Silicon-based fluoride acceptor groups for radiopharmaceuticals

Abstract

# imgabs0 # The invention relates to a novel silicon-based fluoride acceptor group (SiFA group) of formula (Ia, Ib, Ic) wherein R1 and R2 are each a linear or branched C3 to C10 alkyl group, and R3 is selected from (i)-OH or-O-, (ii) a sugar or amino sugar moiety, (iii) an amino acid or oligopeptide moiety, (iv) a PEG moiety, as well as compounds suitable for use in radiopharmaceuticals comprising such groups; and a combination of two or more selected from (ii), (iii) and (iv).

Description

[0001] The present invention relates to novel silicon-based fluoride acceptor groups (SiFA groups) that can be used to target radiopharmaceuticals via rapid and efficient isotope exchange reactions. 18 F mark.

[0002] WO 2019 / 020831 A1 describes dual-mode radiotracers and radiotherapeutic agents that combine a fluorinated silicon acceptor group and one or more chelating groups. WO 2022 / 144463 A1 also relates to compounds containing a fluorinated silicon acceptor group and a chelate, the chelate comprising a chelated radioactive or non-radioactive metal cation and thus being suitable for use as a radiotracer or radiotherapeutic agent. R. Koudih et al., Applied Radiation and Isotopes, 80, 2014, pp. 146-150 discloses an automated synthesis of N-succinimidyl-3-(di-tert-butyl[ 18 F] fluorosilyl)benzoate method.

[0003] Compared to previously published SiFA groups, in particular the most commonly used p-(di-tert-butyl-(fluorosilyl)benzoic acid, the SiFA groups according to the present invention are a) more hydrophilic, SiFA-based 18 The method paves the way for the development of F-labeled ligands with improved in vivo properties, such as reduced hepatobiliary excretion, reduced plasma protein binding and thereby accelerated blood clearance and lower non-specific binding, and b) if necessary, adapted to the structural requirements of the target molecule (receptor, enzyme, etc.) according to structure-activity relationship optimization to enable the development of ligands with improved affinity.

[0004] Thus, the present invention provides a compound or a salt of such a compound, said compound comprising a group selected from the group consisting of formula (Ia), (Ib) and (Ic):

[0005]

[0006] Where R 1 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group; R 2 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group; and R 3 Selected from

[0007] (i) -OH or -O - ,

[0008] (ii) a sugar moiety or an amino sugar moiety,

[0009] (iii) an amino acid portion or an oligopeptide portion,

[0010] (iv) a PEG moiety;

[0011] and a combination of two or more selected from (ii), (iii) and (iv);

[0012] And a wavy line indicates the bond connecting the group to the rest of the compound.

[0013] It will be understood that if R 3 Indicates -O - , then the substituent of the aromatic ring shown in the above formula -C(=O)R 3 is a deprotonated carboxylate group -C(=O)O - .

[0014] In this context, according to the invention, the groups (Ia) to (Ic) are also referred to as SiFA groups.

[0015] Advantageously, such SiFA groups according to the invention can be used in compounds comprising a targeting moiety, such as a receptor binding moiety, an enzyme binding substrate or an enzyme inhibitor, or a peptide, protein or antibody fragment or an engineered antigen binding construct, such as a nanobody. Compounds comprising the SiFA group and a targeting moiety can be used as targeted radiopharmaceuticals.

[0016] Various aspects of the invention and preferred embodiments thereof are summarized in the following items.

[0017] 1. A compound or a salt thereof, wherein the compound comprises a group selected from the group consisting of formula (Ia), (Ib) and (Ic):

[0018]

[0019] in:

[0020] R 1 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group;

[0021] R 2 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group;

[0022] R 3 Selected from

[0023] (i) -OH or -O - ,

[0024] (ii) a sugar moiety or an amino sugar moiety,

[0025] (iii) an amino acid portion or an oligopeptide portion,

[0026] (iv) a PEG moiety;

[0027] and a combination of two or more selected from (ii), (iii) and (iv);

[0028] And a wavy line indicates the bond connecting the group to the rest of the compound.

[0029] 2. The compound according to item 1, which comprises a group of formula (Ia) or a salt of said compound.

[0030] 3. The compound according to item 1, which is a compound of formula (IIa), (IIb) or (IIc), or a salt of the compound:

[0031]

[0032]

[0033] Where R 1 , R 2 and R 3 As defined in item 1, and R E is a group comprising a targeting moiety.

[0034] 4. The compound according to item 3, which comprises a group of formula (IIa) or a salt of said compound.

[0035] 5. The compound or salt according to any one of items 1 to 4, wherein R 1 and R 2 Each is tert-butyl.

[0036] 6. The compound or salt according to any one of items 1 to 5, wherein as R 3 The amino acid moiety is derived from a hydrophilic amino acid which, in addition to the amino and carboxyl groups, contains an additional basic or acidic functional group, or wherein as R 3 The oligopeptide portion is derived from an oligopeptide having at least one hydrophilic amino acid which, in addition to the amino and carboxyl groups, also contains an additional basic or acidic functional group.

[0037] 7. The compound or salt according to any one of items 1 to 6, wherein as R 3 The oligopeptide portion is a linear or branched portion comprising 2 to 10, preferably 2 to 5, and more preferably 2 or 3 amino acid portions.

[0038] 8. The compound or salt according to any one of items 6 or 7, wherein the hydrophilic amino acid is selected from lysine and glutamic acid.

[0039] 9. The compound or salt according to any one of items 1 to 8, wherein as R 3 The PEG moiety is a moiety of the formula:

[0040] -NH-(CH2-CH2-O)XR P1 ,

[0041] The nitrogen atom providing the open bond to R 3 The carbon atom to which it is connected forms an amide bond -NH-C(O)-, x is an integer of 2 to 10, preferably 4 to 10, and more preferably 8, and R P1 Selected from -CH2-COOH and -CH2-CH2-COOH.

[0042] 10. The compound or salt according to any one of items 1 to 9, wherein as R 3 The sugar moiety or amino sugar moiety is a residue derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers.

