Ligand compounds containing chelating groups as bridging groups

Abstract

(a) A compound of formula (I): JPEG2024531844000079.jpg47112 (wherein a is 0 or 1, m is 2 or 3, n is 2 or 3, and R 1 , R 2 , and R 3 is an effector moiety R B R 1 , R 2 , and R 3 Another group selected from the group consisting of silicon-based fluoride acceptor (SiFA) moieties R S R 1 , R 2 , and R 3 The remaining group selected from the formula (R-1) JPEG2024531844000080.jpg20112 (in the formula, R 4 is selected from -H, -OH, and C1-C3 alkyl, and the dashed line represents the bond attaching the group to the remainder of the compound; R 5 is selected from -H, -OH, and C1-C3 alkyl; (b) a salt thereof, and (c) a chelate formed from a compound of formula (I) or a salt thereof and a radioactive or non-radioactive cation. The compounds of the present invention are suitable for therapeutic and diagnostic purposes, such as radionuclide therapy or nuclear diagnostic imaging.

Description

[Background technology]

[0001] Neuroendocrine tumors (NETs) are a heterogeneous group of malignant tumors originating from the neuroendocrine system. This system is composed of neuroendocrine cells in various different tissues such as endocrine glands (pituary, parathyroid, adrenal), 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 rate of 2–5 / 100,000 (0.5% of newly diagnosed malignancies each year), depending on the patient's (ethnic) decent. Tumors of the gastrointestinal tract are the most common at 67%, followed by NETs in the respiratory system at 25%. Although the incidence may be low, the number of entities diagnosed has been increasing over the past 30 years, due to optimized methods in diagnosis [1–4].

[0002] For the purpose of diagnosis and treatment of NETs, ​​the somatostatin receptor (SST), more precisely its five subtypes, SST 1~5 are considered [5, 6]. Their G protein-coupled receptors are naturally expressed on neuroendocrine cells in different tissues, but are overexpressed on various types of NETs and their metastases [5, 7, 8]. Therefore, SST receptors are attractive targets for diagnostic clarification applying positron emission tomography (PET) [6]. Nevertheless, the application is not trivial, since the expression level of each subtype varies, depending on the origin and type of tumor. Moreover, it is not possible to target all SST receptors with sufficient affinity, although many ligands may be very closely related to one or two subtypes. However, SST2 in particular is overexpressed on various NETs, ​​and therefore it is of great interest for the development of new radiopharmaceuticals [5, 6].

[0003] 18 Among the F-series SST tracers, especially 18[F]SiFAlinTATE has gained interest in recent years. [9, 10] The building block of the SiFA system, SiFAlin-aldehyde, contains a permanent positive charge, 18 F labeling has been achieved with promising in vitro and in vivo parameters, leading to the first human clinical trials [11, 12].

[0004] Multimodal approaches, the possibility of combining more than one labeling technique within a single peptide or small molecule, have been explored in a variety of ways. Recently, a professor of medicinal radiochemistry at the Technical University of Munich has developed a methodology for radioactive hybrid (rh) labeling of biomolecules, which allows: 18 F fluoride (for PET) or trivalent radioactive metals (for PET) 68 Ga 3+ , for PRRT 177 Lu 3+ It is now possible to label a generic precursor molecule with either the rh ligand or the rh ligand. 18 When labeled with F fluoride, low-temperature metals can be complexed in molecules, and when labeled with radioactive metals, low-temperature 19 F fluorine is present. Therefore, 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 making them the very same diagnostic and therapeutic tracers, e.g. 18 F / 177 This makes it possible to generate structurally identical theranostic tracers with the in vivo properties of the fluorouracil-based IgG1a (IgG1a and IgG2b analogues).

[0005] The combination of a chelator with another modality for different labeling approaches can be applied in many ways, therefore different multimodal approaches have been investigated so far. Schottelius et al. combined the already established PSMA ligand PSMA I&T with the fluorescent dye sulfo-Cy5, resulting in a fluorescent-radioactive hybrid structure (PSMA I&F)

[13] . Roxin et al. designed what they considered to be a radioactive hybrid concept, a VLA-4 targeting peptide (DOTA-AMBF3-LLP2A) composed of the chelator DOTA and a BF3-based structure. Similar to the already introduced radioactive hybrid concept, DOTA-AMBF3-LLP2A is 18 It can also be labeled with F and trivalent radioactive metals (although initial investigations were limited to uncomplexed compounds)

[14] .

[0006] Frequently, the two modalities are conjugated via a trivalent unit, e.g., diaminoproprionic acid (rhPSMA7), or a lysine unit (PSMA I&F, DOTA-AMBF3-LLP2A), usually resulting in a sterically bulky radioactive or fluorescent-radioactive hybrid moiety.

[0007] A different approach was taken by Gai et al., who designed more complex DOTA- and NOTA-based building blocks that could be directly introduced into the peptide scaffold via standard peptide chemistry or by applying a combination of peptide and click chemistry

[15] .

[0008] The chelator DOTPI has been used to generate the symmetric tetrameric PSMA ligands DOTPI(Trz-KuE)4 and DOTPI(DBCO-KuE)4, or as a bridging unit in αvβ3 integrin addressing tetrameric DOTPI(RGD)4 [16, 17]. Similar examples have been described for multivalent TRAP peptides. Furthermore, a multimodal approach has been published in which dimeric TRAP conjugates are also equipped with the fluorophore rhodamine 6G for fluorescent applications

[18] .

[0009] Due to the general concept of affinity, the application of chelators such as TRAP and DOTPI as multimeric bridges usually results in high affinity peptides

[19] . The combination of carboxylic acids for conjugation with target addressing peptides and hydrophilic phosphinates for complexation of radiometals results in overall highly hydrophilic peptides [16, 18]. Summary of the Invention

[0010] Although typical parameters such as target affinity and lipophilicity are generally promising, the synthesis accessibility of the chelators themselves and multimeric / multimodal peptides is complex and often unfavorable.

[0011] The present invention provides a novel approach for the development of chelator-based radioactive hybrid ligand compounds. In these compounds, the heterocyclic structure of the chelator serves as a bridging structure between the binding motif and the SiFA group as the second labeling structure. Since the chelator structure serves as a linker, no additional linker structure is required to act as a spacer between the binding motif and the chelator, resulting in a simplified overall structure of the ligand compound. The resulting compounds have high affinity, high hydrophilicity, and weak binding to human serum albumin, leading to favorable in vivo results in mouse models.

[0012] Specifically, the present invention relates to The following formula (I)

[0013] [ka]

[0014] (In the formula, a is 0 or 1, preferably 1; m is 2 or 3, preferably 2; n is 2 or 3, preferably 2; R 1 , R2 , and R 3 is an effector moiety R B is a group comprising R 1 , R 2 , and R 3 Another group selected from the group consisting of silicon-based fluoride acceptor (SiFA) moieties R S wherein the moiety comprises a silicon atom and a fluorine atom, the fluorine atom being directly linked to the silicon atom by a covalent bond; 18 By F 19 By isotopic exchange of F 18 may be labeled with F, or 18 Labeled with F, R 1 , R 2 , and R 3 The remaining group selected from the formula (R-1)

[0015] [ka]

[0016] (In the formula, R 4 is selected from -H, -OH, and C1-C3 alkyl, preferably -H, and the dashed line indicates the bond attaching the group to the remainder of the compound; R 5 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; The salt of it, and chelate compounds formed from a compound of formula (I) or a salt thereof and a radioactive or non-radioactive cation. The present invention provides a compound selected from the group consisting of:

[0017] As explained above, the compounds of the present invention are selected from compounds of formula (I), their salts (i.e., salts of compounds of formula (I), typically pharma- ceutically acceptable salts), and chelates formed from compounds of formula (I) or their salts and radioactive or non-radioactive cations. Thus, unless otherwise indicated, any reference herein to a compound of the present invention includes compounds of formula (I) (and preferred embodiments of this formula disclosed herein), their salts, and chelates. Similarly, any racemate, enantiomer, or diastereomer of any chiral compound of formula (I), and their salts, are included, unless the specific stereochemistry of the compound under consideration is indicated in a particular context. Herein, the compounds of the present invention may also be referred to as ligand compounds of the present invention, or simply as ligands.

[0018] Below, the structural elements of the compounds of the present invention are further discussed. As will be understood by the skilled reader, the information provided in this context on the (preferred) structure of the compound of formula (I) also applies to the salts of the compound of formula (I), as well as to chelates formed from the compound of formula (I) or its salts and a radioactive or non-radioactive cation.

[0019] In formula (I), a is 0 or 1, preferably 1. Thus, the compound of formula (I) has the formula (IA)

[0020] [ka]

[0021] (wherein the variables m, n, and R 1 ~R 5 is preferably a compound of the formula: As illustrated by formula (I), the compounds of the present invention include substituted heterocycles containing three nitrogen atoms (when a is 0) or four nitrogen atoms (when a is 1) as ring members. The nitrogen atoms present as ring members in the heterocycle are linked by an ethanediyl group -CH2-CH2- (when m is 2 and n is 2) or by an ethanediyl group and one or two propanediyl groups -CH2-CH2-CH2- (when m is 3 and n is 3 or both m and n are 3). The heterocycle formed by a nitrogen atom and an ethanediyl group, or an ethanediyl group and a propanediyl group, is also referred to herein as a nitrogen-containing macrocycle.

[0022] As will be appreciated by the skilled reader, when a is 0, there is no bracketed moiety [....] bearing the indicator a in formula (I), and the substituent -R 1 A direct bond is formed between the nitrogen atom bearing the --CH.sub.2--CH.sub.2-- group shown on both sides of the moiety in brackets in the formula.

[0023] With regard to the preferences for a, m, and n shown above, it will be appreciated that the combination a=1, m=2, and n=2 is a further preferred combination for compounds of formula (I), as exemplified in the following preferred formula (IB):

[0024] [ka]

[0025] (Wherein, the variable R 1 ~R 3 and R 5 is defined above). In formula (I) and preferred embodiments thereof, R 1 , R 2 , and R 3 (i.e., R 1 or R 2 or R 3 (either of the above) is the effector part RB Such an effector moiety R B A preferred example of R is a binding motif that allows a ligand / receptor interaction to occur between the compounds according to the invention and a receptor of therapeutic and / or diagnostic interest. A preferred example of such a receptor is the somatostatin (SST) receptor. Such a binding motif can serve as a basic affinity anchor for the compound to the receptor. More preferably, R B is a binding motif capable of binding at least to somatostatin receptor 2 or SST2, or to more somatostatin receptor subtypes, or even to all somatostatin receptor subtypes, the latter resulting in a so-called SST pan-receptor ligand.

[0026] R B If a compound containing the binding motif R represents a binding motif consistent with the above, it is generally capable of binding to the receptor with high affinity. In this context, high affinity binding preferably means that the 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, the half maximal inhibitory concentration (IC50) is referred to herein as the concentration required to inhibit 50% of the binding of a radioactive reference ligand to the receptor in vitro. B or a quantitative measure of the molar concentration of a compound according to the present invention that contains it. For example, as a reference ligand for binding to the SST receptor, 125 I]Tyr 3 -Octreotide may be relied upon.

[0027] It will be appreciated that a preferred binding motif for an effector moiety capable of high affinity binding to the SST receptor as referred to herein may exhibit high affinity to more than one SST receptor type. Preferably, the binding moiety R B exhibits the highest binding affinity to SST2 among the SST receptor subtypes.

[0028] Suitable binding motifs include agonists and antagonists of the SST receptor. Effector molecule R B is generally a coupling group, i.e., R B is attached to the remainder of the compound of the invention by a covalent bond. The coupling group may consist of one or more atoms. Exemplary coupling groups may be selected from -NH-, -NR-, where R is a C1-C6 alkyl, preferably methyl, -C(O)-, -O-, -S-, a quaternary ammonium group, and a thiourea bridge, or R B In this context, also in other cases where quaternary ammonium groups are mentioned in this specification as possible coupling groups, the quaternary ammonium group is preferably a group of the formula -N(R)2 + - is a coupling group, and the R groups are independently C1-C6 alkyl, preferably methyl. As will be appreciated, R B The coupling group contained by may be covalently linked to a further complementary coupling group contained by the compound according to the invention, such that the two coupling groups 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 mentioned herein and in further cases below, the substituent R in the alkylated amide bond -C(O)-NR- is a C1-C6 alkyl, preferably methyl. R B It is preferred that R contains a coupling group -NH-, and that the coupling group forms an amide bond -C(O)-NH- with a group -C(O)- contained in the compound according to the present invention. For example, in formulae (R-2a), (R-2b), (IC), and (ID) disclosed herein, R B contains a coupling group -NH- or -NR-, preferably -NH-, and in these formulas, the coupling group is R Bis preferably linked to the -C(O)- group to which it is attached to form an amide bond (-C(O)-NH-) or an alkylated amide bond (-C(O)-NR-), preferably an amide bond.

[0029] Preferably, the effector moiety R B is a peptidic binding motif, i.e. a binding motif comprising a peptide structure capable of binding to a receptor. The peptidic binding motif preferably comprises a cyclic peptide structure or a peptide cyclized by disulfide bridges. As mentioned above, the binding motif is preferably one capable of binding to SST. Various peptides capable of binding to SST are known and described in the literature. They can be used to bind R 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 remainder of the compound. B The group can be provided.

[0030] Therefore, R B may contain a group, preferably Tyr 3 -Octreotate (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-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-NaI 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, and most preferably from TATE. As will be appreciated by the skilled reader, functional groups such as carboxylic acid or amino groups contained in the receptor agonists or antagonists can be used to provide R B By providing a coupling group that attaches the R B The R group may be conveniently derived from the receptor agonists or antagonists listed above. Preferably, these peptidic receptor agonists or antagonists are linked to R by using an amino group contained therein, for example, in an optionally substituted phenylalanine unit contained in the peptide, to form an amide bond with the remainder of the compound of the invention. B For example, in formulas (R-2a), (R-2b), (ID), (IE), (IF), and (IG) disclosed herein, R B And, R B A covalent bond with the carbonyl group -C(O)- to which is attached may be formed using an -NH- coupling group derived from an amino group contained in the receptor agonist or receptor antagonist described above.

[0031] Alternatively, as will be appreciated by the skilled reader, additional functional moieties that provide functional groups that allow for chemical bonds to be formed to the remainder of the compounds of the invention, such as moieties that have isothiocyanates that can be linked to amines to form thiourea bridges, can be added to R B By introducing it into the R BThe R group in the compound according to the invention can be conveniently derived from the receptor agonists or receptor antagonists listed above. As will be appreciated by the skilled reader, other conjugation strategies, typically summarized as "bioconjugation strategies", can be used to attach the R group in the compound according to the invention to the remainder of the compound according to the invention. B Groups can also be linked.

