 summarize the in vitro data for the SST ligands described herein.

[0412] [Table 1]

[0413] The reference ligands in Table 1 illustrate the difficulties in realizing radial hybrid structures (combination of chelators and SiFA-moieties). The incorporated chelators balance the high lipophilicity of the SiFA-moiety (ligands [Ga]1-[Ga]9). However, the use of SiFA-benzoic acid and DOTA or DOTAGA directly linked via the amino acid D-Dap as a trivalent linker results in a significant increase in target affinity (IC 50 ) negatively affected the affinity of the ligand for the target. Therefore, specific optimization steps had to be performed to develop a ligand with sufficient target affinity, lipophilicity and low affinity for human serum albumin, as defined in the claims and illustrated by the following examples.

[0414] [Table 2]

[0415] [Table 3]

[0416] Tables 4, 5 and 6 summarize the results of the in vivo mouse experiments. For all biodistribution studies, female CD1 nu / nu mice bearing AR42J tumor xenografts were used and sacrificed 1 hour after injection.

[0417] [Table 4]

[0418] [Table 5]

[0419] [Table 6]

[0420] Figures 2, 3 and 4 show MIPs of PET / CT scans of AR42J tumor-bearing female mice (CD1 nu / nu). To perform static PET / CT scans, mice were euthanized 1 hour after injection and images were acquired with an imaging time of 45 minutes.

[0421] Figure 2 shows PET / CT MIP of [18F][natGa]19 at 10-30%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = kidney.

[0422] Figure 3 shows PET / CT MIP of [18F][natGa]46 at 5-30%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = overlap between kidney and organs expressing the receptor at physiological levels (e.g. stomach and pancreas).