[0043] 11. A compound or salt according to any one of items 1 to 10, wherein R 3 Selected from

[0044] -OH, lysine moiety, glutamic acid moiety,

[0045] residues derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers, and

[0046] The following part

[0047] -NH-(CH2-CH2-O) X -R P1 ,as well as

[0048] The nitrogen atom providing the open bond to R 3 The carbon atom to which it is connected forms an amide bond -NH-C(O)-, x is an integer of 2 to 10, preferably 4 to 10, and more preferably 8, and R P1 Selected from -CH2-COOH and -CH2-CH2-COOH.

[0049] 12. The compound or salt according to any one of items 3 to 11, wherein R E comprising a targeting moiety selected from:

[0050] Receptor binding moieties, enzyme binding substrates or enzyme inhibitors, peptides, proteins or antibody fragments or engineered antigen binding constructs such as nanobodies.

[0051] 13. The compound or salt according to item 12, wherein R EA targeting moiety is included which is selected from a receptor binding moiety and an enzyme binding substrate or an enzyme inhibitor.

[0052] 14. The compound or salt according to any one of items 3 to 13, wherein the targeting moiety is a peptide moiety.

[0053] 15. A compound or salt according to any one of items 3 to 14, wherein the targeting moiety is a receptor binding moiety which enables the compound of formula (IIa), (IIb) or (IIc) or its salt comprising the targeting moiety to act as a ligand for a receptor selected from the group consisting of gastrin releasing peptide receptor (GRPR), CXC chemokine receptor type 4 (CXCR4), somatostatin receptor (SSTR) and cholecystokinin B receptor (CCK-2R).

[0054] 16. A compound or salt according to any one of items 3 to 14, wherein the targeting moiety is a PSMA binding moiety which enables the compound of formula (IIa), (IIb) or (IIc) or its salt to act as a ligand for prostate specific membrane antigen (PSMA).

[0055] 17. The compound or salt according to any one of items 3 to 16, wherein R E The targeting moiety is directly linked to -C(=O)R E On the carbon atom of the carbonyl group.

[0056] 18. The compound or salt according to any one of items 3 to 16, wherein R E The targeting moiety is linked to -C(=O)R E On the carbon atom of the carbonyl group.

[0057] 19. The compound or salt according to any one of items 3 to 16, wherein R E It further comprises a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated radioactive or non-radioactive metal cation.

[0058] 20. The compound or salt according to item 19, wherein the chelating moiety is a moiety derived from DOTA or DOTAGA.

[0059] 21. The compound or salt according to item 19 or 20, wherein the chelated metal cation is a radioactive metal cation.

[0060] 22. The compound or salt according to any one of items 19 to 21, wherein R E The targeting moiety is linked to -C(=O)R E The chelating moiety or chelate moiety is a part of the linking group.

[0061] 23. The compound or salt according to any one of items 1 to 22, wherein the fluorine attached to the Si atom via a direct covalent bond is [ 18 F] fluorine.

[0062] 24. The compound or salt according to any one of items 1 to 22, wherein the fluorine attached to the Si atom via a direct covalent bond is [ 19 F] fluorine.

[0063] 25. A compound or salt according to any one of items 1 to 24 for use as a medicament.

[0064] 26. A radiopharmaceutical composition comprising a compound or salt according to any one of items 1 to 24, optionally in combination with a pharmaceutically acceptable excipient.

[0065] 27. A compound or salt according to any one of items 1 to 24, or a radiopharmaceutical composition according to item 26, for use in a method for in vivo diagnosis of a disease or disorder.

[0066] 28. The compound, salt or radiopharmaceutical composition according to item 27, wherein the diagnostic method involves nuclear diagnostic imaging.

[0067] 29. The compound, salt or radiopharmaceutical composition according to item 27 or 28, wherein the diagnostic method involves positron emission tomography (PET).

[0068] 30. The compound, salt or radiopharmaceutical composition according to item 27 or 28, wherein the diagnostic method involves SPECT.

[0069] 31. A compound or salt according to any one of items 1 to 24, or a radiopharmaceutical composition according to item 26, for use in a method of treating a disease or condition by radioligand therapy.

[0070] 32. A method for preparing a radiolabeled compound, which comprises reacting a compound or salt according to any one of items 1 to 22 with [ 18 F] fluoride reaction steps to convert [ 19 F] Fluorine 18 F] fluorine exchange, in which the fluorine attached to the Si atom by a direct covalent bond is [ 19 F].

[0071] 33. A group of formula (Ia), (Ib) or (Ic) as defined in item 1 or any one of items 5 to 11 as a silicon-based fluoride acceptor group for use in [ 19 F] fluorine 18 F] Uses of fluorine isotope exchange.

[0072] 34. A group of formula (Ia), (Ib) or (Ic) as defined in item 1 or any one of items 5 to 11 as a silicon-based fluoride acceptor group for use in targeting radiopharmaceuticals. 18 F] Purpose of the mark.

[0073] As described above, compounds of the invention encompass compounds comprising a group selected from formula (Ia), (Ib) and (Ic), as well as compounds of formula (IIa), (IIb) or (IIc). In addition, the invention encompasses salts of the compounds, typically pharmaceutically acceptable salts. Thus, unless otherwise indicated, any reference herein to compounds of the invention encompasses compounds comprising a group selected from formula (Ia), (Ib) and (Ic) (and preferred embodiments of these formulae disclosed herein) and salts thereof, as well as compounds of formula (IIa), (IIb) or (IIc) (and preferred embodiments of these formulae disclosed herein) and salts thereof. Likewise, any racemate, enantiomer or diastereomer of any chiral compound of the invention is included, unless the specific stereochemistry of the compound under consideration is indicated in the particular context.