[0032] Consistent with the above, R B is expressed by the formula (B-1)

[0033] [ka]

[0034] As will be appreciated by the skilled reader, the bond represented by the dashed line in formula (B-1) does not bear a methyl group at its terminus opposite the nitrogen atom, but rather is a bond that attaches R to the remainder of the compound of formula (I). B Preferably, the bond shown by the dashed line in formula (B-1) represents a bond that connects the nitrogen atom of the -NH- group shown in formula (B-1) to an R group such as those in formulas (R-2a), (R-2b), (ID), (IE), (IF), and (IG) disclosed herein in the compounds of the present invention. B represents a covalent bond existing between the carbon atom of the carbonyl group to which it may be attached. In this way, an amide bond can be provided.

[0035] More preferably, R B Formula (B-1a)

[0036] [ka]

[0037] where the dashed line represents the bond attaching the group to the remainder of the compound. Preferably, the effector moiety R B R is a group containing1 , R 2 , and R 3 The group selected from the formula (R-2a) or (R-2b)

[0038] [ka]

[0039] (In the formula, R B is an effector moiety as defined herein, including any preferred embodiments thereof; R 6 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; R 7 is -COOH, The dashed line indicates the bond attaching the group to the remainder of the compound), more preferably a group of formula (R-2a). Thus, as will be appreciated by those of skill in the art, the bond shown with the dashed line represents a CHR 6 Groups and CHR 7 Although each of the groups does not bear a methyl group at its end opposite each other, in the compounds of the present invention, 6 Group or CHR 7 each of the groups and the nitrogen atom in formula (I) or the effector moiety R B R is a group containing 1 , R 2 , and R 3 represents a covalent bond that exists between the preferred embodiment and a group selected from the following is attached.

[0040] R 1 , R 2 , and R 3 Another group selected from the group consisting of the moieties R B One of the two groups that is not a group containing a silicon-based fluoride acceptor (SiFA) moiety R S Such a SiFA moiety comprises a silicon atom and a fluorine atom, the fluorine atom being directly linked to the silicon atom by a covalent bond. 18By F 19 By isotopic exchange of F 18 may be labeled with F, or 18 Labeled with F.

[0041] Preferably, the SiFA moiety R S is expressed by the formula (S-1)

[0042] [ka]

[0043] (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, R 3S is a divalent C1-C20 hydrocarbon group containing one or more aromatic and / or aliphatic moieties, optionally containing up to three heteroatoms selected from O and S, preferably R 3S is a divalent C6-C12 hydrocarbon group that contains an aromatic ring and may contain one or more aliphatic moieties, The dashed line represents the bond attaching the group to the remainder of the compound.

[0044] More preferably, the SiFA moiety R S is expressed as (S-2)

[0045] [ka]

[0046] (In the formula, R 1S and R 2S are each independently a linear or branched C3 to C10 alkyl group, preferably R 1Sand R 2S is selected from isopropyl and tert-butyl, more preferably R 1S and R 2S is tert-butyl, Phe is a phenylene group, y is an integer from 0 to 6, preferably 0 or 1, more preferably 1, and the dashed line represents the bond attaching the group to the remainder of the compound. The two substituents on the phenylene group are preferably in the para position relative to each other. S The group includes a group of formula (S-2), R 1S and R 2S It is particularly preferred that is tert-butyl and y is 1.

[0047] Together with the Si and F atoms, preferably in the form of a group as shown above, the SiFA group R S is R S But R S The compound may also include a coupling group that allows it to be attached to the remainder of the compound of the invention by a covalent bond formed between the group and its point of attachment in formula (I). The coupling group may consist of one or more atoms. Exemplary coupling groups include -NH-, -NR-, -C(O)-, -O-, -S-, -N(R)2 + -(CH2) r -C(O)-, and thiourea bridges, or R S In the above exemplary groups, R is a C1-C6 alkyl, preferably methyl, and r is 1, 2, or 3, preferably 1. The coupling groups are selected from groups that form such thiourea bridges together with the complementary group to which R is attached. In the above exemplary groups, R is a C1-C6 alkyl, preferably methyl, and r is 1, 2, or 3, preferably 1. The coupling groups are selected from groups that form such thiourea bridges together with the complementary group to which R is attached, in the compounds of the present invention. S The two coupling groups may be covalently linked at the attachment point of -C(O)-NH-, such that the two coupling groups 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-, preferably an amide bond. Preferred coupling groups are -C(O)- and -N(R)2 + -(CH2) r -C(O)-. Similarly, R SThese coupling groups are encompassed by R S It is preferred that the coupling group forms an amide bond at the point of attachment with a complementary coupling group provided in the compounds of the invention.

[0048] Alternatively, in the compound of formula (I) R S R is bonded to a quaternary ammonium group as a coupling group provided at the attachment point of S The group may be attached to the remainder of the compound of the invention. As mentioned above, the quaternary ammonium group is preferably of the formula -N(R)2 + -, where the R groups are independently C1-C6 alkyl, preferably methyl. As will be appreciated by the skilled reader, this can be accomplished, for example, by using a compound having a tertiary amino group that is converted to a quaternary amino group upon conjugation with the SiFA group, to form a coupling group of R S This can be accomplished if a unit carrying the

[0049] Consistent with the above, the SiFA moiety R S is expressed as (S-3)

[0050] [ka]

[0051] (In the formula, r is 1, 2, or 3, preferably 1, and -(CH2) s -s is an integer of 1 to 6, preferably 1; R is independently C1-C6 alkyl, 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 2Sis tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound) is particularly preferred.

[0052] Further, consistent with the above, the group of formula (S-3) and thus the SiFA moiety R S is most preferably represented by the formula (S-4)

[0053] [ka]

[0054] (In the formula, t Bu represents a tert-butyl group and the dashed line represents the bond attaching the group to the remainder of the compound). As will be appreciated by those skilled in the art, the bond shown by the dashed line in formulas (S-3) and (S-4) does not carry a methyl group at its end opposite the -C(O)- group, but rather serves to attach the group to the remainder of the compound. Preferably, the bond shown by the dashed line in formulas (S-3) and (S-4) connects the carbon atom of the -C(O)- group shown in formulas (S-3) and (S-4) to the carbon atom of the R S For example, the formula (R-3a), (R-3c), or (ID) shown below (wherein R S is attached to D or the formula (R-3b), (R-3d), or (IE) shown below (in each formula, R S is attached to T or an —NH— group which may be contained in R S1 represents the covalent bond that exists between the nitrogen atom of the -NH- group contained in formula (IF) or (IG) to which it is attached. In this way, an amide bond can be provided as a linking unit.

[0055] Exemplary counterions of the positively charged quaternary ammonium groups shown in formulas (S-3) and (S-4) (bearing two substituents R (in formula (S-3)) or two methyl substituents (in formula (S-4)), respectively) are anions as discussed herein with respect to salt forms of the compound of formula (I), including, for example, trifluoroacetate or acetate.

[0056] The fluorine atom represented by the formulae (S-1) to (S-4) is 18 F atom, or 18 By F 19 F is exchanged by isotope exchange 18 F can be provided 19 It may be an F atom.

[0057] Preferably, the SiFA moiety R S R is a group containing 1 , R 2 , and R 3 The group selected from the formula (R-3a), (R-3b), (R-3c), or (R-3d)

[0058] [ka]

[0059] (In the formula, R S is a SiFA moiety, as defined herein, including any preferred embodiments thereof; R 8 and R 9 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; R 10 and R 11 is -COOH, L D is a divalent linking group, L T is a trivalent linking group, R H is a hydrophilic modifying group, The dashed line indicates the bond attaching the group to the remainder of the compound), more preferably a group of formula (R-3a) or (R-3b). Thus, as will be appreciated by those of skill in the art, the bond shown with the dashed line represents a CHR 8 Group, CHR 9 Group, CHR 10 group, and CHR 11 Although each of the groups does not bear a methyl group at its end opposite each other, in the compounds of the present invention, 8 Group, CHR 9 Group, CHR 10 group, and CHR 11 each of the groups and the nitrogen atom in formula (I) or the SiFA moiety R S R is a group containing 1 , R 2 , and R 3 represents a covalent bond that exists between the preferred embodiment and a group selected from the following is attached.

[0060] R 1 , R 2 , and R 3 The remaining groups selected from (i.e., groups that are not groups that contain an effector moiety RB or a SiFA moiety) are represented by formula (R-1):

[0061] [ka]

[0062] (In the formula, R 4 is selected from -H, -OH, and C1-C3 alkyl, preferably -H, and the dashed line represents the bond attaching the group to the remainder of the compound. Thus, as will be appreciated by those of skill in the art, the bond represented by the dashed line in formula (R-1) represents a CHR 4 It does not bear a methyl group at its terminus opposite the group, but rather serves to attach the group to the nitrogen atom shown in formula (I), which is the preferred embodiment.

[0063] Consistent with the above, R 1 , R 2 , and R 3 Various exemplary combinations of are included.

[0064] [Table A]

[0065] In the table, "R B "R S Reference to "a group comprising" includes these groups, as well as R B and R S As such, it will be understood that these encompass preferred variations. Among these exemplary combinations, preferred are combinations No. 2 and No. 5. Accordingly, particularly preferred are combinations No. 2 and No. 5 in which a is 1.

[0066] Consistent with the above, the compound of formula (I) preferably has the formula (IC)

[0067] [ka]

[0068] (In the formula, i)R 1A is a group of formula (R-2a) as defined herein; R 3A is selected from groups of formulae (R-3a), (R-3b), (R-3c), and (R-3d) as defined herein; or ii) R 1A is selected from groups of formulae (R-2a) and (R-2b) as defined herein; R 3A is a compound of formula (R-3a) and (R-3b) selected from groups as defined herein.

[0069] Furthermore, the compound of formula (I) is more preferably of formula (ID) or (IE)

[0070] [ka]

[0071] (In the formula, R B is an effector moiety, including any preferred embodiments thereof, as defined herein; R S is a SiFA moiety, as defined herein, including any preferred embodiments thereof; L D is a divalent linking group, L T is a trivalent linking group, R H is a hydrophilic modifying group).

[0072] Thus, even when the compound of formula (I) is a compound of formula (IC) or, preferably, a compound of formula (ID) or (IE), R B Tyr 3 -Octreotate (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-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-NaI 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8a moiety that can be derived from a receptor agonist or receptor antagonist selected from 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)); R S is a group of formula (S-3) as defined above, whereas R 1S and R 2S Both are tert-butyl. It will be appreciated that further preferences are given to formulae (IC), (ID) and (IE).

[0073] Even more preferably, in formulae (IC), (ID) and (IE), R B is a group of formula (B-1a) as defined above, R S is a group of formula (S-4) as defined above.

[0074] L shown in the above formulas (R-3a), (R-3b), (R-3c), (R-3d), (ID), and (IE) D The group is a divalent linking group. D may contain, at each of its two ends, for example, an -NH- group or an -NR- group (wherein R is a C1-C6 alkyl, preferably methyl) as a coupling group for attachment to an adjacent group. More preferably, each of the NH- or -NR- groups combines with a carbonyl group (-C(O)-) as the adjacent group to form an amide bond -NH-C(O)- or an alkylated amide bond -NR-C(O)-. Among the -NH- and -NR- groups, preference is given to -NH-. For example, the linking group L D is -NH-R L1may comprise or consist of —NH— groups, R L1 is an alkanediyl group, such as a C1-C6 alkanediyl group, which may carry one or more, such as one, two or three, substituents selected from -OH, -COOH, -CONH2, or -NH2.

[0075] Preferably, the divalent linking group L D is the (L-1) group

[0076] [ka]

[0077] where e is an integer from 1 to 6, preferably 1 to 4, and the dashed lines denote bonds attaching groups to adjacent groups, and preferably each bond additionally indicated by an asterisk is R S or L T Such an (L-1) group may conveniently be derived from an amino acid selected from diaminopropionic acid (Dap), diaminobutyric acid (Dab), ornithine (Orn) and lysine (Lys) by using the -NH2 group contained in these amino acids to provide a coupling group -NH-, where a bond to one hydrogen atom in the -NH2 group is replaced by a bond to another adjacent atom or group. When an (L-1) group is present and derived from an amino acid mentioned above, the amino acid is preferably in the D configuration.

[0078] Divalent Linking Group L Dmay also comprise or consist of one or more hydrophilic units selected from carbohydrate units, polyhydric alcohol units, polycarboxylic acid units, and amino acid units derived from hydrophilic amino acids that contain further hydrophilic functional groups in addition to their -NH2 and -COOH functional groups. As will be understood by those skilled in the art, in this context too, the units are named according to the chemical structure from which they are derived. For example, these one or more hydrophilic units may be combined with a group of formula (L-1) to form a linking group L D may be provided.

[0079] Consistent with the above, the divalent linking group L D A preferred structure is represented by the formula (L-2):

[0080] [ka]

[0081] (In the formula, e is an integer of 1 to 6, preferably 1 to 4; f is an integer of 0 to 5, preferably 0 or 1; A H1 is, when f is greater than 1, independently for each occurrence, an amino acid unit derived from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH and -COOH functional groups; The dashed lines denote bonds attaching groups to adjacent groups, and each additional bond indicated by an asterisk represents a bond R S or R T (attached to the

[0082] A H1is an amino acid unit. 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., a compound that contains an amino group and a carboxylic acid group in the same molecule. A particular amino acid unit is typically identified by the name of the amino acid from which it can be derived, such as, for example, an ornithine unit, a lysine unit, etc. Unless otherwise indicated in a particular context, the amino acid from which the amino acid unit can be derived is preferably an α-amino acid. When an amino acid unit can be derived from a chiral amino acid, preference is given to the D configuration.

[0083] As will be further appreciated, the amino acid unit may be derived from an amino acid that uses one or more of its 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 in the amino group 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, such that 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.

[0084] Specifically, in formula (L-2), A H1 is, independently for each occurrence, an amino acid unit derived from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH2 and -COOH functional groups, when f is greater than 1. Such units may be referred to herein for brevity as "hydrophilic amino acid units".

[0085] For example, the amino acid unit A H1When f is greater than 1, the additional hydrophilic functional groups may be independently selected for each occurrence from -NH, -COOH, -NH-C(=NH)-NH, -C(=O)NH, -NH-C(=O)-NH, -OH, and -P(=O)(OH).

[0086] Preferably, f amino acid units A H1 Each of, when f is greater than 1, independently for each occurrence, has a side chain of -(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 It contains a side chain having a terminal hydrophilic functional group selected from -P(=O)(OH)2 (wherein v is 1-4).