[0423] Figure 4 shows PET / CT MIP of [18F][natGa]50 at 5-40%ID / mL in female AR42 tumor-bearing CD1 nu / nu mice. Arrows indicate organs / volumes of interest: solid line = tumor, dotted line = overlap between kidney and organs expressing the receptor at physiological levels (e.g. stomach and pancreas). References 1. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors [eng]. Endocr Rev. 2004; doi:10.1210 / er.2003-0014. 2. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors [eng]. Cancer. 2003; doi:10.1002 / cncr.11105. 3. Taal BG, Visser O. Epidemiology of neuroendocrine tumours [eng]. Neuroendocrinology. 2004; doi:10.1159 / 000080731. 4. Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas [eng]. Neoplasia. 2017; doi:10.1016 / j.neo.2017.09.002. 5. Papotti M, Croce S, BelloM, Bongiovanni M, Allia E, Schindler M, et al. Expression of somatostatin receptor types 2, 3 and 5 in biopsies and surgical specimens of human lung tumours. Correlation with preoperative octreotide scintigraphy [eng]. Virchows Arch. 2001; doi:10.1007 / s004280100494. 6. Gunther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp H-J, et al. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature [eng]. Pharmacol Rev. 2018; doi:10.1124 / pr.117.015388. 7. Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PPA, et al. Classification and nomenclature of somatostatin receptors. Trends in Pharmacological Sciences. 1995; doi:10.1016 / s0165-6147(00)88988-9. 8. Reubi JC, Waser B, Schaer JC, Laissue JA. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands [eng]. Eur J Nucl Med. 2001; doi:10.1007 / s002590100541. 9. Taniyama Y, Suzuki T, Mikami Y, Moriya T, Satomi S, Sasano H. Systemic distribution of somatostatin receptor subtypes in human: an immunohistochemical study [eng]. Endocr J. 2005; doi:10.1507 / endocrj.52.605. 10. Patel YC. Somatostatin and its receptor family [eng]. Front Neuroendocrinol. 1999; doi:10.1006 / frne.1999.0183. 11. Xu C, Zhang H. Somatostatin receptor based imaging and radionuclide therapy [eng]. Biomed Res Int. 2015; doi:10.1155 / 2015 / 917968. 12. Tredwell M, Gouverneur V. 18F labeling of arenes [eng]. Angew Chem Int Ed Engl. 2012; doi:10.1002 / anie.201204687. 13. Yusubov MS, Svitich DY, Yoshimura A, Nemykin VN, Zhdankin VV. 2-Iodoxybenzoic acid organosulfonates: preparation, X-ray structure and reactivity of new, powerful hypervalent iodine(V) oxidants [eng]. Chem Commun (Camb ). 2013; doi:10.1039 / c3cc47090c. 14. Bernard-Gauthier V, Wangler C, Schirrmacher E, Kostikov A, Jurkschat K, Wangler B, et al. 18 F-labeled silicon-based fluoride acceptors: potential opportunities for novel positron emitting radiopharmaceuticals [eng]. Biomed Res Int. 2014; doi:10.1155 / 2014 / 454503. 15. Bernard-Gauthier V, Bailey JJ, Liu Z, Wangler B, Wangler C, Jurkschat K, et al. From Unorthodox to Established: The Current Status of (18)F-Trifluoroborate- and (18)F-SiFA-Based Radiopharmaceuticals in PET Nuclear Imaging [eng]. Bioconjug Chem. 2016; doi:10.1021 / acs.bioconjchem.5b00560. 16. Schirrmacher R, Bradtmoller G, Schirrmacher E, Thews O, Tillmanns J, Siessmeier T, et al. 18F-labeling of peptides by means of an organosilicon-based fluoride acceptor [eng]. Angew Chem Int Ed Engl. 2006; doi:10.1002 / anie.200600795. 17. Iovkova L, Konning D, Wangler B, Schirrmacher R, Schoof S, Arndt H-D, et al. SiFA-Modified Phenylalanine: A Key Compound for the Efficient Synthesis of 18F-Labelled Peptides. Eur. J. Inorg. Chem. 2011; doi:10.1002 / ejic.201100142. 18. Litau S, Niedermoser S, Vogler N, Roscher M, Schirrmacher R, Fricker G, et al. Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics [eng]. Bioconjug Chem. 2015; doi:10.1021 / acs.bioconjchem.5b00510. 19. Niedermoser S, Chin J, Wangler C, Kostikov A, Bernard-Gauthier V, Vogler N, et al. In Vivo Evaluation of 18F-SiFAlin-Modified TATE: A Potential Challenge for 68 Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET [eng]. J Nucl Med. 2015; doi:10.2967 / jnumed.114.149583. 20. Ilhan H, Todica A, Lindner S, Boening G, Gosewisch A, Wangler C, et al. First-in-human 18F-SiFAlin-TATE PET / CT for NET imaging and theranostics [eng]. Eur J Nucl Med Mol Imaging. 2019; doi:10.1007 / s00259-019-04448-8. 21. Goffin K. Al18F-NOTA-octreotide and 18F-SiFAlin-TATE: two 'new kids on the block' in somatostatin receptor imaging [eng]. Eur J Nucl Med Mol Imaging. 2019; doi:10.1007 / s00259-019-04474-6. 22. Ilhan H, Lindner S, Todica A, Cyran CC, Tiling R, Auernhammer CJ, et al. Biodistribution and first clinical results of 18F-SiFAlin-TATE PET: a novel 18F-labeled somatostatin analog for imaging of neuroendocrine tumors [eng]. Eur J Nucl Med Mol Imaging. 2019; doi:10.1007 / s00259-019-04501-6. 23. Lindner S, Simmet M, Gildehaus FJ, Jurkschat K, Wangler C, Wangler B, et al. Automated production of 18FSiTATE on a Scintomics GRP TM platform for PET / CT imaging of neuroendocrine tumors [eng]. Nucl Med Biol. 2020; doi:10.1016 / j.nucmedbio.2020.07.008. 24. Wurzer A, DiCarlo D, Schmidt A, Beck R, Eiber M, Schwaiger M, et al. Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA-inhibitors [eng]. J Nucl Med. 2019; doi:10.2967 / jnumed.119.234922. 25. 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Claims