[0074] As a general aspect, the present invention provides a compound or a salt of such a compound, said compound comprising a group selected from the group consisting of formula (Ia), (Ib) and (Ic):

[0075]

[0076]

[0077] Where R 1 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group; R 2 is a linear or branched C3 to C10 alkyl group, preferably a branched C3 to C10 alkyl group, and more preferably a tert-butyl group; R 3 Selected from

[0078] (i) -OH or -O - ,

[0079] (ii) an amino acid portion or an oligopeptide portion,

[0080] (iii) a sugar moiety or an amino sugar moiety,

[0081] (iv) a PEG moiety;

[0082] and a combination of two or more selected from (ii), (iii) and (iv);

[0083] And a wavy line indicates the bond connecting the group to the rest of the compound.

[0084] As another general aspect, the present invention provides a compound of formula (IIa), (IIb) or (IIc) or a salt of said compound:

[0085]

[0086] Where R 1 , R 2 and R 3 As defined for the groups of formula (Ia), (Ib) and (Ic), including any preferred embodiments thereof, and R E is a group comprising a targeting moiety. As will be appreciated by those skilled in the art, R E The targeting moiety may be directly (ie, via a direct covalent bond) attached to the moiety in the above formula E The carbon atom of the carbonyl group forming the bond may be attached to the carbon atom via a linking group. E The compound of formula (IIa), (IIb) or (IIc) or its salt is capable of binding to a target structure, for example a target structure overexpressed in a human disease such as cancer. E The compound or salt is suitable for use as a targeted radiopharmaceutical, especially as a targeted radiopharmaceutical for use in the human body.

[0087] Among the groups of formulae (Ia), (Ib) and (Ic), the group of formula (Ia) is preferred.

[0088] Therefore, according to the above, further preferred compounds as compounds of the present invention are compounds comprising a group of formula (Ia) or salts of such compounds, and wherein R 1 and R 2 Each is tert-butyl.

[0089] Similarly, among the compounds of formula (IIa), (IIb) and (IIc) and their salts, the compounds of formula (IIa) and their salts are preferred.

[0090] Therefore, according to the above, compound (IIa) or a salt of such a compound is further preferred as the compound of the present invention, wherein R 1 and R 2 Each is tert-butyl.

[0091] In the above formulae (Ia), (Ib) and (Ic) and (IIa), (IIb) and (IIc), R 3 Selected from (i) -OH or -O - , (ii) an amino acid portion or an oligopeptide portion, (iii) a sugar portion or an aminosugar portion, (iv) a PEG portion, and a combination of two or more selected from (ii), (iii) and (iv).

[0092] I would understand that if R 3 Is -OH or -O - , then carry R 3 Substituent -C(=O)R 3 is a carboxyl group -C(=O)OH or a deprotonated carboxylate group -C(=O)O - As exemplary counterions of the deprotonated carboxylate groups, reference may be made to the cations listed below, which may be present as counterions in the salt form of the compounds according to the invention, such as ammonium ions or alkali metal cations. Thus, the compounds according to the invention contain carboxylic acids or carboxylates as salts thereof, for example in the form of ammonium salts or alkali metal salts of carboxylic acids.

[0093] In addition, R 3 It may be an amino acid moiety or an oligopeptide moiety, with an amino acid moiety being preferred.

[0094] Those skilled in the art will appreciate that an amino acid moiety is a group that can be derived from an amino acid, i.e., derived from a compound that contains an amino group -NH2 and a carboxyl group -COOH in the same molecule. Unless otherwise indicated in the specific context, in addition to the amino and carboxyl groups, one or more other functional groups may also be present in the amino acid from which the amino acid moiety can be derived. A specific amino acid moiety is usually identified by the name of the amino acid from which it can be derived, e.g., a lysine moiety, a glutamic acid moiety, etc. Unless otherwise indicated in the specific context, the amino acid from which the amino acid moiety can be derived is preferably an α-amino acid. If R 3 Included or provided R 3 The amino acid portion may be derived from a chiral amino acid, preferably in the L-configuration.

[0095] If R 3 represents an amino acid moiety, it will be further understood that the amino acid moiety can be obtained by using one of the functional groups of the amino acid, usually the amino group, with R 3 The carbon atom to which it is attached provides a bond, preferably an amide bond -NH-C(O)-, and is derived from an amino acid. 3 The amino acid portion of R 3 The attached carbon atoms form an amide bond.

[0096] If R 3If the amino acid moiety is an amino acid moiety, the amino acid moiety is preferably derived from a hydrophilic amino acid, which, in addition to its amino group and its carboxyl group, also contains another hydrophilic functional group, such as a basic or acidic functional group. Such a moiety may be referred to herein as a "hydrophilic amino acid moiety". For example, the other hydrophilic functional group of the hydrophilic amino acid may be selected from -NH2, COOH, -NH-C(=NH)-NH2, -C(=O)NH2 and -NH-C(=O)-NH2. Among them, -NH2 and -COOH are preferred.

[0097] Therefore, if R 3 "" represents an amino acid moiety, and it is further preferred that the amino acid moiety is selected from a 2,3-diaminopropionic acid (Dap) moiety, a 2,4-diaminobutyric acid (Dab) moiety, an ornithine (Orn) moiety, a lysine (Lys) moiety, an arginine (Arg) moiety, a glutamic acid (Glu) moiety, an aspartic acid (Asp) moiety, an asparagine (Asn) moiety, a glutamine (Gln) moiety, and a citrulline (Cit) moiety. More preferred is a moiety selected from a lysine moiety and a glutamic acid moiety, and most preferred is a lysine moiety.

[0098] If R 3 Represents an oligopeptide portion, the portion may be a linear or branched oligopeptide portion. Preferably, the oligopeptide portion is a portion that can be derived from an oligopeptide, the oligopeptide comprising or consisting of 2 to 10, more preferably 2 to 5, and more preferably 2 or 3 amino acid portions. For each occurrence, the amino acid providing the amino acid portion of the oligopeptide portion may independently be a natural amino acid or a synthetic amino acid. The amino acid portions are connected via an amide bond -C(O)-NH-. This includes the possibility of forming an amide bond via a functional group in the amino acid side chain. It will further be understood that the oligopeptide portion may be formed by using one of its functional groups constituting the amino acid portion, typically an amino group, to bind to R 3 The carbon atom to which it is attached forms a bond, preferably an amide bond -NH-C(O)-, and is derived from an oligopeptide. 3 The oligopeptide portion is preferably 3 The attached carbon atoms form an amide bond.