[0087] Therefore, the amino acid unit A H1is preferably selected independently for 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, a thiocitrulline unit, a methylisothiocitrulline unit, a canavanine unit, a thiocanavanine unit, an α-amino-γ-(thioureaoxy)-n-butyric acid unit, an α-amino-γ-(thioureathio)-n-butyric acid unit, and a phosphonomethylalanine (Pma) unit, when f is greater than 1. They are preferably units that can be derived from amino acids of the D configuration. Particularly 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. Thus, for example, the preferred group [A H1 ] f (wherein f is 1) may be provided by an Asp unit or by a Glu unit.

[0088] Preferably, -[A H1 ] f The - group is -[A H1 ] f the C-terminus forming an amide bond with the NH group to which the - group is attached, and L T or R S and the N-terminus which forms an amide bond with each other.

[0089] Consistent with the above, -[A H1 ] f The unit preferably has the formula

[0090] [ka]

[0091] (wherein f is as defined above, and f R H1 Each of the groups, when f is greater than 1, independently for each occurrence: -(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) (selected from ).

[0092] The amino acid unit -C(O)-CH(R H1 )-NH-, when f is greater than 1, is more preferably selected independently for 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, and the phosphonomethylalanine (Pma) unit. They are preferably units which can be derived from amino acids in the D configuration. Thus, for example, the preferred group -[C(O)-CH(R H1 )-NH] f - (wherein f is 1) may be provided by an Asp unit or by a Glu unit.

[0093] -[C(O)-CH(R H1 )-NH] f The C-terminus of the - group is generally -[A H1 ] f -group forms an amide bond with the NH group to which it is attached, and the N-terminus is preferably L Tor R S and form an amide bond, respectively.

[0094] L shown in the above formulas (R-3b), (R-3d), and (IE) T The group is a trivalent linking group. Preferably, L T is a trivalent amino acid unit, i.e. a unit derived from an amino acid which contains an additional functional group in addition to the amino and carboxylic acid groups required for the amino acid. It is preferred that the additional functional group is also an amino or carboxylic acid group, and that in the compounds of the invention there are attached to the unit three amide bonds formed using the amino group, the carboxylic acid group and the additional functional group provided by the amino acid from which the amino acid unit is derived.

[0095] More preferably, L T is the following (i) and (ii) (i) a trivalent amino acid unit which may be derived from an amino acid which contains a carboxylic acid group and an amino group together with a further functional group selected from a carboxylic acid group and an amino group; (ii), -N(R)2 + - group, where R is independently a C1-C6 alkyl, preferably methyl, and may be derived from a trifunctional amino acid that contains a tertiary amino group as a third functional group in addition to its -NH2 and -COOH groups. Of these, (i) is preferred.

[0096] For example, a trivalent amino acid unit that may be derived from an amino acid containing a carboxylic acid group and an amino group together with a further functional group selected from a carboxylic acid group and an amino group, consistent with (i) above, may be an amino acid unit selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit, and a lysine (Lys) unit, most preferably a Dap unit. From the point of view of stereochemistry, the amino acids from which these units are derived are preferably in the D configuration.

[0097] For example, -N(R)2, which corresponds to (ii) above + Trivalent amino acid units containing a - group can be derived from N-dialkylated 2,3-diaminopropionic acid (Dap), N-dialkylated 2,4-diaminobutanoic acid (Dab), N-dialkylated ornithine (Orn), and N-dialkylated lysine (Lys).

[0098] Consistent with the above, the trivalent linking unit L T A preferred structure is represented by the following formula (L-3):

[0099] [ka]

[0100] wherein either h is 0 and k is an integer from 1 to 4, more preferably 1, or k is 0 and h is an integer from 1 to 4, more preferably 1; the dashed lines indicate bonds that are attached to adjacent atoms or units, and the bond indicated by the dashed line in the carbonyl group, -C(O)-, is L D This can be exemplified by the following:

[0101] Hydrophilic modification group -R H comprises one or more hydrophilic units selected from carbohydrate units, polyhydric alcohol units, polycarboxylic acid units, and amino acid units derived from hydrophilic amino acids which contain further hydrophilic functional groups in addition to their -NH2 and -COOH functional groups.

[0102] R shown in the above formulas (R-3b), (R-3d), and (IE) H is a hydrophilic modifying group, ie a group that enhances the hydrophilic properties of the compounds according to the invention. Preferably, the hydrophilic modifying group -R H Formula (H-1)

[0103] [ka]

[0104] (In the formula, g is an integer from 0 to 5, preferably from 1 to 3, and even more preferably 2 or 3; A H2 is, when g is greater than 1, an amino acid unit derived, independently for each occurrence, from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH and -COOH functional groups; R HT is the amino acid unit A H2 a terminal hydrogen atom attached to the aryl group, an acetyl group, or a hydrophilic unit selected from a carbohydrate group, a polyhydric alcohol unit, and a polycarboxylic acid unit; The dashed line represents the bond that attaches the group to the remainder of the compound. Thus, as will be understood by one of ordinary skill in the art, the bond represented by the dashed line represents the bond that attaches the group to the remainder of the compound. H2 does not bear a methyl group on the opposite side of R in the above formula. H ~L T represents the covalent bond attaching

[0105] As will be understood from the above, when g is 1 or more, R HT can be any of a terminal hydrogen atom, an acetyl group, or a hydrophilic unit selected from a carbohydrate group, a polyhydric alcohol unit (e.g., provided by an acyl group derived from quinic acid), and a polycarboxylic acid unit. When g is 0, R HT is preferably a hydrophilic unit selected from a carbohydrate group, a polyhydric alcohol unit, and a polycarboxylic acid unit.

[0106] A H2 is an amino acid unit, i.e. a group that can be derived from an amino acid. Unless otherwise indicated in a particular context, the amino acids from which the amino acid unit can be derived are preferably α-amino acids. When the amino acid unit can be derived from a chiral amino acid, preference is given to the D configuration.

[0107] As will be further appreciated, the amino acid unit may be derived from an amino acid that uses one or more of its 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 in the amino group 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, such that 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.

[0108] Specifically, in formula (H-1), A H2 is, when g is greater than 1, an amino acid unit derived, independently for each occurrence, from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH2 and -COOH functional groups.

[0109] For example, the amino acid unit A H2 When g is greater than 1, the additional hydrophilic functional groups may be independently selected for each occurrence from -NH, -COOH, -NH-C(=NH)-NH, -C(=O)NH, -NH-C(=O)-NH, -OH, and -P(=O)(OH).

[0110] Preferably, g amino acid units A H2 Each of, when f is greater than 1, independently for each occurrence, has a side chain of -(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 It contains a side chain having a terminal hydrophilic functional group selected from -P(=O)(OH)2 (wherein v is 1-4).

[0111] Therefore, the amino acid unit A H2 is preferably selected independently for 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, a thiocitrulline unit, a methylisothiocitrulline unit, a canavanine unit, a thiocanavanine unit, an α-amino-γ-(thioureaoxy)-n-butyric acid unit, an α-amino-γ-(thioureathio)-n-butyric acid unit, and a phosphonomethylalanine (Pma) unit, when g is greater than 1. They are preferably units that can be derived from amino acids of the D configuration. Particularly 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. Thus, for example, the preferred group [A H2 ] g (wherein f is 1) may be provided by an Asp unit or by a Glu unit.

[0112] Preferably, -[A H2 ] g The - group is represented by the formula (H-1) -[A H2 ] g the C-terminus forming an amide bond with the NH group to which the - group is attached, and L Tor R S and the N-terminus which forms an amide bond with each other.

[0113] Consistent with the above, -R H The group preferably has the formula

[0114] [ka]

[0115] (wherein g is as defined above. g R H2 Each of the groups, when g is greater than 1, independently for each occurrence: -(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) is a group selected from

[0116] The amino acid unit -C(O)-CH(R H2 )-NH-, when g is greater than 1, is preferably selected independently for 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, and the phosphonomethylalanine (Pma) unit. They are preferably units which can be derived from amino acids in the D configuration. Thus, for example, the preferred group -[C(O)-CH(R H2 )-NH] gmay be provided by three hydrophilic amino acid units comprising two Glu units or two Cit units and a third unit selected from a Cit unit, a Glu unit, a Dap unit, and a Lys unit.

[0117] Further consistent with the above, particularly preferred compounds of formula (I) are those of the following formulae (IF) and (IG):

[0118] [ka]

[0119] wherein the variables have the meanings as defined herein, including any preferred embodiments thereof, and R S1 is a SiFA group of formula (S-3) as defined herein, preferably of formula (S-4) as defined herein.

[0120] As mentioned above, the compounds according to the invention include compounds of formula (I), their salts, and chelate compounds formed from compounds of formula (I) or their salts and radioactive or non-radioactive cations. The salts are preferably pharmaceutically acceptable, i.e., salts formed with pharmaceutically acceptable anions or cations. Salts may be formed, for example, by protonating an atom carrying a lone pair of electrons susceptible to protonation, such as a nitrogen atom, with an inorganic or organic acid, or by removing a proton from an acidic group, such as a carboxylic acid group, for example, by neutralization with a base. Other charged groups that may be present in the compounds according to the invention and provide the compounds in the form of a salt include permanently charged groups, such as quaternary ammonium groups (wherein the nitrogen is replaced by four organyl groups) containing an ammonium cation, or charged chelate complexes.

[0121] Exemplary anions that may be present as counterions in the salt form of the compounds of the present invention include, for example, anions selected from chloride, bromide, iodide, sulfate, nitrate, phosphate (such as, for example, a salt of phosphoric acid, hydrogen phosphate, or dihydrogen phosphate), carbonate, hydrogen carbonate, or perchlorate; acetate, trifluoroacetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate, or ascorbate; sulfonate, such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate. As illustrated in the examples provided herein, trifluoroacetic acid can be used during the synthesis of compounds according to the invention, so that salts of trifluoroacetic acid can be conveniently provided or, if desired, can be conveniently converted to salts of acetate, with the salts of trifluoroacetic acid and acetate being referred to as preferred salt forms.

[0122] Exemplary cations that may be present as counterions in the salt forms of the compounds of the invention, when the salt forms include negatively charged forms of the compounds of formula (I) or (II), may include, for example, cations selected from alkali metal cations such as lithium, sodium, or potassium, alkaline earth metal cations such as calcium or magnesium; and ammonium (including ammonium ions substituted by organic groups).

[0123] As noted above, the compounds of the present invention also include chelates formed from a compound of formula (I) or a salt thereof and a radioactive or non-radioactive cation. As exemplified by formula (I) (or by its preferred embodiments, such as (IA)-(IF)), the compounds of the present invention contain substituted nitrogen-containing heterocycles, which will be recognized by the skilled reader as being capable of conveniently providing chelating ligands for cations. Thus, in the compounds of the present invention, chelating compounds can be conveniently obtained by providing chelating ligands using substituted nitrogen-containing heterocycles contained in formula (I) (or by its preferred embodiments, such as (IA)-(IF)). The chelating compounds contain radioactive or non-radioactive cations as chelated cations. As will be understood, the chelating ligands act as ligands for radioactive or non-radioactive cations in the chelating compounds.

[0124] The compounds of the invention comprise an effector moiety R B (or a group containing such a moiety), and a SiFA moiety R S Since the compounds of the present invention contain a substituted nitrogen-containing heterocycle suitable as a chelating ligand as a bridging group with (or a group containing such a moiety, respectively), the compounds of the present invention can be considered to be compounds which contain a chelating group as a bridging group.

[0125] Exemplary radioactive or non-radioactive cations that may be included as cations chelated by such chelating compounds include: 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, 86Y、 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227 cations of Th, cations of non-radioactive isotopes of these metals, or 18 F-[AlF] 2+ etc. 18 F or 19 Cationic molecules containing F are included.

[0126] Preferably, the radioactive or non-radioactive cation is 177 Cations of Lu, such as cations of Lu or of non-radioactive isotopes of Lu; 90 a cation of Y, such as a cation of Y or of a non-radioactive isotope of Y; or 68 Cations of Ga, such as cations of Ga or of non-radioactive isotopes of Ga. Particularly preferred are 68 A cation of Ga, such as a cation of Ga, or of a non-radioactive isotope of Ga.

[0127] 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 less than -4.0.

[0128] This partition coefficient can be determined by measuring the equilibrium partition of a compound according to the invention in a two-phase system containing equal volumes of n-octanol and PBS (pH=7.4), such as 1.00 ml each, at room temperature (20° C.), and calculating the log 10 As logD 7.4 Alternatively, instead of the (absolute) concentrations of the compound according to the invention in octanol and in PBS, parameters proportional to the concentration of the compound in each phase may also be used for the calculation, such as the radioactivity if the compound contains a radioactive moiety, e.g. a radioactive chelate.

[0129] The compounds of the present invention can provide advantageous binding properties to human serum albumin (HSA).Medium to low HSA binding values, expressed as apparent molecular weight in kDa and determined by radioactive inverse affinity chromatography (RIAC) as described in the Examples section below, can be achieved.Preferably, HSA binding values ​​are less than 22 kDa, more preferably less than 10 kDa.

[0130] As exemplary compounds according to the invention the following may further be mentioned: Ligand compound 01 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0131] Ligand compound 02 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0132] Ligand compound 03 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0133] Ligand compound 04 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0134] Ligand compound 05 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0135] Ligand compound 06 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0136] Ligand compound 07 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0137] Ligand compound 08 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0138] Ligand compound 09 having the formula shown in the Examples section below or a salt thereof, or a chelate compound formed from the ligand compound or a salt thereof and a radioactive or non-radioactive cation.

[0139] Exemplary radioactive or non-radioactive cations chelated in exemplary chelating compounds formed from ligand compounds 01 to 09 or salts thereof include, respectively: 68 a Ga cation, such as a Ga cation or a cation of a non-radioactive isotope of Ga, and 177 Mention may be made of a cation of Lu, such as a cation of Lu or a cation of a non-radioactive isotope of Lu.

[0140] 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 compound according to the present invention. As mentioned above, the compound may be a compound of formula (I) or a preferred embodiment thereof disclosed herein, a salt of the compound of formula (I) or a preferred embodiment thereof, or a chelate compound formed from the compound of formula (I) or a preferred embodiment thereof or from a salt thereof. In a related aspect, the compound according to the present invention is provided for use in therapy or for use as a medicament. Thus, the compound of the present invention can be used in therapy, the method may comprise administering the ligand compound to a subject. The subject may be a human or an animal, preferably a human. Preferably, the compound of the present invention is provided for use in a method of treatment of the human or animal body by therapy, the therapy being radionuclide therapy.