1. Formula (I): 【Chemistry 1】 [In the formula, R Ｂ is a binding motif capable of binding to the somatostatin receptor, L Ｄ１ is a divalent linking group, m is an integer from 2 to 6, A Ｈ１ represents independently for each occurrence -NH of a hydrophilic amino acid ２ and amino acid units derived from hydrophilic amino acids which contain, in addition to the -COOH functionality, further hydrophilic functional groups, m unit A Ｈ１ one of the groups may further have a hydrophilic unit other than an amino acid attached to the hydrophilic functional group; L Ｔ１ is a trivalent linking group, R ＣＨ is a chelating group which may contain a chelated radioactive or non-radioactive cation, R Ｍ１ is a hydrophilic modifying group, p is 0 or 1, L Ｄ２ is a divalent linking group, q is 0 or 1, R Ｓ is a silicon fluoride acceptor (SiFA) group having one of the following formulae, which contains a silicon atom and a fluorine atom: １９ F. １８ By isotope exchange with F １８ It may be labeled with F, or １８ It is labeled with F, When p is 1, R Ｓ represents a group of formula (S-3) or a group of formula (S-4): 【Chemistry 2】 (In the formula, r is 1, 2 or 3; -(CH ２ ) ｓ -s is an integer from 1 to 6, R groups are independently H or C1-C6 alkyl; R １Ｓ and R ２Ｓ are, independently of each other, a straight or branched C3 to C10 alkyl group, and the dashed line indicates the bond connecting said group to the remainder of the compound. and When p is 0, R Ｓ is a group of formula (S-4) as defined above. or a salt thereof.

2. Binding motif R Ｂ But, Tyr ３ , Thr ８ -Octreotide (TATE), Tyr ３ -Octreotide (TOC), Thr ８ -Octreotide (ATE), 1-NaI ３ -Octreotide (NOC), 1-Nal ３ , Thr ８ -Octreotide (NOCATE), BzThi ３ -Octreotide (BOC), BzThi ３ , Thr ８ A compound or salt according to claim 1 which contains a group derivable from a receptor agonist or receptor antagonist selected from octreotide (BOCATE), JR11, BASS and KE121.

3. Binding motif R Ｂ is a group of formula (B-1) or (B-2): 【Chemistry 3】 where the dashed line represents the bond attaching the group to the remainder of the compound.

2. The compound or salt of claim 1, comprising:

4. Chelating group R ＣＨ However, diethylenetriaminepentamethylenephosphonic acid (EDTMP) and its derivatives, diethylenetriaminepentaacetic acid (DTPA) and its derivatives, 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]-(hydroxyphenyl)-N'-[5-[[4-[5-aminopentyl ... )amino]-4-oxobutanoyl]-amino]pentyl]-N-hydroxybutanediamide (DFO) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecane-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 (DO TAM), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphato) (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane -4,7,10-triacetate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetate (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetate (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-tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), as well as triethylenetetraminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H, ２ Macropa), 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-carboxylate) 1,4,7,10-Tri(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid (DO3AM), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1,4,7, 10-Tetraazacyclododecanetetraacetic acid, hydrazinonicotinic acid (HYNIC), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA) and its derivatives, pentadeca-1,4,7,10,13-penta-aminopentaacetic acid (PEPA), hexadeca-1,4,7,10,13,16-hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl))carbazone} N-(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-triaminetriacetic acid (BPAM), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamine]ethane (DEDPA, H ２ DEDPA), deferoxamine (DFO) and its derivatives, 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) and its derivatives, tetraadicyclodecane-phosphinic acid (TEAP) , 6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid (AAZTA), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr), 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 (H ２ Vispa ２ ), 1,2-[{6-(carboxylato)pyridin-2-yl}methylamino]-ethane (H ２ Dedopa), N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H ４ Octapa), N,N'-bis(2-hydroxy-5-sulfonylbenzyl)-N,N'-bis-(2-methylpyridyl)ethylenediamine (H ６ and its derivatives, triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetic acid (TTHA), 2-aminomethylpiperidinetriacetic acid (2-AMPTA) and its derivatives, 4-nitro-2-hydroxybenzyl-2-{[(6)-trans-2-[benzyl(carboxymethyl)amino]cyclohexyl](carboxymethyl)amino}acetic acid (RESCA) and its derivatives, and 6-carboxy-1,4,8,11-tetraazaundecane (N ４ 2. The compound or salt of claim 1, comprising a group derivable from a chelating agent selected from the group consisting of aryl, aryloxy ...