[0099] Unless otherwise indicated in the specific context, in addition to the amino and carboxylic acid groups, one or more other functional groups may be present in the amino acids from which the amino acid moieties comprised by the oligopeptide can be derived. Also herein, specific amino acid moieties are usually identified by the name of the amino acid from which they can be derived, such as lysine moieties, glutamic acid moieties, etc. Unless otherwise indicated in the specific context, the amino acids from which the amino acid moieties can be derived are preferably α-amino acids. If the amino acid moieties constituting the oligopeptide can be derived from chiral amino acids, the L-configuration is preferred.

[0100] If R 3 If the oligopeptide portion is represented by the term "hydrophilic amino acid portion", then the one or more amino acid portions constituting the oligopeptide portion are preferably derived from hydrophilic amino acids, which, in addition to their amino and carboxyl functional groups, also contain additional hydrophilic functional groups, such as basic or acidic functional groups. As described above, the hydrophilic amino acid may be a natural or synthetic amino acid. Such a portion may be referred to herein as a "hydrophilic amino acid portion". For example, the additional hydrophilic functional groups of the hydrophilic amino acid may be selected from -NH2, -COOH, -NH-C(=NH)-NH2, -C(=O)NH2 and -NH-C(=O)-NH2. Among them, -NH2 and -COOH are preferred. Additional hydrophilic functional groups may also be used to form bonds, typically amide bonds, with adjacent amino acid portions in the oligopeptide.

[0101] Therefore, if R 3 If the oligopeptide moiety is represented, it is further preferred that the one or more amino acid moieties constituting the oligopeptide moiety are selected from 2,3-diaminopropionic acid (Dap) moiety, 2,4-diaminobutyric acid (Dab) moiety, ornithine (Orn) moiety, lysine (Lys) moiety, arginine (Arg) moiety, glutamic acid (Glu) moiety, aspartic acid (Asp) moiety, asparagine (Asn) moiety, glutamine (Gln) moiety and citrulline (Cit) moiety. More preferred is a moiety selected from a lysine moiety and a glutamic acid moiety, and most preferred is a lysine moiety.

[0102] If R 3 represents a sugar moiety or an amino sugar moiety, preferably a moiety that can be derived from a monosaccharide, wherein the monosaccharide may be a monosaccharide in which the hydroxyl group is replaced by an amino group. 3 represents a sugar moiety or an amino sugar moiety, it will be further understood that the sugar moiety or the amino sugar moiety can be derived from a sugar or an amino sugar, for example, by reacting the hydroxyl group of the sugar or the amino sugar with R 3 The carbon atom connected forms an ester bond -OC(O)-, or by using the amino group of the amino sugar to form an ester bond with R 3 The carbon atom to which it is attached provides an amide bond -NH-C(O)-. Of the sugar moieties and the amino sugar moieties, the amino sugar moieties are preferred. The amino sugar moieties are preferably connected to R3 The attached carbon atoms form an amide bond.

[0103] As R 3 Examples of sugar moieties or amino sugar moieties include residues derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers, residues derived from 1-amino-1-deoxy-glucopyranose, residues derived from 1-amino-1-deoxy-galactopyranose and residues derived from 1-amino-1-deoxy-fructose.

[0104] As R 3 The polyethylene glycol (PEG) moiety preferably represents a polyethylene glycol (PEG) moiety comprising the formula -(CH2-CH2-O) X - group, wherein x is an integer of 2 to 10, preferably 4 to 10, and more preferably 8.

[0105] More preferably, the PEG moiety is a moiety of the formula

[0106] -NH-(CH2-CH2-O) X -R P1

[0107] The nitrogen atom providing the open bond is R 3 The carbon atom to which it is connected forms an amide bond -NH-C(O)-, x is an integer of 2 to 10, preferably 4 to 10, and more preferably 8, and R P1 Selected from -CH2-COOH and -CH2-CH2-COOH.

[0108] According to the above, R 3 As an example of a combination of two or more of (ii), (iii) and (iv), reference may be made to a combination of an amino acid moiety and an amino sugar moiety, wherein the amino acid moiety and R 3 The carbon atoms connected form an amide bond, and accordingly the amino sugar part forms an amide bond -NH-C(O)- with the carboxyl group of the amino acid part using its amino group. As another example, reference can be made to the combination of an oligopeptide part and an amino sugar part, wherein the oligopeptide part is connected to R 3 The connected carbon atoms form an amide bond, and accordingly the amino sugar portion forms an amide bond -NH-C(O)- with the carboxyl group of the oligopeptide portion using its amino group.

[0109] In the above discussion, R 3 Among the options, R is preferred 3 Indicates -OH, -O - The present invention relates to a group or an amino acid moiety or an oligopeptide moiety, more preferably an amino acid moiety or an oligopeptide moiety. Among the amino acid moiety and the oligopeptide moiety, the amino acid moiety is preferred. As discussed above, the amino acid moiety is preferably a hydrophilic amino acid moiety, and the oligopeptide moiety preferably comprises one or more hydrophilic amino acid moieties.

[0110] Therefore, according to the above, the compounds of the present invention preferably contain a compound of formula (Ia), wherein R 1 and R 2 Each is tert-butyl, and wherein R 3 Selected from -OH, -O - , amino acid moieties and oligopeptide moieties, more preferably selected from amino acid moieties and oligopeptide moieties, or salts of such compounds. Among amino acid moieties and oligopeptide moieties, amino acid moieties are preferred. As also discussed above, it is preferred that the amino acid moiety is a hydrophilic amino acid moiety, and it is preferred that the oligopeptide moiety comprises one or more hydrophilic amino acid moieties.