[0141] The above mentioned treatments or therapeutic methods are aimed at the treatment or prevention of a disease or disorder of the human or animal body, such as cancer. The effector moiety R encompassed by formula (I) B is a binding motif capable of binding to a somatostatin receptor, the disease or disorder may be a disease or disorder associated with increased or abnormal expression of a somatostatin receptor. For example, such a disease or disorder may be a tumor that overexpresses at least one of SST1-SST5, such as SST2. For example, such a tumor may be a neuroendocrine tumor.

[0142] for example, 177 Lu cation or 90 Compounds according to the invention that are chelating compounds comprising a chelated radioactive cation, such as a Y cation, can be advantageously used in radionuclide therapy, such as radionuclide therapy of diseases or disorders as discussed above.

[0143] In another aspect, the present invention provides a diagnostic composition comprising or consisting of one or more types, preferably one type, of the compounds according to the present invention. As mentioned above, the compound may be a compound of formula (I), or a preferred embodiment thereof disclosed herein, a salt of the compound of formula (I), or a preferred embodiment thereof, or a chelate compound formed from the compound of formula (I) or a preferred embodiment thereof, or a salt thereof. In a related aspect, the compounds according to the present invention are provided for use in a method of in vivo diagnosis of a disease or disorder. Thus, the compounds according to the present invention can be used in a method of diagnosis, which may include administering a ligand compound to a subject and detecting the compound in the subject or monitoring the distribution of the compound in the subject, thereby detecting or monitoring the disease to be diagnosed. For example, nuclear imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT), respectively, can be used to detect or monitor the compounds according to the present invention. The subject may be a human or an animal, preferably a human. Alternatively, methods of diagnosis may also involve adding a compound to a sample, for example a physiological sample obtained from a subject in vitro or ex vivo, and detecting the compound in the sample.

[0144] The diagnostic methods referred to above aim at identifying diseases or disorders of the human or animal body, such as cancer. Thus, in terms of diagnostic applications, the compounds of the present invention are preferably provided for use in methods of in vivo diagnosis of cancer.

[0145] The effector moiety R encompassed by formula (I) Bis a binding motif capable of binding to a somatostatin receptor, the disease or disorder may be a disease or disorder associated with increased or abnormal expression of a somatostatin receptor. For example, such a disease or disorder may be a tumor that overexpresses at least one of SST1-SST5, such as SST2. For example, such a tumor may be a neuroendocrine tumor.

[0146] For example, the SiFA group 18 Radioactive cations containing F fluoride or to which the compounds of the invention are chelated, e.g. 68 The compounds of the invention, which are chelates containing a Ga cation, can be advantageously used for nuclear diagnostic imaging, such as diagnosis by positron emission tomography (PET) or by single photon emission computed tomography (SPECT).

[0147] It will be appreciated that suitability for therapeutic and diagnostic applications is not mutually exclusive, i.e., a compound 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 radioactive hybrid (rh) ligands. Such rh ligands can alternatively be 18 F] fluoride (e.g. for PET) or radioactive metals (e.g. for PET) 68 Ga cations, or for radiation therapy 177 Lu cation, etc.) can be used. 18 If the rh ligand is labeled with [F] fluoride, the low-temperature (non-radioactive) metal cation may, but does not necessarily have to, be complexed elsewhere in the molecule, whereas if it is labeled with the corresponding radioactive metal cation, the low-temperature [ 19 F] fluorine may be included. 18F-labeled compounds, and the corresponding radioactive metal-labeled analogs, can have the same chemical structure and therefore identical in vitro and in vivo properties, thereby enabling them to be used as identical diagnostic and therapeutic tracers (e.g., 18 F / 177 This allows the generation of structurally identical theranostic tracers with the in vivo properties of fluorouracil (e.g., fluorouracil-based 10-Met-Lu analogues)

[20] .

[0148] Thus, consistent with this approach, the compounds of the present invention contain silicon-based fluoride acceptor groups 18 F, and the chelating group is a chelated non-radioactive cation ( nat Lu or nat Ga), and the chelating group is a compound containing a chelated radioactive cation ( 177 Lu or 68 Ga, etc.) and the silicon-based fluoride acceptor group is 18 Not labeled with F (hence 19 Similarly, the present invention provides a compound of the present 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 a somatostatin receptor, as discussed above, the method comprising first reacting a compound of the present invention with a silicon-fluoride acceptor group bearing 18 F-labeled, and the chelating group is a non-radioactive cation ( nat Lu or nat In the compounds of the invention containing a chelation group containing a chelated radioactive cation, the silicon-fluoride acceptor group is 18 The present invention includes administration of compounds that are not labeled with F.

[0149] Thus, in another aspect, the present invention provides a dedicated composition comprising or consisting of one or more types, preferably one type, of the compounds according to the present invention for use in a method of in vivo imaging of a disease or disorder. As mentioned above, the compound may be a compound of formula (I) or a preferred embodiment thereof disclosed herein, a salt of the compound of formula (I) or a preferred embodiment thereof, or a chelate compound formed from the compound of formula (I) or a preferred embodiment thereof or a salt thereof. The compounds according to the present invention may be used in an imaging method, the method may comprise administering the ligand compound to a subject and detecting the ligand compound in the subject and monitoring the distribution of the ligand compound in vivo at different time points after injection for the purpose of calculating a dosimetry before or during a therapeutic treatment. The subject may be a human or an animal, preferably a human. The imaging method may be used for the calculation of a dosimetry before or during a therapeutic treatment of a disease or disorder of the human or animal body, such as cancer. The effector moiety R encompassed by formula (I) B is a binding motif capable of binding to a somatostatin receptor, the disease or disorder may be a disease or disorder associated with increased or abnormal expression of a somatostatin receptor. For example, such a disease or disorder may be a tumor that overexpresses at least one of SST1-SST5, such as SST2. For example, such a tumor may be a neuroendocrine tumor.

[0150] For example, the SiFA group is 18 F Fluoride and Non-Radioactive nat The compounds of the invention containing Lu or a chelating group are capable of reacting with a chelated radioactive cation, e.g. 177The compounds of the invention, which contain a Lu cation whereas the SiFA is non-radioactive, can advantageously be used for nuclear imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT), respectively, to monitor the distribution of the applied compound and subsequently calculate individual dose measurements using quantitative distribution kinetics.

[0151] 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 buffers (with or without saline), water for injection, emulsions such as oil / water emulsions, various wetting agents, sterile solutions, and the like. Compositions comprising such carriers can be formulated by well-known conventional methods. These compositions can be administered to a subject in a suitable dose. Administration of suitable compositions may be accomplished in different 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 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 field, the dosage for any one patient depends on many factors, including the patient's size, body surface area, age, the particular compound to be administered, dosimetry, sex, time and route of administration, general health, and other drugs administered at the same time. The compounds may be administered, for example, in amounts between 0.1 ng and 10 μg / kg body weight. For example, in diagnostic applications, typical dosages of the compounds of the invention or their salts range from <100 μg / patient, for example 0.1 to 30 μg / patient, however, higher or lower dosages can be envisaged if necessary. Typical dosages of the compounds of the invention or their salts in radiotherapy applications range from 50 to 200 μg / patient, preferably 75 to 150 μg / patient, however, higher or lower dosages can be envisaged if necessary.

[0152] The following sections summarize aspects of the present invention. It will be understood that these sections are closely related to the above portions of the description, and that the information provided in these sections may supplement the above portions of the description, and vice versa.

[0153] 1. (a) Formula (I)

[0154] [ka]

[0155] (In the formula, a is 0 or 1, preferably 1; m is 2 or 3, preferably 2; n is 2 or 3, preferably 2; R 1 , R 2 , and R 3 is an effector moiety R B R 1 , R 2 , and R 3 Another group selected from the group consisting of silicon-based fluoride acceptor (SiFA) moieties R S wherein the moiety comprises a silicon atom and a fluorine atom, the fluorine atom being directly linked to the silicon atom by a covalent bond; 18 By F 19 By isotopic exchange of F 18 may be labeled with F, or 18 Labeled with F, R 1 , R 2 , and R 3 The remaining group selected from the formula (R-1)

[0156] [ka]

[0157] (In the formula, R 4is selected from -H, -OH, and C1-C3 alkyl, preferably -H, and the dashed line indicates the bond attaching the group to the remainder of the compound; R 5 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; (b) its salts, and (c) a chelate compound formed from a compound of formula (I) or a salt thereof and a radioactive or non-radioactive cation. A compound selected from:

[0158] 2.SiFA part R S But, formula (S-1)

[0159] [ka]

[0160] (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, R 3S is a divalent C1-C20 hydrocarbon group containing one or more aromatic and / or aliphatic moieties, optionally containing up to three heteroatoms selected from O and S, preferably R 3S is a divalent C6-C12 hydrocarbon group that contains an aromatic ring and may contain one or more aliphatic moieties, and the dashed line indicates the bond attaching the group to the remainder of the compound. The compound according to item 1, comprising the group:

[0161] 3.SiFA part R S But, formula (S-2)

[0162] [ka]

[0163] (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, Phe is a phenylene group, y is an integer from 0 to 6, preferably 1, and the dashed line represents the bond attaching the group to the remainder of the compound. 3. The compound according to item 1 or 2, comprising the group

[0164] 4.SiFA part R S But, formula (S-3)

[0165] [ka]

[0166] (In the formula, r is 1, 2, or 3, preferably 1; s is an integer from 1 to 6, preferably 1; R is independently C1-C6 alkyl, 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 represents the bond attaching that group to the remainder of the compound. 4. The compound according to any one of claims 1 to 3, wherein

[0167] 5.SiFA part R S But, formula (S-4)

[0168] [ka]

[0169] (In the formula, t Bu represents a tert-butyl group and the dashed line represents the bond attaching the group to the remainder of the compound. 5. The compound according to any one of claims 1 to 4, wherein

[0170] 6. Effector part R B is a peptidic binding motif capable of binding to a receptor. 7.R B is a peptidic binding motif capable of binding to a somatostatin receptor, preferably to somatostatin receptor 2 (SST2).

[0171] 8.R B But Tyr 3 -Octreotate (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-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-NaI 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 -Octreotide (BOC), BzThi 3 ,Thr 8- the compound according to item 7, which is a moiety that can be derived from a receptor agonist or receptor antagonist selected from 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)).

[0172] 9.R B However, formula (B-1)

[0173] [ka]

[0174] where the dashed line represents the bond attaching the group to the remainder of the compound. The compound of item 8, which is a group represented by the formula: 10. The compound of formula (I) is represented by the formula (IB)

[0175] [ka]

[0176] (In the formula, R 1 , R 2 , R 3 , and R 5 is defined in one of the preceding items) 10. The compound according to any one of items 1 to 9, which is a compound of the formula:

[0177] 11. Effector part R B The group containing the formula (R-2a) or (R-2b)

[0178] [ka]

[0179] (In the formula, R B is as defined in any one of the preceding items; R 6 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; R 7 is -COOH, The dashed line indicates the bond attaching the group to the remainder of the compound. The compound according to any one of items 1 to 10, which is preferably a group of formula (R-2a):

[0180] 12.SiFA part R S The group containing the formula (R-3a), (R-3b), (R-3c), or (R-3d)

[0181] [ka]

[0182] (In the formula, R S is as defined in any one of the preceding items; R 8 and R 9 is selected from -H, -OH, and C1-C3 alkyl, preferably -H; R 10 and R 11 is -COOH, L D is a divalent linking group, L T is a trivalent linking group, R H is a hydrophilic modifying group, The dashed line indicates the bond attaching the group to the remainder of the compound. 12. The compound according to any one of items 1 to 11, which is preferably a group of formula (R-3a) or (R-3b).

[0183] 13. The compound of formula (I) is represented by the formula (IC)

[0184] [ka]

[0185] (In the formula, i)R 1A is a group of formula (R-2a) as defined in item 11, R 3A is selected from the groups of formulae (R-3a), (R-3b), (R-3c), and (R-3d) as defined in item 12, or ii) R 1A is selected from the groups of formulae (R-2a) and (R-2b) as defined in item 11, R 3A is selected from the groups of formulae (R-3a) and (R-3b) as defined in item 12. 13. The compound according to any one of items 11 or 12, which is a compound of

[0186] 14. The compound of formula (I) is represented by the formula (ID) or (IE)

[0187] [ka]

[0188] (In the formula, R B and R S is as defined in any one of the preceding items; L D is a divalent linking group, L T is a trivalent linking group, R H is a hydrophilic modifying group) 14. The compound according to any one of items 1 to 13,

[0189] 15. Divalent Linking Group L Dcontains at each of its two termini an -NH- group for attachment to an adjacent group. 16. Divalent Linking Group L D However, (L-1) group

[0190] [ka]

[0191] where e is an integer from 1 to 6, preferably 1 to 4, and the dashed lines denote bonds attaching groups to adjacent groups, and preferably each bond additionally indicated by an asterisk is R S or L T attached to 16. The compound according to any one of items 12 to 15, comprising or consisting of:

[0192] 17. Divalent Linking Group L D comprises one or more hydrophilic units selected from a hydrocarbon unit, a polyhydric alcohol unit, a polycarboxylic acid unit and an amino acid unit derived from a hydrophilic amino acid which contains further hydrophilic functional groups in addition to its -NH2 and -COOH functional groups.

[0193] 18. Divalent Linking Group L D But, formula (L-2)

[0194] [ka]

[0195] (In the formula, e is an integer of 1 to 6, preferably 1 to 4; f is an integer of 0 to 5, preferably 0 or 1; A H1 is, when f is greater than 1, independently for each occurrence, an amino acid unit derived from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH and -COOH functional groups; The dashed lines denote bonds attaching groups to adjacent groups, and each additional bond indicated by an asterisk represents a bond R S or R T attached to 18. The compound according to any one of items 12 to 17, wherein

[0196] 19. The hydrophilic amino acid unit is L D 19. The compound according to item 17 or 18, wherein when more than one of these units is present in, each occurrence 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.

[0197] 20.L T 20. The compound according to any one of items 12 to 19, wherein is a trivalent amino acid unit. 21.L T However, the following (i) and (ii) (i) a trivalent amino acid unit which may be derived from an amino acid which contains a carboxylic acid group and an amino group together with a further functional group selected from a carboxylic acid group and an amino group; (ii), -N(R)2 + - group, where R is independently C1-C6 alkyl, preferably methyl, and may be derived from a trifunctional amino acid that contains a tertiary amino group as a third functional group in addition to its -NH2 and -COOH groups. 21. The compound according to item 20, wherein the trivalent amino acid unit is selected from the group consisting of (i) and (ii).