5. Chelating group R ＣＨ 5. The compound or salt of claim 4, wherein said chelating group comprises a group derivable from a chelating agent selected from DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, and wherein said chelating group may comprise a chelated radioactive or non-radioactive cation.

6. R ＣＨ which may contain a chelated radioactive or non-radioactive cation, and which has the formula (CH-1), (CH-2) or (CH-3): 【Chemistry 4】 where the dashed line represents the bond attaching the group to the remainder of the compound.

2. The compound or salt of claim 1,

7. the group of formula (S-3) is a group of formula (S-3a) and the group of formula (S-4) is a group of formula (S-4a), 【Chemistry 5】 During the ceremony, ｔ 2. The compound or salt of claim 1, wherein Bu represents a tert-butyl group and the dashed line represents the bond attaching said group to the remainder of the compound.

8. Amino acid unit A Ｈ１ The further hydrophilic functional group of -NH ２ , -COOH, -NH-C(=NH)-NH ２ , -C(=O)NH ２ , -NH-C(=O)-NH ２ , -OH and -P(=O)(OH) ２ 2. The compound or salt of claim 1, independently selected from:

9. Amino acid unit A Ｈ１ are independently selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit and a phosphonomethylalanine (Pma) unit.

10. p is 1, and the hydrophilic modifying group R Ｍ１ is an amino acid unit selected from a diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, or p is 0.

11. The compound or salt according to claim 10, wherein p is 1 and the hydrophilic modifying group R M1 is a diaminopropionic acid unit.

12. q is 1, and the divalent linking group L Ｄ２ Formula (L-2): -[A Ｌ２ ] ｗ - (L-2) [In the formula, A Ｌ２ is, independently for each occurrence when w is greater than 1, an amino acid unit; w is 1 to 5, 1 to 3, or 1 or 2. or q is 0.

5. The compound or salt of claim 1,

13. Formula (I.2): 【Chemistry 6】 [In the formula, R Ｂ , L Ｄ１ , A Ｈ１ , m, L Ｔ１ , R ＣＨ and R Ｍ１ is defined as in claim 1, R Ｓ２ represents a group of formula (S-3): 【Chemistry 7】 (In the formula, R １Ｓ and R ２Ｓ are, independently of each other, a straight or branched C3 to C10 alkyl group, and the dashed line indicates the bond connecting said group to the remainder of the compound. is] 2. The compound or salt of claim 1, which is

14. Formula (I.4) or (I.5): 【Chemistry 8】 [In the formula, R Ｂ , L Ｄ１ , A Ｈ１ , m, L Ｔ１ , R Ｍ１ , L Ｄ２ , q and R ＣＨ is defined as in claim 1, R Ｓ３ represents a group of formula (S-4): 【Chemistry 9】 (In the formula, r is 1, 2, or 3; s is an integer from 1 to 6; R is independently H or C1-C6 alkyl; R １Ｓ and R ２Ｓ are, independently of each other, a straight or branched C3 to C10 alkyl group, and the dashed line represents the bond connecting said group to the remainder of the compound. is] 2. The compound or salt according to claim 1, which is a compound of the formula:

15. R Ｂ is Tyr ３ , Thr ８ -Octreotide (TATE), Tyr ３ -Octreotide (TOC), Thr ８ -Octreotide (ATE), 1-NaI ３ -Octreotide (NOC), 1-Nal ３ , Thr ８ -Octreotide (NOCATE), BzThi ３ -Octreotide (BOC), BzThi ３ , Thr ８ - containing a group derivable from a receptor agonist or receptor antagonist selected from octreotide (BOCATE), JR11, BASS, and KE121, R ＣＨ comprises a group derivable from a chelating agent selected from DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA, the chelating group may comprise a chelated radioactive or non-radioactive cation; A Ｈ１ is independently selected at each occurrence from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, a lysine (Lys) unit, an arginine (Arg) unit, a glutamic acid (Glu) unit, an aspartic acid (Asp) unit, an asparagine (Asn) unit, a glutamine (Gln) unit, a serine (Ser) unit, a citrulline (Cit) unit and a phosphonomethylalanine (Pma) unit.

16. 16. A pharmaceutical or diagnostic composition comprising or consisting of one or more compounds or salts according to any one of claims 1 to 15.

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