[0111] For example, compounds comprising a group of formula (Ia) are therefore preferred as compounds according to the invention, wherein R 1 and R 2 Each is tert-butyl, and wherein R 3 Selected from -OH, -O - and a hydrophilic amino acid moiety, such as a lysine moiety, or a salt of such a compound.

[0112] The group R in the compound of formula (IIa), (IIb) or (IIc) or its salt E Contains a targeting moiety. Group R containing a targeting moiety E The presence of enables the compound of formula (IIa), (IIb) or (IIc) or its salt further comprising the SiFA group according to the present invention to bind to the target structure. Therefore, the compound of the present invention or its salt can be used as a targeted radiopharmaceutical, in particular as a targeted radiopharmaceutical for in vivo application in the human body, such as in vivo functional molecular imaging. This includes radiolabeled compounds of formula (IIa), (IIb) or (IIc) or their salts, which can be used directly as targeted radiopharmaceuticals, for example, the SiFA group according to the present invention is 18 F-labeled compounds, as well as non-radiolabeled compounds, represent valuable precursors that can be radiolabeled prior to use as targeted radiopharmaceuticals.

[0113] In the compounds of formula (IIa), (IIb) and (IIc) and their salts, R E The targeting moiety included may be, for example, directly linked to the -C(=O)R E In this case, R E Can represent the targeting moiety, i.e. R E It can consist of a targeting moiety. If the targeting moiety is directly linked to a EIf the carbonyl group in the substituent is on the carbon atom of the carbonyl group, then the carbonyl group and the targeting moiety preferably form an amide bond -C(O)-NH-, wherein the -NH- coupling group of the amide bond is provided by the targeting moiety.

[0114] Alternatively, the group R E For example, it may further comprise a linking group, and R E The included targeting moiety can be connected to the C(=O)R of formula (IIa), (IIb) and (IIc) via the linking group. E In the latter case, the linking group is usually directly (i.e., by a direct covalent bond) connected to the R-carrying radical in formula (IIa), (IIb) and (IIc). E The targeting moiety is typically directly attached to the linking group. It will be appreciated by those skilled in the art that the presence of the linking group can be used, for example, to facilitate the coupling of the SiFA group and the targeting moiety, or to prevent the SiFA group from interfering with the R E The targeting function of the included targeting moiety. If such a linker is present and is attached to the R E On the carbon atom of the carbonyl group in the substituent, the carbonyl group and the linking group preferably form an amide bond -C(O)-NH-, wherein the -NH- coupling group of the amide bond is provided by the linking group. In addition, it is also preferred that the targeting part and R E The included linking group forms an amide bond -C(O)-NH-.

[0115] If the linking group has a branched structure, more than one, for example two, targeting moieties may be attached thereto. E Contains a targeting moiety.

[0116] Therefore, the group R E It can be composed of a linking group and a targeting moiety. In this case, the group R in formula (IIa), (IIb) and (IIc) E Can have structure -LR T , where L is R E The connecting group contained in R T YesR E The targeting moiety included in the formula is obtained to obtain the compounds of formula (IIa'), (IIb') and (IIc') or their salts as shown below, wherein the compound of formula (IIa') is further preferred. As will be understood, R in these formulas 1 , R 2 and R 3As defined above for formula (IIa), (IIb) and (IIc), including any preferred embodiments. In addition, for the linking group L in formula (IIa'), (IIb') and (IIc'), it is preferred that the linking group and the carbonyl -C(O)- to which it is connected form an amide bond -C(O)-NH-, wherein the -NH- coupling group in the amide bond is provided by the linking group L. In addition, it is preferred that the linking group L and R T They are connected to each other via an amide bond -C(O)-NH-. Formulas (IIa'), (IIb') and (IIc') represent preferred embodiments of formulas (IIa), (IIb) and (IIc), respectively. Therefore, unless otherwise indicated in the specific context, any reference to formulas (IIa), (IIb) and (IIc) herein includes formulas (IIa'), (IIb') and (IIc').

[0117]

[0118] Unless otherwise stated, the R E The general reference to or to targeting moieties encompassed relates to all the various types of targeting moieties discussed above for compounds of formula (IIa), (IIb) and (IIc) or their salts, and compounds of formula (IIa'), (IIIb') and (IIIc') or their salts as preferred embodiments thereof. Thus, it encompasses, for example, direct attachment to a moiety comprising R E The targeting moiety of the carbonyl group in the substituent, or the targeting moiety connected by a linker, such as the targeting moiety R in formula (IIa'), (IIb') and (IIc') T .

[0119] In the compounds of formula (IIa), (IIb) and (IIc) or their salts, the group R comprising a targeting moiety E (and in the compounds of formula (IIa'), (IIb') and (IIc') or their salts as R E A specific embodiment of the invention and having R T Represents the targeting moiety -LR T The compound or salt is capable of binding to the target structure. E or -LR T The compounds of the present invention or their salts can be used as targeted radiopharmaceuticals, in particular as targeted radiopharmaceuticals for in vivo human applications, such as in vivo functional molecular imaging. A variety of targeting moieties are known in the field of radiopharmaceuticals, which enable compounds or salts containing such targeting moieties to bind to target structures of interest, and in the context of the present invention, they can be used as R E The targeting moiety or targeting moiety R TSuch targeting moieties are also referred to as targeting vectors or biological targeting moieties. It will be appreciated that the target structure of interest is typically a biological target structure, more specifically a biological target structure associated with a disease or condition, such as a target structure that is overexpressed in a human disease such as cancer. Furthermore, it will be appreciated that a compound comprising a targeting moiety will typically preferentially bind to a target structure of interest over other sites in the body of, for example, a patient to whom the compound is administered.

[0120] Compounds comprising a targeting moiety, i.e., in particular compounds of formula (IIa), (IIb) and (IIc) or salts thereof, or compounds of formula (IIa'), (IIb') and (IIc') or salts thereof, typically bind to the corresponding target structure with high affinity, for example, with an IC in the low nanomolar range (preferably 50 nM or less, more preferably 10 nM or less, even more preferably 5 nM or less). 50 As indicated. The half maximal inhibitory concentration (IC 50 ) is defined herein as a quantitative measure of the molar concentration of a compound according to the invention comprising a targeting moiety which is necessary to inhibit by 50% the binding of a radioactive reference ligand to a receptor in vitro.