[0198] 22. The compound according to item 21, wherein the trivalent amino acid unit which can be derived from an amino acid comprising a carboxylic acid group and an amino group together with a further functional group selected from a carboxylic acid group and an amino group is an amino acid unit selected from a 2,3-diaminopropionic acid (Dap) unit, a 2,4-diaminobutanoic acid (Dab) unit, an ornithine (Orn) unit and a lysine (Lys) unit, more preferably a Dap unit.

[0199] 23.-N(R)2 + 22. The compound according to claim 21, wherein the trivalent amino acid unit containing a - group is derived from N-dialkylated 2,3-diaminopropionic acid (Dap), N-dialkylated 2,4-diaminobutanoic acid (Dab), N-dialkylated ornithine (Orn), and N-dialkylated lysine (Lys).

[0200] 24.Hydrophilic modification group-R H comprises one or more hydrophilic units selected from a hydrocarbon unit, a polyhydric alcohol unit, a polycarboxylic acid unit and an amino acid unit derived from a hydrophilic amino acid which contains further hydrophilic functional groups in addition to its -NH2 and -COOH functional groups.

[0201] 25.Hydrophilic modification group-R H However, formula (H-1)

[0202] [ka]

[0203] (In the formula, g is an integer of 0 to 5, preferably 1 to 3; A H2 is, when g is greater than 1, an amino acid unit derived, independently for each occurrence, from a hydrophilic amino acid that contains an additional hydrophilic functional group in addition to its -NH and -COOH functional groups; R H1 is the amino acid unit A H2a terminal hydrogen atom attached to the aryl group, an acetyl group, or a hydrophilic unit selected from a carbohydrate group, a polyhydric alcohol unit, and a polycarboxylic acid unit; The dashed line indicates the bond attaching the group to the remainder of the compound. 25. The compound according to any one of items 12 to 24, wherein

[0204] 26. Hydrophilic Amino Acid Unit A H2 and when g is greater than 1, is independently for each occurrence 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.

[0205] 27. The radioactive or non-radioactive cation of a chelate compound is 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, 152 Tb, 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 selected from the cations of Th and its non-radioactive isotopes; or 18 F-[AlF] 2+ etc. 18 F or 19 A cationic molecule containing F, more preferably 68 Ga, 90 Y, or177 27. The compound according to any one of items 1 to 26, wherein the cation is selected from the cations of Lu and from the cations of Ga, Y or non-radioactive isotopes of Lu.

[0206] 28. The compound according to any one of items 1 to 27, which is a chelating compound containing a chelated radioactive or non-radioactive gallium cation. 29. A chelating compound containing a chelated radioactive cation, the SiFA group being 18 29. The compound according to any one of items 1 to 28, which is not labeled with F.

[0207] 30. Chelated radioactive cations 68 30. The compound according to item 29, which is a cation of Ga. 31. A chelating compound that contains a chelated non-radioactive cation or does not contain a chelated cation and has a SiFA group 18 29. A compound according to any one of items 1 to 28, labeled with F.

[0208] 32. A pharmaceutical composition comprising or consisting of one or more compounds according to any one of items 1 to 31. 33. A compound according to any one of items 1 to 31 for use as a medicament.

[0209] 34. A compound according to any one of items 1 to 31 or a pharmaceutical composition according to item 32 for use in a method of treatment of the human or animal body by therapy, wherein the therapy is radionuclide therapy.

[0210] 35. A compound according to any one of items 1 to 31 or a pharmaceutical composition according to item 32 for use in the treatment of cancer. 36. The compound or pharmaceutical composition for use according to item 35, wherein the cancer is a tumor that overexpresses at least one of SST1 to SST5.

[0211] 37. A diagnostic composition comprising or consisting of one or more compounds according to any one of items 1 to 31. 38. A compound according to any one of items 1 to 31 or a diagnostic composition according to item 36 for use in a method for diagnosing a disease or disorder in vivo.

[0212] 39. The compound or diagnostic composition for use in accordance with item 37, wherein the disease or disorder is cancer. 40. The compound or diagnostic composition for use according to item 38, wherein the cancer is a tumor that overexpresses at least one of SST1 to SST5.

[0213] 41. The compound or salt or diagnostic composition for use according to any one of items 37 to 39, wherein the method for diagnosing comprises nuclear diagnostic imaging, and the nuclear diagnostic imaging is preferably positron emission tomography or single photon emission computed tomography imaging.

[0214] In this specification, a number of documents are cited, including patent applications and manufacturer's instructions.The disclosures of these documents are not considered relevant to the patentability of this invention, but are incorporated herein by reference in their entirety.More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0215] 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. 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. 6. Xu C, Zhang H. Somatostatin receptor based imaging and radionuclide therapy [eng]. Biomed Res Int. 2015; doi:10.1155 / 2015 / 917968. 7. 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. 8. Patel YC. Somatostatin and its receptor family [eng]. Front Neuroendocrinol. 1999; doi:10.1006 / frne.1999.0183. 9. 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. 10. 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. 11. 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. 12. Niedermoser S, Chin J, Wangler C, Kostikov A, Bernard-Gauthier V, Vogler N, et al. In Vivo Evaluation of 18 F-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. 13. Schottelius M, Wurzer A, Wissmiller K, Beck R, Koch M, Gorpas D, et al. Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer [eng]. J Nucl Med. 2019; doi:10.2967 / jnumed.118.212720. 14. Roxin A, Zhang C, Huh S, Lepage M, Zhang Z, Lin K-S, et al. A Metal-Free DOTA-Conjugated 18F-Labeled Radiotracer: 18FDOTA-AMBF3-LLP2A for Imaging VLA-4 Over-Expression in Murine Melanoma with Improved Tumor Uptake and Greatly Enhanced Renal Clearance [eng]. Bioconjug Chem. 2019; doi:10.1021 / acs.bioconjchem.9b00146. 15. Gai Y, Xiang G, Ma X, Hui W, Ouyang Q, Sun L, et al. Universal Molecular Scaffold for Facile Construction of Multivalent and Multimodal Imaging Probes [eng]. Bioconjug Chem. 2016; doi:10.1021 / acs.bioconjchem.6b00034. 16. Wurzer A, Vagner A, Horvath D, Fellegi F, Wester H-J, Kalman FK, et al. Synthesis of Symmetrical Tetrameric Conjugates of the Radiolanthanide Chelator DOTPI for Application in Endoradiotherapy by Means of Click Chemistry [eng]. Frontiers in chemistry. 2018; doi:10.3389 / fchem.2018.00107. 17. Simecek J, Hermann P, Havlickova J, Herdtweck E, Kapp TG, Engelbogen N, et al. A cyclen-based tetraphosphinate chelator for the preparation of radiolabeled tetrameric bioconjugates [eng]. Chemistry. 2013; doi:10.1002 / chem.201300338. 18. Notni J, Simecek J, Hermann P, Wester H-J. TRAP, a powerful and versatile framework for gallium-68 radiopharmaceuticals [eng]. Chemistry - A European Journal. 2011; doi:10.1002 / chem.201103503. 19. Poethko T, Schottelius M, Thumshirn G, Herz M, Haubner R, Henriksen G, et al. Chemoselective pre-conjugate radiohalogenation of unprotected mono- and multimeric peptides via oxime formation. Radiochimica Acta. 2004; doi:10.1524 / ract.92.4.317.35591. 20. 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. 21. Notni J, Pohle K, Wester HJ. Comparative gallium-68 labeling of TRAP-, NOTA-, and DOTA-peptides: practical consequences for the future of gallium-68-PET [eng]. EJNMMI Res. 2012; doi:10.1186 / 2191-219X-2-28. 22. Wangler C, Niedermoser S, Chin J, Orchowski K, Schirrmacher E, Jurkschat K, et al. One-step (18)F-labeling of peptides for positron emission tomography imaging using the SiFA methodology [eng]. Nat Protoc. 2012; doi:10.1038 / nprot.2012.109.

[0216] [Table B-1]

[0217] [Table B-2] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0218] The following examples are intended to further illustrate the invention. EXAMPLES

[0219] I. Materials and Methods 1. Organic synthesis: Synthesis of SiFA-Br

[0220] [ka]

[0221] ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane (B2)

[0222] [ka]

[0223] In a round bottom flask, 4.68 g of 4-bromobenzyl alcohol (B1, 25.0 mmol, 1.00 equiv.) is dissolved in 70 mL of dry 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 under stirring. The mixture is left to react at room temperature for 20 h. The reaction 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 removed under reduced pressure and the crude product is purified by column chromatography (5% EtOAc in petroleum ether). After removal of 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, H Ar ), 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, Cp ), 64.2, (s, CH2), 25.8 (s, C-CH3), 18.2, (s, C-CH3) 5.4 (s, Si-CH3).

[0224] Di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane (B3)

[0225] [ka]

[0226] In an argon atmosphere, 7.24 g of B2 (24.1 mmol, 1.00 equiv.) is dissolved in 67 mL of dry THF and cooled to -78°C (dry ice and acetone). Over a period of 1.5 h, 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. The mixture is left to stir at -78°C for an additional 30 min. 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 dry THF and also cooled to -78°C. Over a period of 2 h, the mixture of B2 and tBuLi in THF is slowly added dropwise to the solution of di-tert-butyldifluorosilane under constant stirring. The reaction is allowed to warm to room temperature and left to stir for an additional 15 h. The reaction is quenched by adding 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 removed 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).

[0227] (4-(di-tert-butylfluorosilyl)phenyl)methanol (B4)

[0228] [ka]

[0229] Compound B3 (9.14 g, 23.9 mmol, 1.00 equiv.) is dissolved in 50 mL of MeOH. The solution is left for reaction at room temperature for 18 h after adding 3.00 mL of concentrated HCl (97.9 mmol, 4.10 equiv.). The mixture is concentrated under reduced pressure, the precipitate is dissolved in 50 mL of 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 removed 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, 3J ( 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 =10.7min.

[0230] (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (SiFA-Br)

[0231] [ka]

[0232] 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 small portions over a period of 30 min. The solution was stirred at room temperature for 2 h. The solvent was removed in vacuum 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 vacuum. 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 =9.2min, K'=3.73. 1H-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).

[0233] 2.General method 2.1 Solvents and Reagents solvent All solvents were used without further purification. They are purchased from Sigma-Aldrich Chemie GmbH (Munich, Germany) or VWR International GmbH (Bruchsal, Germany). HO is purified by a Barnstead MicroPure system from Thermo Fischer Scientific Inc. (Waltham, USA) before use. Quality control or nat Final purification of the product for complexation with Ga is carried out in trace pure water from Merck Millipore (Darmstadt, Germany).

[0234] Reagents for peptide synthesis AA is purchased from Iris Biotech GmbH (Marktredwitz, Germany), Sigma-Aldrich Chemie GmbH (Munich, Germany), or Merck Millipore (Darmstadt, Germany). Coupling reagents and chemicals are purchased from Sigma-Aldrich Chemie GmbH (Steinheim, Germany), Molekula GmbH (Garching, Germany), and Macrocyclics Inc. (Dallas, USA).

[0235] General synthesis reagents Chemicals for general synthesis are purchased from Sigma-Aldrich Chemie GmbH (Steinheim, Germany) and Merck KGaA (Darmstadt, Germany). Unless otherwise stated, reagents are used without further purification.

[0236] Chelating Agents The chelator DOTA(tBu)2 is purchased from CheMatech (Dijon, France).

[0237] biochemical substances

[0238] [Table 1]

[0239] 2.2 Equipment and Software High-performance liquid chromatography High performance liquid chromatography (HPLC) is performed using analytical reversed-phase (RP) HPLC with a linear gradient of an isocratic solvent mixture of MeCN (with 2% HO and 0.1% trifluoroacetic acid (TFA); v / v) in HO (with 0.1% TFA) in 15 min, followed by 95% MeCN (v / v) in HO until completion (standard: 5 min). Detection is performed at λ = 220 nm (peptide bonds) or λ = 254 nm (aromatic systems). RP-HPLC chromatograms are analyzed using LabSolution Software from Shimadzu Corporation (Kyoto). For analytical investigations, two different systems were used: 1) A MultoKrom® 100-5 C column with two LC-20AD gradient pumps, a CBM-20A communications module, a CTO-20A column oven, an SPD-20A ultraviolet / visible (UV / VIS) detector, and a flow rate of 1 ml / min 18 The column (125 × 4.6 mm, 5 μm particle size, CS Chromatographie GmbH) was manufactured by Shimadzu Corporation (Kyoto); 2) Two LC-20AD gradient pumps, a CBM-20A communication module, a Smartline UV detector 2500 from Dr. Ing. Herbert Knauer GmbH (Berlin, Germany), and a MultoKrom® 100-5 C with a flow rate of 1 ml / min. 18The column (125 × 4.6 mm, 5 μm particle size, CS Chromatographie GmbH) was manufactured by Shimadzu Corporation (Kyoto, Japan). Use.

[0240] Purification of the final product is performed using preparative RP-HPLC with a linear gradient of an isocratic solvent mixture of MeCN (with 5% HO and 0.1% TFA; v / v) in HO (with 0.1% TFA; v / v) at 15 or 20 min, followed by 95% MeCN (v / v) in HO until completion (standard: 5 min). Detection is performed at λ = 220 nm (peptide bonds) or λ = 254 nm (aromatic systems). RP-HPLC chromatograms are analyzed using LabSolution Software from Shimadzu Corporation (Kyoto). For preparative purification, three separation systems were used: 1) A Multospher 100 C with two LC-20AP gradient pumps, a DGU-20A degassing unit, a CBM-20A communication module, a CTO-20A column oven, a SPD-20A UV / VIS detector, and a flow rate of 8 ml / min. 18 The column (5 μm, 250 × 20 mm, CS Chromatography GmbH) was manufactured by Shimadzu Corporation (Kyoto); 2) Multospher100 C with two LC-20AT gradient pumps, a DGU-20A degassing unit, a CBM-20A communication module, an SPD-20A UV / VIS detector, and a flow rate of 5ml / min 18 The column (5 μm, 250 × 10 mm, CS Chromatographie GmbH) was manufactured by Shimadzu Corporation (Kyoto); 3) A Multospher100 C with two LC-20AP gradient pumps, a CBM-20A communication module, an SPD-20A UV / VIS detector, a SIL-10AP autosampler, an FRC-10A fraction collector, and a flow rate of 8 ml / min. 18 Column (5 μm, 250 × 20 mm, CS Chromatographie GmbH), Shimadzu Corporation (Kyoto) is used.