[0121] As R E The exemplary targeting moieties included may include receptor binding moieties, enzyme binding substrates or enzyme inhibitors, peptides, proteins or antibody fragments or engineered antigen binding constructs, such as nanobodies. Among these exemplary moieties, the targeting moieties selected from receptor binding moieties, enzyme binding substrates and enzyme inhibitors are preferred.

[0122] For example, R E The targeting moiety included can be a peptide targeting moiety, i.e. a part consisting of amino acid units (e.g. 2 to 20 amino acid units, or preferably 2 to 10 amino acid units). Peptides suitable for providing peptide targeting moieties include linear and cyclic peptides, or peptides in combination with linear and cyclic parts.

[0123] Typically, if the targeting moiety is a receptor binding moiety as mentioned above, the presence of the targeting moiety in the compound of the invention or its salt enables the compound or salt to act as a ligand for the relevant receptor. Similarly, if the targeting moiety is a moiety that binds to prostate-specific membrane antigen (PSMA binding moiety) as mentioned above, the presence of the targeting moiety in the compound of the invention or its salt enables the compound or salt to act as a ligand for PSMA.

[0124] If R E The included targeting moiety represents a binding site for a receptor binding moiety or an enzyme binding substrate according to the above, then the compounds of the present invention comprising the targeting moiety are generally capable of binding to a receptor or an enzyme, respectively, with high affinity. In this context, high affinity binding preferably means that the compound comprising the receptor binding moiety or the enzyme binding substrate exhibits an IC in the low nanomolar range. 50, preferably 50 nM or lower, more preferably 10 nM or lower, and even more preferably 5 nM or lower. For clarity, the half maximal inhibitory concentration (IC 50 ) is defined as a quantitative measure of the molar concentration of a compound according to the invention comprising a receptor binding moiety or an enzyme binding substrate, respectively, which is necessary to inhibit the binding of a radioactive reference ligand to a receptor by 50% in vitro.

[0125] For R E The targeting moieties included, exemplary receptors of the target structures of interest that can be mentioned are gastrin releasing peptide receptor (GRPR), CXC chemokine receptor type 4 (CXCR4), somatostatin receptor (SSTR), cholecystokinin B receptor (CCK-2R) and prostate specific membrane antigen (PSMA). Therefore, exemplary receptor binding moieties as targeting moieties include gastrin releasing peptide receptor (GRPR) binding moieties, CXC chemokine receptor type 4 (CXCR4) binding moieties, somatostatin receptor (SSTR) binding moieties or cholecystokinin B receptor (CCK-2R) binding moieties.

[0126] As suitable as R E As examples of SSTR binding moieties included in the targeting moiety, there may be mentioned moieties derivable from a receptor agonist or receptor antagonist selected from the group consisting of: Tyr 3 -Octreotate (or Tyr 3 ,Thr 8 -Octreotide, TATE, HD-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-OH), Thr 8 -Octreotide (ATE), Phe 1 ,Tyr 3 -Octreotide (TOC, HD-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), Nal 3 -Octreotide (NOC, HD-Phe-cyclo(L-Cys-L-1-Nal-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), 1-Nal 3 ,Thr 8 -Octreotide (NOCATE), BzThi 3 - Octreotide (BOC), BzThi 3 ,Thr 8-octreotide (BOCATE), JR11 (HL-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2), BASS (HL-Phe(4-NO2)-cyclo(D-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2) and KE121 (cyclo(D-Dab-L-Arg-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe)), more preferably selected from TATE or JR11, and most preferably selected from TATE. As will be appreciated by those skilled in the art, the receptor binding moiety as a targeting moiety can be conveniently derived from the exemplary receptor agonists or antagonists listed above, by using the functional groups contained in the receptor agonists or antagonists, such as carboxyl or amino groups, to provide a coupling group that connects the targeting moiety to the remainder of the compounds of the invention. Preferably, these receptor agonists or receptor antagonists provide the targeting moiety by using the amino groups contained therein (e.g., in the optionally substituted phenylalanine unit) to form an amide bond -C(O)-NH- with the remainder of the compounds of the invention.

[0127] In particular, a moiety of one of the following formulae may be mentioned as an exemplary SSTR binding moiety suitable as a targeting moiety, wherein the dotted line marks the bond connecting the group to the rest of the compound of the invention:

[0128]

[0129]

[0130] As suitable as R E Exemplary CXCR4 binding moieties encompassed by the targeting moiety include moieties of the formula: B1 is H or I, and the dashed line marks the bond connecting the group to the rest of the compound of the invention:

[0131]

[0132] As suitable as R E As exemplary PSMA-binding moieties encompassed by the targeting moiety, there may be mentioned moieties of the following formula:

[0133]

[0134] in:

[0135] m is an integer from 2 to 6, preferably from 2 to 4, more preferably 2;

[0136] n is an integer from 1 to 6, preferably from 2 to 4, more preferably 2 or 4;

[0137] R 1 P is CH2, NH or O, preferably NH;

[0138] R 3 P is CH2, NH or O, preferably NH;

[0139] R 2 P is C or P(OH), preferably C;

[0140] and wherein the dashed line indicates the bond connecting the group to the rest of the compound of the invention. Typically, the PSMA binding moiety is connected to the rest of the compound of the invention via an amide bond -NH-C(O)-, and thus preferably a group -NH- or a group -C(O)-, more preferably a group -NH-, is further provided at the position indicated by the dashed line in the above formula, said group forming part of such an amide bond. More preferably, the PSMA binding moiety is part of the formula:

[0141]

[0142] in:

[0143] m is an integer from 2 to 6, preferably from 2 to 4, more preferably 2;

[0144] n is an integer from 1 to 6, preferably from 2 to 4, more preferably 2 or 4;

[0145] and wherein the dashed line indicates the bond connecting the group to the rest of the compound of the invention. Typically, the more preferred PSMA binding moiety is connected to the rest of the compound of the invention via an amide bond -NH-C(O)-, and thus preferably a group -NH- or a group -C(O)-, more preferably a group -NH-, is further provided at the position indicated by the dashed line in the above formula, the group forming part of such an amide bond.

[0146] As suitable as R E As exemplary GRPR binding moieties included in the targeting moiety, mention can be made of the targeting moiety included in the modified GRPR antagonist peptide disclosed in WO 2021 / 121735.

[0147] As suitable as R E As a particularly preferred example of the GRPR binding portion of the targeting portion included, the following group included in the GRPR antagonist RM2 can be mentioned, namely -Pip-D-Phe-L-Gln-L-Trp-L-Ala-L-Val-Gly-L-His-L-Sta-L-Leu-NH2,

[0148] Wherein Pip represents a 4-amino-1-carboxymethyl-piperidine residue, and forms an amide bond with D-Phe via the carboxyl group.

[0149] As suitable as R E As exemplary CCK-2R binding portions of the targeting moiety included, mention may be made of the peptidomimetic amino acid polymers disclosed in WO 2018 / 224665.

[0150] As suitable as R E As a particularly preferred example of the CCK-2R binding moiety of the targeting moiety, the peptide group contained in the ligand compound PP-F11 or PP-F11N may be mentioned, namely

[0151] -D-GIu-D-GIu-D-GIu-D-GIu-D-GIu-D-GIu-L-Ala-L-Tyr-Gly-L-Trp-L-Met-L-Asp-L-Phe-NH2 and

[0152] -D-GIu-D-GIu-D-GIu-D-GIu-D-GIu-D-GIu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-Phe-NH2, and

[0153] -D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-(N-Me)Nle-L-Asp-L-1Nal-NH2.

[0154] In addition to the targeting moiety, the group R E A chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation may also be included. If present, the chelate / chelate moiety typically forms a chelate that can be chelated by R E The chelate / chelate moiety may be part of a linear linker structure, or may be part of a branched linker structure, for example by providing a branch thereof.

[0155] The chelating moiety is preferably a moiety derivable from a chelating agent selected from the group consisting of diethylidenetriaminepenta(methylenephosphonic acid) (EDTMP) and its derivatives, diethylidenetriaminepentaacetic acid (DTPA) and its derivatives, di(carboxymethyl)-1,4,8,11-tetraaza-bicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]- ]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]-amino]pentyl]-N-hydroxysuccinamide (DFO) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-glutaric acid (DOTAGA or DOTA-GA) 、1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), N,N'-dipyridyloxyethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HED TA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] hexadecane (TE2A), 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneamine)tetraacetic acid (TMT), 1,4,7,10-tetraazacyclotridecane-N,N',N",N"'-tetraacetic acid (TRITA), and triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl} heptanediol bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide (TH P), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid (TRAP), 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (DO3AM), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra[methylene(2-carboxyethyl)phosphinic acid (TRAP). Phosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr), 6-amino-6-methylperhydro-1,4-diazepine. -N,N,N',N'-tetraacetic acid (AAZTA) and its derivatives, such as (6-pentanoic acid)-6-(amino)methyl-1,4-diazepine triacetate (DATA), pentadecane-1,4,7,10,13-penta-aminopentaacetic acid (PEPA), hexadecane-1,4,7,10,13,16-hexamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (BPAMD), N(4-{[bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-nonane-1,4,7-triaminetriacetic acid (BPAM), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamine]ethane (DEDPA, H2DEDPA), deferoxamine (DF O) and its derivatives, deferiprone, (4-acetylamino-4-yl){2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}-pimelic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (CP256) and its derivatives such as YM103; tetraazacyclododecane-phosphinic acid (TEAP), 6,6'-[{9-hydroxy-1,5-bis-(methoxycarbonyl)-2,4-di(pyridin-2-yl)-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl}bis(methylene)]dipicolinic acid (H2bispa 2 ), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamino]-ethane (H2dedpa), N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid (H4octapa), N,N'-bis(2-hydroxy-5-sulfonylbenzyl)-N,N'-di-(2-methylpyridyl)ethylenediamine (H6Sbbpen) and its derivatives, triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid (TTHA), 2-aminomethylpiperidinyltriacetic acid (2-AMPTA) and its derivatives, for example, with additional peptide structures suitable for conjugation. 2-(N-(2-hydroxybenzyl)aminomethyl)piperidine (2-AMPTA-HB) further functionalized derivatives of 2-AMPTA, 4-nitro-2-hydroxybenzyl-2-{[(6)-trans-2-[benzyl(carboxymethyl)amino]cyclohexyl](carboxymethyl)amino}acetic acid (RESCA) and its derivatives, and 6-carboxy-1,4,8,11-tetraazaundecane (N4) and its derivatives. Among these chelating agents, DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA are preferred. Most preferred are DOTA and DOTAGA.

[0156] As will be appreciated by those skilled in the art, preferred chelate moieties are formed from the preferred chelating moieties discussed above and the chelated metal cation.

[0157] As will be further appreciated by those skilled in the art, the chelating moiety or chelate moiety in the compounds according to the invention can be conveniently derived from the chelating agents listed above, by using at least one, for example one or two functional groups contained in the chelating agent, such as a carboxyl group, a carboxamide group, an amino group or a hydroxyl group, to provide a coupling group, for example selected from -C(O)-, -NH- and -O-, which connects the chelating moiety to the remainder of the compound. Preferably, the carboxyl group is used to provide a coupling group -C(O)- to connect the chelating moiety or chelate moiety via an amide bond -C(O)-NH-.

[0158] The metal cation that can be chelated in the chelate moiety can be a radioactive or non-radioactive metal cation.