[0241] The investigation of radioactive substances is carried out using two different analytical radioactive RP-HPLC systems with a linear gradient of an isocratic solvent mixture of MeCN (with 2% HO and 0.1% TFA; v / v) in HO (with 0.1% TFA; v / v) in 15 min, followed by 95% MeCN (v / v) in HO until completion (standard: 5 min). Detection is carried out at λ=220 nm (peptide bonds) or λ=254 nm (aromatic systems) or using a radioactive detector. The two systems are 1) Shimadzu Corporation (Kyoto), consisting of two LC-20AD gradient pumps, a DGU-20A degassing unit, a SIL-20A autosampler, a CTO-10AS column oven, an FRC-10A fraction collector, an SPD-20A UV / VIS detector, a HERM LB500 (NaI scintillation crystal) radiation detector from Berthold Technologies GmbH (Bad Wilbad, Germany), a CBM-20A communication module, and a Multospher® 100 RP18 column (5 μm, 125 × 4.6 mm, CS Chromatographie GmbH); 2) Two LC-20AD gradient pumps, an SPD-20A UV / VIS detector, a HERM LB500 (NaI scintillation crystal) radiation detector from Berthold Technologies GmbH (Bad Wilbad, Germany), a CBM-20A communication module, and a MultoKrom® 100-5 C 18 The column (125 × 4.6 mm, 5 μm particle size, CS Chromatographie GmbH) was manufactured by Shimadzu Corporation (Kyoto, Japan). It is composed of:

[0242] The capacity factor (K') is determined by the experimental retention time (t R ), and an experimentally determined dead time (t0),

[0243]

number

[0244] It is calculated as follows: Determination of HSA binding For the determination of the HSA binding in percentage, a Shimadzu analytical chromatography system 1 is used in combination with a chiral HSA column (5 μm, 50 × 3 mm) with a flow rate of 0.5 ml / min from Chiral Technologies Europa SAS (Illkirchen-Graffenstaden, France). The solvent is exchanged with 50 mM aqueous NH4OAc (pH = 6.9), and iPrOH. Gradient: 0-3 min: 0-100% NH4OAc in iPrOH; then isocratic, 80% NH4OAc in iPrOH.

[0245] Electrospray ionization-mass spectrometry Mass spectrometry (MS) is performed using a Varian 500-MS IT mass spectrometer with electrospray ionization (ESI) and an ion trap detector from Agilent Technologies (Santa Clara, USA).

[0246] Radioactive RP thin layer chromatography Silica gel 60RP-18F from Merck Millipore (Darmstadt, Germany). 254 Radioactive RP thin layer chromatography (TLC) is performed on TLC strips (1×10 cm) and analyzed using a Scan-RAM Radio TLC detector from LabLogic Systems Ltd (Sheffield, UK) and Laura software.

[0247] Gamma Counter To quantify the radioactive samples, a model 2480 Wizard from PerkinElmer Inc. (Waltham, USA) was used. 2 Use a gamma counter.

[0248] Dose Calibrator To estimate the activity of the radioactive samples, a CRC®-55tW dose calibrator / well counter from Mirion Technologies (Florham Park, USA) is used.

[0249] Incubator The culture and incubation of Chinese Hamster Ovary (CHO) and AR42J cells is carried out at 37° C. in an atmosphere containing 5% CO 2 in a HERAcell 150i-incubator from Thermo Fischer Scientific Inc. (Waltham, USA).

[0250] freeze dryer Freeze drying of intermediate and final products is carried out in an Alpha 1-2 freeze dryer from Christ (Osterode am Harz, Germany) coupled to an Edwards nXDS10i vacuum pump from Edwards Limited (Burgess Hill, UK).

[0251] 1.3 Radionuclides 18 F Radioactive [ 18 F]F was purchased from the Rechts der Isar clinic (Munich, Germany) and delivered in a 2.5 ml aqueous solution (approximately 4-10 GBq).

[0252] 125 I [ 125 I]NaI solution, 125 Radioactive iodination was performed with I.

[0253] 3 General Synthetic Procedure (GSP) Resin filling of GSP1 2-CTC resin 2-Chlorotrityl chloride resin (2-CTC; maximum occupancy: 1.6 mmol / g) (1 equivalent (eq.), 1 g) is added to a solution of N,N-diisopropylethylamine (DIPEA, 2.25 eq.) and Fmoc-protected AA in N,N-dimethylformamide (DMF, total volume: ca. 15 ml) and stirred for 3 h at room temperature (RT). MeOH (4 ml) is added to the solution and stirred for 15 min at RT. The resin is washed with solutions with increasing percentages of MeOH in DMF (25%, 50%, 75%, 100%) and dichloromethane (DCM, 5×15 ml). The resin is dried overnight in a desiccator. The resin occupancy is calculated using the following equation:

[0254]

number

[0255] is determined in accordance with

[0256]

number

[0257] is used. GSP2 Fmoc deprotection N-terminal deprotection of the Fmoc-protected amine is carried out by adding 10 ml of piperidine (20% in DMF; v / v). The solution is added twice (1×15 min, 1×5 min) followed by washing of the resin (6×5 ml of DMF, 4×5 ml of DCM). The resin is then used in the following reaction or dried overnight in a desiccator.

[0258] To prevent elimination reactions in SiFAlin-containing molecules, final deprotection of Fmoc-protected amines is carried out in less than 5 min using the method described above using piperidine (20% v / v in DMF).

[0259] GSP3 Dde deprotection For deprotection of the Dde group, a solution of hydroxylamine hydrochloride (1.25 g) and imidazole (0.92 g) in N-methyl-2-pyrrolidine (NMP; 5 ml) and DCM (1 ml) is prepared. The resin is swollen in DMF and shaken in the mixture for 3 h. The resin is washed with NMP (4 x 5 ml), DMF (4 x 5 ml), DCM (4 x 5 ml) and dried overnight in a desiccator.

[0260] GSP4 Standard solid phase peptide coupling The loaded resin is swelled in DMF for 30 min. A solution of Fmoc-protected AA (1.5 eq.), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU; 1.5 eq.), 1-hydroxy-7-azabenzotriazole (HOAt, 1.5 eq.), and DIPEA (4.5 eq.) in DMF is preactivated (10 min) and added to the resin. The solution is shaken for 2 h and the resin is washed with DMF (6 x 5 ml) and DCM (4 x 5 ml). The syringe containing the resin is dried overnight in a desiccator.

[0261] GSP5 Fmoc-L-Cys(Acm)-OH AA coupling The loaded resin is swelled in DMF for 30 min. A solution of Fmoc-L-Cys(Acm)-OH (2.0 eq.), N,N'-diisopropylcarbodiimide (DIC, 4.0 eq.), ethyl cyanohydroxyiminoacetate (Oxyma) (2.0 eq.), and DIPEA (0.8 eq.) in DMF is preactivated (2 min) and added to the resin. The solution is shaken for 2 h and the resin is washed with DMF (6 x 5 ml) and DCM (4 x 5 ml). The syringe containing the resin is dried overnight in a desiccator.

[0262] GSP6 Dap AA coupling The loaded resin is swelled in DMF for 30 min. A solution of Fmoc-protected Dap AA (1.5 eq.), TBTU (1.5 eq.), HOAt (1.5 eq.), and sym-collidine (5.0 eq.) in DMF is preactivated (2 min) and added to the resin. The solution is shaken for 2 h and the resin is washed with DMF (6×5 ml) and DCM (4×5 ml). The syringe containing the resin is dried overnight in a desiccator.

[0263] Coupling of GSP7 DOTA(tBu)2 For the coupling of trans-(di-tert-butyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(tBu)2), a solution of DOTA(tBu)2 (3.0 equiv.), HOAt (3.0 equiv.), and TBTU (3.0 equiv.) in DMF with sym-collidine (11.0 equiv.) is prepared and preactivated for 10 min. The solution is added to the Fmoc-deprotected, swollen resin and stirred overnight. The resin is washed with DMF (6 x 5 ml) and DCM (4 x 5 ml). The syringe containing the resin is dried in a desiccator.

[0264] GSP8 SiFA-Br coupling For coupling with (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (SiFA-Br), the resin was swollen in DCM. To a solution in DCM (2 ml), a solution of DIPEA (6 eq.) and SiFA-Br (3 eq.) was added and stirred overnight. The resin was washed with DCM (5×5 ml) and dried in a desiccator.

[0265] GSP9 Cyclization with thallium(III) trifluoroacetate The resin is swelled in DMF for 30 min. A solution of thallium(III) trifluoroacetate (TTFA) (2 eq.) and glycerol (4 eq.) (8 ml + 2 ml) in DMF is prepared and added to the swollen resin. The suspension is stirred for 1 h. The solution is then replaced with fresh solution and stirred for 1 h. The resin is washed with DMF (10 x 8 ml) and DCM (5 x 8 ml) and dried in a desiccator overnight.

[0266] GSP10 Resin cleavage with retention of acid-labile protecting groups Add 10 ml of a solution of hexafluoroisopropanol (HFIP in DCM; 20%; v / v) to the dried resin and shake for 45 min. Repeat the procedure and wash the resin with DCM (3 x 5 ml). Collect the combined solution in a round-bottom flask and evaporate the volatile components under reduced pressure.

[0267] GSP11 Resin cleavage under cleavage of acid-labile protecting groups Add a solution of TFA (87.5%), triisopropylsilane (TIPS; 2.5%), and HO (10%) to the resin. After incubation (2 × 45 min), wash the resin with TFA (5 ml) and collect all fractions in a round-bottom flask. Evaporate the volatile components in a stream of N2 to obtain the crude product.

[0268] GSP12 nat Complexation with Ga nat For incorporation into the Ga chelator, a solution of the compound in 2 mM dimethylsulfoxide (DMSO) is combined with a solution of Ga(NO3)3 (20 mM in H2O, 1.5 eq.) and dissolved to 1 mM by adding DMSO. The mixture is incubated at 70 °C for 1 h to give the product.

[0269] GSP13 Freeze-drying The dried product is dissolved in a small amount of tBuOH and HO and frozen at -80° C. Volatile components are completely removed under reduced pressure (lyophilization).

[0270] GSP14 nat Complexation with Lu nat For incorporation of Lu into the chelator, a 2 mM solution of the compound in dimethylsulfoxide (DMSO) is combined with a solution of LuCl3 (20 mM in HO, 1.5 eq.) and dissolved to 1 mM by adding DMSO. The mixture is incubated at 90°C for 1 h to give the product.

[0271] 4. Synthesis of Fmoc-TATE(PG)-2-CT

[0272] [ka]

[0273] The synthesis of resin-bound Fmoc-TATE(PG)-2-CT is carried out according to the procedure described by Niedermoser et al.

[23] . 2-CTC resin is loaded with Fmoc-L-Thr(tBu)-OH according to GSP1 (resin occupancy: 0.5–0.7 mmol / g). After Fmoc deprotection (GSP2), Fmoc-L-Cys(Acm)-OH (GSP5) is coupled, followed by Fmoc-L-Thr(tBu)-OH (GSP2, GSP4), Fmoc-L-Lys(Boc)-OH (GSP2, GSP4), Fmoc-D-Trp(Boc)-OH (GSP2, GSP4), Fmoc-L-Tyr(tBu)-OH (GSP2, GSP4), Fmoc-L-Cys(Acm)-OH (GSP2, GSP5), and Fmoc-D-Phe-OH (GSP2, GSP4). Oxidative cyclization of the resulting peptide chain with simultaneous deprotection of the Acm protecting group is carried out according to GSP9 to give the resin-bound Fmoc-TATE(PG)-2-CT. Test cleavage is carried out under acidic conditions with TFA (10 min, RT). Analytical RP-HPLC and ESI-MS are used to confirm the formation of the appropriate product.

[0274] Fmoc-D-Phe-cyclo[L-Cys-L-Tyr(tBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(tBu)-L-Cys]-L-Thr-OH RP-HPLC (analytical): (10–90% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 10.8 min; K' = 4.1. MS (ESI positive): C 64 H 74 N 10 O 14 Calculated m / z for S2: 1270.48, actual: 1315.1 [M+CO2+H] + .

[0275] 5. Synthesis of Ligands 5.1 Synthesis of 01

[0276] [ka]

[0277] 01 is synthesized starting from the 2-CT-TATE(PG)-Fmoc precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (5 x 10 ml). Dimethylglycine hydrochloride (GSP2, GSP4) is coupled followed by SiFA-Br (GSP8). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0278] 01 (N-SiFAlin-N,N-Me2-Gly-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 12.7 min; K' = 5.0.

[0279] RP-HPLC (preparative): (33–50% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 18.5 min; K' = 5.5. MS (ESI positive): C 90 H 133 FN 17 O 21 S2Si + Calculated m / z: 1898.91, actual: 634.0 [M+3H] 3+ , 950.3[M+2H] 2+ , 1899.8[M+H] + .

[0280] 5.2 Synthesis of 02

[0281] [ka]

[0282] Ligand 02 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.) and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Dap-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (5 x 10 ml). Dimethylglycine hydrochloride (GSP2, GSP4) is coupled followed by SiFA-Br (GSP8). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Quality control (QC) confirms the formation of the appropriate product using analytical RP-HPLC and ESI-MS.

[0283] 02 (N-SiFAlin-N,N-Me2-Gly-D-Dap(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 12.6 min; K' = 5.0.

[0284] RP-HPLC (preparative): (35–47% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 17.2 min; K' = 5.2. MS (ESI positive): C 87 H 127 FN 17 O 21 S2Si + Calculated m / z: 1856.86, actual: 619.9 [M+3H] 3+ , 929.3[M+2H] 2+ .

[0285] 5.3 Synthesis of 03

[0286] [ka]

[0287] 03 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Cit-OH (GSP4) is coupled, followed by Fmoc-D-Cit-OH (GSP2, GSP4) and Fmoc-D-Cit-OH (GSP2, GSP4). SiFA-Br is coupled (GSP8) and the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0288] 03 (HD-Cit-D-Cit-D-Cit-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.2 min; K' = 4.3.

[0289] RP-HPLC (preparative): (33–41% MeCN / HO with 0.1% TFA, v / v, 20 min): R= 15.9 min; K' = 5.1. MS (ESI positive): C 111 H 172 FN 28 O 28 S2Si + Calculated m / z: 2456.21, actual: 819.9 [M+3H] 3+ , 1229.1[M+2H] 2+ , 1639.2[2M+3H] 3+ , 1843.9[3M+4H] 4+ .

[0290] 5.4 Synthesis of 04

[0291] [ka]

[0292] 04 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Cit-OH (GSP4) is coupled, followed by Fmoc-D-Cit-OH (GSP2, GSP4) and Fmoc-D-Glu(tBu)-OH (GSP2, GSP4). SiFA-Br is coupled (GSP8) and the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0293] 04 (HD-Glu-D-Cit-D-Cit-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.3 min; K' = 4.4.

[0294] RP-HPLC (preparative): (33–40% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 17.1 min; K' = 5.4. MS (ESI positive): C 110 H 168 FN 26 O29 S2Si + Calculated m / z: 2428.17, actual: 810.3 [M+3H] 3+ , 1215.2[M+2H] 2+ , 1619.9[2M+3H] 3+ .

[0295] 5.5 Synthesis of 05

[0296] [ka]

[0297] 05 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Dap(Boc)-OH (GSP6) is coupled followed by Fmoc-D-Glu(tBu)-OH (GSP2, GSP4) and Fmoc-D-Glu(tBu)-OH (GSP2, GSP4). SiFA-Br is coupled (GSP8) and the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0298] 05 (HD-Glu-D-Glu-D-Dap-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.2 min; K' = 4.3.

[0299] RP-HPLC (preparative): (30–43% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 17.6 min; K' = 5.8. MS (ESI positive): C 106 H 159 FN 23 O 29 S2Si + Calculated m / z: 2329.09, actual: 583.2 [M+4H] 4+ , 777.1[M+3H] 3+ , 1165.2[M+2H] 2+ , 1553.6[2M+3H] 3+ , 1748.9[3M+4H] 4+ .

[0300] 5.6 Synthesis of 06

[0301] [ka]

[0302] 06 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Lys(Boc)-OH (GSP4) is coupled followed by Fmoc-D-Glu(tBu)-OH (GSP2, GSP4) and Fmoc-D-Glu(tBu)-OH (GSP2, GSP4). SiFA-Br is coupled (GSP8) and the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0303] 06 (HD-Glu-D-Glu-D-Lys-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.1 min; K' = 4.3.

[0304] RP-HPLC (preparative): (30–47% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 15.7 min; K' = 4.7. MS (ESI positive): C 109 H 165 FN 23O 29 S2Si + Calculated m / z: 2371.13, actual: 791.2 [M+3H] 3+ , 1186.8[M+2H] 2+ , 1582.5[2M+3H] 3+ .

[0305] 5.7 Synthesis of 07

[0306] [ka]

[0307] 07 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Glu(tBu)-OH (GSP4) is coupled, followed by Fmoc-D-Glu(tBu)-OH (GSP2, GSP4) and Fmoc-D-Glu(tBu)-OH (GSP2, GSP4). SiFA-Br is coupled (GSP8) and the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous deprotection of all acid labile groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0308] 07 (HD-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.5 min; K' = 4.5.

[0309] RP-HPLC (preparative): (30–43% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 17.2 min; K' = 5.3. MS (ESI positive): C 108 H 160 FN 22 O 31 S2Si + Calculated m / z: 2372.08, actual: 593.2 [M+4H] 4+ , 791.0[M+3H] 3+ , 1185.9[M+2H] 2+ , 1581.1[2M+3H] 3+ , 1779.2[3M+4H] 4+ .

[0310] 5.8 Synthesis of 08

[0311] [ka]

[0312] 08 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. After washing with DMF (6 × 5 ml), the compound is coupled to Fmoc-D-Glu(tBu)-OH (GSP2, GSP4) and Fmoc-D-Dap(Dde)-OH (GSP2, GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Glu(tBu)-OH is coupled three times (GSP4) with intermittent Fmoc deprotection (GSP2). After coupling of SiFA-Br (GSP8), the last Fmoc group is removed (GSP2). The product is cleaved from the resin with simultaneous cleavage of the acid-labile protecting group (GSP11), purified by RP-HPLC and lyophilized. Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0313] 08 (HD-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Glu-D-Lys(trans-DOTA-TATE)-OH: RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.2 min; K' = 4.3.

[0314] RP-HPLC (preparative): (30–60% MeCN / HO with 0.1% TFA, v / v, 20 min): R = 18.1 min; K' = 2.1. MS (ESI positive): C 113 H 167 FN 23 O34 S2Si + Calculated m / z: 2501.12, actual: 625.8 [M+4H] 4+ , 834.0[M+3H] 3+ , 1250.5[M+2H] 2+ , 1667.1[2M+3H] 3+ , 1875.3[3M+4H] 4+ .

[0315] 5.9 Synthesis of 09

[0316] [ka]

[0317] 09 is synthesized starting from the Fmoc-TATE(PG)-2-CT precursor described in chapter 4. The precursor is Fmoc-deprotected (GSP2) and coupled to DOTA(tBu)2 (GSP7). A solution of TBTU (1.5 eq.), HOAt (1.5 eq.), and DIPEA (4.5 eq.) in DMF (2.5 ml) is added to the resin and preactivated for 10 min. A solution of Fmoc-D-Lys-OtBu (1.5 eq.) in DMF (2.5 ml) is added to the preactivated resin and stirred for 2 h. The resin is washed with DMF (6 × 5 ml) and Fmoc-D-Dap(Dde)-OH is coupled (GSP6). The Dde group is cleaved (GSP3) and dimethylglycine hydrochloride is coupled (GSP4). After Fmoc deprotection (GSP2), Fmoc-D-Glu(tBu)-OH (GSP4) is coupled, followed by Fmoc-D-Glu(tBu)-OH (GSP2, GSP4) and Fmoc-D-Glu(tBu)-OH (GSP2, GSP4). After Fmoc deprotection (GSP2), quinic acid is coupled twice (2xGSP4) followed by SiFA-Br (GSP8). The compound is cleaved from the resin with cleavage of all acid labile protecting groups (GSP11), purified by preparative RP-HPLC and lyophilized (GSP13). Formation of the appropriate product is confirmed by QC using analytical RP-HPLC and ESI-MS.

[0318] 09 (D-(-)-Quinic acid-D-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-DOTA-TATE)-OH): RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.6 min; K' = 4.5.

[0319] RP-HPLC (preparative): (38–42% MeCN / HO with 0.1% TFA, v / v, 30 min): R = 24.4 min; K' = 3.4. MS (ESI positive): C 115 H 170 FN 22 O 36 S2Si + Calculated m / z: 2546.13, actual: 849.1 [M+3H] 3+ , 1272.9[M+2H] 2+ , 1696.8[2M+3H] 3+ .

[0320] 5. nat Ga or nat Complexation with Lu According to GSP12 or GSP14, nat Ga or nat Complexation with Lu is performed. Analytical RP-HPLC and ESI-MS are applied to confirm the formation of the appropriate product by QC.

[0321] [ nat Ga]01: N-SiFAlin-N,N-Me2-Gly-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 13.2 min; K' = 5.3. MS (ESI positive): C90 H 131 FGaN 17 O 21 S2Si + Calculated m / z: 1965.82, actual: 656.2 [M+3H] 3+ , 983.8[M+2H] 2+ , 1311.8[2M+3H] 3+ .

[0322] [ nat Ga]02: N-SiFAlin-N,N-Me2-Gly-D-Dap (trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 13.1 min; K' = 5.2. MS (ESI positive): C 87 H 125 FGaN 17 O 21 S2Si + Calculated m / z: 1923.77, actual: 642.2 [M+3H] 3+ , 962.7[M+2H] 2+ , 1283.5[2M+3H] 3+ .

[0323] [ nat Ga]03: HD-Cit-D-Cit-D-Cit-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.5 min; K' = 4.5. MS (ESI positive): C 111 H 170 FGaN 28 O 28 S2Si+ Calculated m / z: 2523.12, actual: 841.7 [M+3H] 3+ , 1262.3[M+2H] 2+ , 1682.8[2M+3H] 3+ .

[0324] [ nat Ga]04: HD-Glu-D-Cit-D-Cit-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.5 min; K' = 4.5. MS (ESI positive): C 110 H 166 FGaN 26 O 29 S2Si + Calculated m / z: 2495.08, actual: 832.3 [M+3H] 3+ , 1248.3[M+2H] 2+ , 1664.2[2M+3H] 3+ .

[0325] [ nat Ga]05: HD-Glu-D-Glu-D-Dap-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.3 min; K' = 4.4. MS (ESI positive): C 106 H 157 FGaN 23 O 29 S2Si +Calculated m / z: 2396.00, actual: 600.3 [M+4H] 4+ , 799.7[M+3H] 3+ , 1199.1[M+2H] 2+ , 1598.5[2M+3H] 3+ .

[0326] [ nat Lu]05: HD-Glu-D-Glu-D-Dap-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Lu]DOTA-TATE)-OH RP-HPLC (analytical): (10–90% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 8.10 min; K' = 4.4. MS (ESI positive): C 106 H 157 FLuN 23 O 29 S2Si + Calculated m / z: 2502.01, actual: 834.6 [M+3H] 3+ , 861.0[M+DMSO+3H] 3+ 1251.8[M+2H] 2+ .

[0327] [ nat Ga]06: HD-Glu-D-Glu-D-Lys-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.2 min; K' = 4.3. MS (ESI positive): C 109 H 163 FGaN 23 O 29 S2Si +Calculated m / z: 2438.04, actual: 610.6 [M+4H] 4+ , 813.9[M+3H] 3+ , 1220.3[M+2H] 2+ , 1626.7[2M+3H] 3+ . [ nat Ga]07: HD-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.7 min; K' = 4.6. MS (ESI positive): C 108 H 158 FGaN 22 O 31 S2Si + Calculated m / z: 2438.99, actual: 610.2 [M+4H] 4+ , 813.2[M+3H] 3+ , 1219.2[M+2H] 2+ , 1625.4[2M+3H] 3+ , 1828.7[3M+4H] 4+ .

[0328] [ nat Ga]08: HD-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Glu-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.5 min; K' = 4.5. MS (ESI positive): C 113 H 165 FGaN 23 O 34S2Si + Calculated m / z: 2568.03, actual: 856.4 [M+3H] 3+ , 1283.7[M+2H] 2+ , 1711.6[2M+3H] 3+ .

[0329] [ nat Ga]09: D-(-)-Quinic acid-D-Glu-D-Glu-D-Glu-D-Dap(N-SiFAlin-N,N-Me2-Gly)-D-Lys(trans-[ nat Ga]DOTA-TATE)-OH RP-HPLC (analytical): (10–60% MeCN / HO with 0.1% TFA, v / v, 15 min): R = 11.9 min; K' = 4.7. MS (ESI positive): C 115 H 168 FGaN 22 O 36 S2Si + Calculated m / z: 2613.04, actual: 871.7 [M+3H] 3+ , 1306.9[M+2H] 2+ , 1742.3[2M+3H] 3+ , 1960.5 [3M+4H] 4+ . MS (ESI positive): C 117 H 176 FGaN 26 O 34 S2Si + Calculated m / z: 2669.13, actual: 890.3 [M+3H] 3+ , 1334.9[M+2H] 2+ , 1779.5[2M+3H] 3+ .

[0330] 6. Synthesis of Radioligand 6.1 [ 125 Synthesis of [I]TOC

[0331] [ka]

[0332] Following previously published procedures, we synthesized the reference ligand for in vitro studies [ 125 [I]TOC was prepared.

[21] 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) of [ 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 RT for 15 min and separating the solution from the oxidized material. RP-HPLC [(20% to 50% B in 15 min):t R =9.4min] by 125 The crude product of [I]I-TOC was purified, and the final dissolved product was treated with 10 Vol-% 100 mM Na-ascorbate solution in H2O to prevent radiolysis.

[0333] 6.2 Ion exchange reaction 18 F Fluorination 18 For F labeling, a previously published procedure was applied

[22] . 7. In Vitro Experiments 7.1 Cell culture Prior to the cultivation of AR42J or CHO-SST2 cells, all biochemicals used are heated to 37°C.

[0334] Cultivation of AR42J cells AR42J cells were cultured in RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v) and incubated at 37°C in a humidified 5% CO2 atmosphere. To ensure a constant rate of cell growth, cells were split every 3-4 days.

[0335] The exhausted medium was discarded and the adherent cells were washed with PBS (10 ml). The cells were then removed from the cell culture flask by treatment with 0.1% EDTA in PBS (5 ml, 10 min, 37 °C) and resuspended by adding 5 ml of RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v). The suspension was centrifuged (1300 revolutions per minute (rpm), 3 min, RT), the supernatant was discarded and the cell pellet was resuspended in fresh RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v). 10-50% of the suspension was transferred to a new cell culture flask and the volume was brought to 25 ml with fresh RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v).

[0336] For internalization assessment, resuspend the cell pellet in 20 ml of RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v). Mix 10 μl of the suspension with 10 μl of trypan blue solution. 10 μl of the resulting mixture is counted in a Neubauer hemocytometer (0.1 mm depth, 0.0025 mm). 2 The cells are counted under a light microscope and the cell concentration of the 20 ml suspension is calculated using the following formula:

[0337]

number

[0338] The decision shall be made in accordance with the following: The cells were then seeded (2.0 × 10 5 The cells were incubated in 1 ml of RPMI 1640 medium (with 2 mM L-Glu, 10% FCS; v / v) for 24 ± 2 h at 37 °C in a humidified 5% CO2 atmosphere.

[0339] Cultivation of CHO-SST2 cells SST2-transfected CHO-SST2 cells were cultured in DMEM / F12 (with 10% FCS; v / v) and incubated at 37 °C in a humidified 5% CO2 atmosphere. To ensure a constant rate of cell growth, cells were split every 2-3 days.

[0340] The exhausted medium was discarded and the adherent cells were washed with PBS (10 ml). The cells were then removed from the cell culture flask by treatment with trypsin / EDTA (5 ml, 5 min, 37° C.) and resuspended by adding 5 ml of DMEM / F-12 (with 10% FCS; v / v) medium. The suspension was centrifuged (1300 rpm, 3 min, RT), the supernatant was discarded and the cell pellet was resuspended in 20 ml of fresh DMEM / F-12 (with 10% FCS; v / v) medium. A portion of the suspension was transferred to a new cell culture flask and the volume was made up to 25 ml with fresh DMEM / F-12 (with 10% FCS; v / v) medium.

[0341] I C 50 For the determination of the value, resuspend the cell pellet in 20 ml of DMEM / F-12 (with 10% FCS; v / v) medium. Mix 10 μl of the suspension with 10 μl of trypan blue solution. 10 μl of the resulting mixture is counted in a Neubauer hemocytometer (0.1 mm depth, 0.0025 mm). 2 The cells are counted under a light microscope and the cell concentration of the 20 ml suspension is calculated using the following formula:

[0342]

number

[0343] The decision shall be made in accordance with the following: The cells were then seeded (1.0 × 10 5 cells) were incubated in 1 ml of DMEM / F-12 (with 10% FCS; v / v) medium for 24±2 h at 37° C. in a humidified 5% CO2 atmosphere.

[0344] 7.2 IC50 evaluation SST2-transfected CHO cells were cultured in DMEM / F12 (with 10% FCS) and incubated at 37°C in a humidified 5% CO2 atmosphere. 50 For the determination of , cells were harvested 24 ± 2 h before the experiment and seeded (1.0 × 10 5 cells) were incubated in 1 ml / well of culture medium.

[0345] After removing the culture medium, the cells are washed once with 400 μl of HBSA and 200 μl of fresh HBSA is added. Then, 25 μl of HBSA of either the respective ligand (control) or increasing concentrations (10 -10 ~10 -4 HBSA) followed by 25 μl of [ 125 I]TOC (1.0 nM in HBSA) was added. Each concentration is investigated in triplicate. After 60 min incubation at RT, the experiment was terminated by removing the assay medium followed by washing with 300 μl cold PBS. The medium from both steps was combined into one fraction, representing the amount of unbound radioligand. Cells were then lysed with 300 μl 1 M NaOH (15 min, RT) and combined with 300 μl 1 M NaOH in a subsequent washing step.

[0346] Quantification of bound and unbound radioligand was performed in a gamma counter. Mathematical analysis was performed using GraphPad PRISM software.

[0347] 7.3 Internalization research AR42J cells were cultured in RPMI1640 medium (with 2 mM L-Glu, 10% FCS; v / v) and incubated at 37°C in a humidified 5% CO2 atmosphere. For quantification of internalization, cells were harvested 24 ± 2 h before the experiment and seeded (2.0 × 10 5 cells) were incubated in 1 ml / well of culture medium.

[0348] After removing the culture medium, the cells were washed with 300 μl of assay medium (RPMI1640 medium with 2 mM L-Glu, 5% BSA; v / v) and pre-incubated in 200 μl of assay medium for at least 15 min at 37° C. 18 F-labeled ligand (20 nM) 125 25 μl of a mixture with I-TOC (1 nM) is added to the wells, followed by either 25 μl of TOC in assay medium (100 μM, competition experiments) or 25 μl of assay medium (internalization experiments). One 24-well plate per study time (15, 30, and 60 min) is incubated for each time (37° C., 5% CO2). The plates are cooled on ice, the supernatant is collected, and the wells are washed with 300 μl of ice-cold washing solution (RPMI 1640 medium) and combined with the supernatant. 300 μl of acidic washing solution (0.9% NaCl, 50 mM sodium acetate / acetic acid buffer, pH=4.6) is added and incubated on ice for 15 min. The supernatant is collected and the cells are washed with 300 μl of ice-cold acidic washing solution. 300 μl of aqueous NaOH solution (1 M) is added to the cells and incubated for at least 15 min at RT. The solution is withdrawn and the wells are washed with 300 μl of NaOH solution.

[0349] In the gamma counter, 18 F activity, followed by 125 Quantify I activity. 8. In Vivo Experiments 8.1 Mouse and tumor models All animal experiments were performed in accordance with the general German animal welfare regulations and the prescribed guidelines for the care and use of animals. To establish tumor xenografts, AR42J cells (5 × 10 6Cells (100 μL) were suspended in Dulbecco's modified Eagle's medium / Nutrition Mixture F-12 with Glutamax-I (1:1) and inoculated subcutaneously into the right shoulder of 8-week-old female CD1 nu / nu mice (Charles River, Sulzfeld, Germany). When tumors had grown to a diameter of 5–9 mm (7–15 days after inoculation), the mice were used for experiments.

[0350] 8.2 Biodistribution Approximately 0.5 to 2.0 MBq (0.05 to 0.20 nmol) 18 F-labeled SST2 ligand was injected into the tail vein of AR42J tumor-bearing female CD1 nu / nu mice. Mice were sacrificed 1 h after injection (n=3-5). Selected organs were removed, weighed, and measured in a γ counter.

[0351] 9. Further Research 9.1 HSA binding studies RIAC method A gel filtration column Superdex75 Increase 10 / 300GL (GE Healthcare, Uppsala, Sweden) was pre-calibrated according to the manufacturer's recommendations using a commercially available 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 of known molecular weight. AMSEC experiments were performed using a constant flow rate of 0.8 mL / min at rt. As mobile phase, a solution of HSA in PBS at physiological concentration (700 μM) was used. PSMA ligand was labeled with a molar activity of 10–20 GBq / μmol as described. A probe of 1.0 MBq of radioactive ligand 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 determined calibration curve.

[0352] Figure 1 shows the calibration graph of the Superdex75 Increase gel filtration column using the low molecular weight gel filtration calibration kit. MW: molecular weight. R : experimentally determined retention time. V: elution volume. K av :Partition coefficient.

[0353] For the evaluation, the experimentally determined retention time t R First, multiply the flow rate by the elution volume V e and then convert it to the partition coefficient Kav according to the following equation:

[0354]

number

[0355] where V0 is the empty volume of the column (8.027 mL) and V c is the column volume of the geometry (which is 24 mL). The equation given by the trend line graph of the column calibration is K av =-0.18ln(MW)+2.0967 Using The apparent molecular weight MW is

[0356]

number

[0357] Calculated according to: 9.2 Octanol-water partition coefficient The radioligand of interest (0.7-1.0 MBq) was added to a mixture of n-octanol and PBS (1 ml, 1 / 1; v / v) in a 1.5 ml reaction tube and shaken vigorously for 3 min. The resulting mixture was centrifuged (9000 rpm, 5 min, RT) to separate the 100 μl octanol and PBS phases.

[0358] Quantification is performed by determining the activity of each separate probe in a gamma counter using the following equation:

[0359]

number

[0360] By LogD pH=7.4 Determine the value. Final LogD pH=7.4 Values ​​are determined in octets, and after removing outliers, the mean and standard deviation are determined.

[0361] II. Results

[0362] [Table 2]

[0363] The results of the biodistribution study are shown in FIG. [Brief description of the drawings]

[0364] [Figure 1] Figure 1 shows the calibration graph of a Superdex75 Increase gel filtration column using a low molecular weight gel filtration calibration kit. MW: molecular weight. tR: experimentally determined retention time. V: elution volume. Kav: partition coefficient. [Diagram 2] The results of the biodistribution study are shown in FIG.

Claims

1. (a) Formula (I) 【Chemical 1】 (wherein a is 0 or 1, m is 2 or 3, n is 2 or 3, R １ 、 R ２ 、 and R ３ One group selected from is a group containing the effector moiety R Ｂ and R １ , R ２ , and R ３ Another group selected from is a group containing a silicon-based fluoride acceptor (SiFA) moiety R Ｓ , the moiety contains a silicon atom and a fluorine atom, and the fluorine atom is directly linked to the silicon atom by a covalent bond, １８ by F １９ by isotope exchange of F １８ can be labeled with F, or １８ is labeled with F, R １ 、 R ２ 、 and R ３ The remaining groups selected from are of formula (R-1) 【Chemical 2】 (wherein R ４ is a group selected from -H, -OH, and C1-C3 alkyl, and the dashed line represents a bond attaching the group to the remainder of the compound), R ５ is a compound selected from -H, -OH, and C1-C3 alkyl); (b) its salt, and (c) a chelate compound formed from a compound of formula (I) or its salt and a radioactive or non-radioactive cation A compound selected from

2. SiFA part R Ｓ is of formula (S-2) 【Chemical Formula 3】 (wherein R １Ｓ and R ２Ｓ are, independently of one another, a straight-chain or branched C3-C10 alkyl group, Phe is a phenylene group, y is an integer from 0 to 6, and the dashed line indicates a bond attaching the group to the remainder of the compound) The compound according to claim 1, comprising the group of

3. SiFA part R Ｓ is of formula (S-3) 【Chemical Formula 4】 (wherein r is 1, 2, or 3, s is an integer from 1 to 6, R is independently C1-C6 alkyl, R １Ｓ and R ２Ｓ are each, independently of one another, a straight-chain or branched C3-C10 alkyl group, and the dashed line indicates the bond attaching the group to the remainder of the compound) The compound according to claim 1, which is a group of

4. Effector moiety R Ｂ The compound according to claim 1, wherein Ｂ is a peptidic binding motif capable of binding to a receptor.

5. R Ｂ The compound according to claim 4, wherein R is a peptidic binding motif capable of binding to a somatostatin receptor.

6. R Ｂ is Tyr ３ -octreotate (TATE, H-D-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, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), NaI ３ -octreotide (NOC, H-D-Phe-cyclo(L-Cys-L-1-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-NaI ３ , Thr ８ -octreotide (NOCATE), BzThi ３ -octreotide (BOC), BzThi ３ , Thr ８ -octreotide (BOCATE), JR11 (H-L-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH ２ ), BASS (H-L-Phe(4-NO ２ )-cyclo(D-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH ２ ), and KE121 (cyclo(D-Dab-L-Arg-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe)), and is a moiety that can be derived from a receptor agonist or receptor antagonist selected from the group consisting of: the compound according to claim 5.

7. Effector portion R Ｂ A group containing is of formula (R-2a) or (R-2b) 【Chemical Formula 5】 (wherein R Ｂ is Is a peptidic binding motif capable of binding to a receptor, Is a peptidic binding motif capable of binding to a somatostatin receptor, Tyr3-octreotate (TATE, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-OH), Thr8-octreotide (ATE), Phe1-Tyr3-octreotide (TOC, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), NaI3-octreotide (NOC, H-D-Phe-cyclo(L-Cys-L-1-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-NaI3, Thr8-octreotide (NOCATE), BzThi3-octreotide (BOC), BzThi3, Thr8-octreotide (BOCATE), JR11 (H-L-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2), BASS (H-L-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)) which may be derived from a receptor agonist or receptor antagonist selected from R ６ is selected from -H, -OH, and C1-C3 alkyl, preferably -H, R ７ is -COOH, The dashed line indicates the bond attaching the group to the remainder of the compound) Preferably a group of formula (R-2a), the compound according to claim 1

8. SiFA moiety R Ｓ The group containing is of formula (R-3a), (R-3b), (R-3c), or (R-3d) [Chemical Formula 6] (wherein R Ｓ is Formula (S-2) 【Chemical Formula 6a】 wherein R1S and R2S are each independently a linear or branched C3-C10 alkyl group, Phe is a phenylene group, y is an integer from 0 to 6, and the dashed line represents a bond attaching the group to the remainder of the compound) comprises a group of Formula (S-3) 【Chemical Formula 6b】 wherein r is 1, 2, or 3, s is an integer from 1 to 6, R is independently C1-C6 alkyl, R1S and R2S are each independently a linear or branched C3-C10 alkyl group, and the dashed line represents a bond attaching the group to the remainder of the compound) is a group of R ８ and R ９ is selected from -H, -OH, and C1-C3 alkyl, preferably -H, R １０ and R １１ is -COOH, L Ｄ is a divalent linking group, L Ｔ is a trivalent linking group, R Ｈ is a hydrophilic modifying group, The dashed line represents a bond attaching the group to the remainder of the compound) The compound according to claim 1, which is preferably a group of formula (R-3a) or (R-3b).

9. The compound of formula (I) is a compound of formula (IC) 【Chemical Formula 7】 wherein i) R １Ａ is a group of formula (R-2a) as defined in claim 7, and R ３Ａ is selected from the groups of formula (R-3a), (R-3b), (R-3c), and (R-3d) as defined in claim 8, or ii) R １Ａ is selected from the groups of formulae (R-2a) and (R-2b) as defined in claim 7, and R ３Ａ is selected from the groups of formulae (R-3a) and (R-3b) as defined in claim 8) The compound according to claim 7 or 8.

10. The compound of formula (I) is of formula (ID) or (IE) 【Chemical 8】 wherein LD is a divalent linking group L Ｔ is a trivalent linking group, R Ｈ is a hydrophilic modifying group) The compound according to claim 1.

11. R Ｂ is Tyr ３ -octreotate (TATE, H-D-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, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-all), NaI ３ -octreotide (NOC, H-D-Phe-cyclo(L-Cys-L-1-NaI-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-all), 1-NaI ３ , Thr ８ -octreotide (NOCATE), BzThi ３ -octreotide (BOC), BzThi ３ , Thr ８ -octreotide (BOCATE), JR11 (H-L-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH ２ ), BASS (H-L-Phe(4-NO ２ )-cyclo(D-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH ２ ), and KE121 (cyclo(D-Dab-L-Arg-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe)), and may be a moiety derived from a receptor agonist or receptor antagonist selected from R Ｓ is the formula (S-3) 【Chemical Formula 9】 is a group of wherein r is 1, 2, or 3, s is an integer from 1 to 6, R is independently C1-C6 alkyl, R １Ｓ and R ２Ｓ are both tert-butyl, and the dashed line indicates the bond attaching the group to the remainder of the compound) The compound according to claim 9.

12. divalent linking group L Ｄ is represented by formula (L-2) 【Chemical 10】 wherein e is an integer from 1 to 6, preferably from 1 to 4, f is an integer from 0 to 5, preferably 0 or 1, A Ｈ１ is, when f is greater than 1, for each occurrence independently, an amino acid unit derived from a hydrophilic amino acid containing, in addition to its own -NH ２ and -COOH functional groups, a further hydrophilic functional group, The dashed line indicates a bond attaching the group to an adjacent group, and each of the bonds additionally indicated by an asterisk is attached to R Ｓ or R Ｔ (attached to) The compound according to claim 8.

13. Hydrophilic modifying group - R Ｈ is represented by the formula (H-1) 【Chemical 11】 wherein g is an integer from 0 to 5, preferably from 1 to 3, A Ｈ２ When g is greater than 1, for each occurrence, independently, it is an amino acid unit derived from a hydrophilic amino acid containing an additional hydrophilic functional group in addition to its own -NH ２ and -COOH functional groups, R Ｈ１ is selected from a terminal hydrogen atom, an acetyl group, or a hydrophilic unit selected from a carbohydrate group, a polyhydric alcohol unit, and a polyvalent carboxylic acid unit, attached to the amino acid unit A Ｈ２ and The dashed line represents a bond attaching the group to the remainder of the compound) The compound according to claim 8.

14. The radioactive or non-radioactive cation of the chelate compound is 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, １５２ Tb, 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 selected from the cations of Th and the cations of its non-radioactive isotopes, or １８ F−[AlF] ２＋ such as １８ F or １９ a cationic molecule containing F, preferably ６８ Ga, ９０ Y, or １７７ selected from the cations of Lu and the cations of the non-radioactive isotopes of Ga, Y or Lu, the compound according to claim 1.

15. A pharmaceutical composition or a diagnostic composition comprising or consisting of one or more of the compounds according to claim 1.

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