[0159] The metal cations that can be chelated in the chelate part are preferably selected from the following cations: 43 Sc, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 55 Co. 57 Co. 58 Co. 52 Fe, 56 You, 57 You, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y. 86 Y. 94m Tc, 99m Tc, 97 Such as 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 2. 165 2. 169 2. 171 2. 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 Th, and non-radioactive isotopes of any of these metals. The chelated cation may be a complex cation, such as a metal ion carrying an additional coordinating ligand in addition to the chelating group, such as a 99m Tc(V)-oxo core( 99m The oxo-ligand in the chelate of Tc(V)-oxo core).

[0160] Particularly preferred chelated cations are radioactive or non-radioactive cations of Ga or Lu, such as 177 Lu or 68 Ga.

[0161] According to the above, if the compound of the present invention comprises a chelating part or a chelate part formed by a chelating part and a chelated radioactive or non-radioactive metal cation, it is preferred that the chelating part is derived from DOTA or DOTAGA, usually by using the carboxyl group contained in DOTA or DOTAGA to provide a coupling group -C(O)- to connect the chelating part to the rest of the compound, and the chelated cation of the chelate part is a cation of Ga or Lu, and it can be radioactive, for example 177 Lu or 68 The cation of Ga may be non-radioactive.

[0162] According to the above, the group R in the compounds of formula (IIa), (IIb), (IIc) and their salts E The mandatory component is a targeting moiety, which is composed of the group R in the compounds of formula (IIa'), (IIb') and (IIc') and their salts. T The group R in the compounds of formula (IIa), (IIb), (IIIc) and their salts E The optional component is a linking group. This linking group is preferably composed of R E Contains, for example, L in preferred compounds of formula (IIa'), (IIb') or (IIc') and their salts, wherein -R E By -LR T Represents. Group R E Another optional component is a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated radioactive or non-radioactive metal cation. E Including, the linker is usually also composed of R E It comprises, for example, the linker L, and the chelating part / chelate part forms a part of the linker.

[0163] As discussed above, the linker can be composed of R in formula (IIa), (IIb) and (IIc). E Including, as in formula (IIa'), (IIb') and (IIc') the linking group L, which may have, for example, a straight or branched backbone structure. The linking group may include one or more moieties that provide additional functionality in the compounds of the invention, such as a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation. Such moieties having additional functionality may, for example, be incorporated into the branched or straight backbone of the linking group.

[0164] As examples of moieties suitable as linkers, amino acid moieties or oligoamide moieties may be mentioned. As mentioned above, such amino acid moieties or oligoamide moieties as linkers may optionally contain one or more other moieties providing additional functions in the compounds of the invention, such as chelating moieties or chelate moieties formed by chelating moieties and chelated metal cations.

[0165] For example, the amino acid moiety acting as a linker may be a bifunctional moiety that provides a coupling group -NH-, such as for coupling to R E The attached carbonyl group forms an amide bond, and the coupling group -C(O)- is used, for example, to bind R E The targeting moiety (e.g. R T ) to form an amide bond, wherein the -NH- coupling group in the amide bond is provided by the targeting moiety. As another example, the amino acid moiety can be a trifunctional moiety that provides a coupling group -NH-, such as for use with R E The carbonyl group to which it is attached forms an amide bond, and the coupling group -C(O)- is used, for example, to bind R E The targeting moiety is included to form an amide bond, and another functional group, such as another carboxyl group or another amino group.

[0166] For R E The oligoamide part of the exemplary linker included is similarly preferred that the linker and R E The attached carbonyl -C(O)- forms an amide bond -C(O)-NH-, wherein the -NH- coupling group in the amide bond is provided by the oligoamide part. In addition, it is preferred that the oligoamide part and R E (such as R T ) forms an amide bond -C(O)-NH-.

[0167] Those skilled in the art will appreciate that the oligoamide portion comprises two or more, for example 2 to 10, preferably 2 to 8, and more preferably 2 to 6 subunits, which are connected to each other via an amide bond-C (O)-NH-. For example, each subunit can be formed by 7 to 30 atoms. If one of the subunits provides two or more (e.g., three) coupling groups selected from-C (O)- and-NH- that are suitable for forming an amide bond-C (O)-NH-, the oligoamide portion can be a side chain portion.

[0168] Those skilled in the art will appreciate that subunits suitable for use in linear or branched oligoamide linkers may be selected, for example, from

[0169] - a unit providing a coupling group -NH- and a coupling group -C(O)-, said unit being derived, for example, from an amino acid,

[0170] - a unit providing two coupling groups -NH-, said unit being derived, for example, from a diamino compound, or from a compound containing two amino groups in combination with one or more other functional groups, for example an amino acid comprising a side chain carrying a further terminal amino group,

[0171] - units providing two coupling groups -C(O)-, which units may be derived, for example, from dicarboxylic acids, or from compounds containing two carboxyl groups in combination with one or more other functional groups, such as amino acids comprising side chains carrying further terminal carboxyl groups, and chelators comprising two, three or four carboxyl groups or carboxamide groups, wherein two of the carboxyl groups or carboxamide groups provide coupling groups -C(O)-;

[0172] - a unit providing two coupling groups -NH- and one coupling group -C(O)-, said unit being derived, for example, from an amino acid comprising a side chain carrying a terminal amino group, and

[0173] - a unit providing two coupling groups -C(O)- and one coupling group -NH-, said unit being derived, for example, from an amino acid comprising a side chain carrying a terminal carboxyl group.

[0174] The oligoamide part having a branched structure serving as a linker L generally comprises one terminal subunit which forms only one amide bond -C(O)-NH- with the adjacent unit. For example, mention may be made of units derived from chelating agents which comprise two, three or four carboxyl or carboxamide groups, one of which provides a coupling group -C(O)-.

[0175] For example, according to the above, preferred compounds of the present invention are therefore compounds of formula (IIa) or formula (IIa') or salts of such compounds, wherein R E , L and R T As defined above, including any preferred embodiments thereof, and wherein R 1 and R 2 Each is tert-butyl, and R 3 Selected from -OH, -O - , amino acid moiety and oligopeptide moiety, more preferably selected from amino acid moiety and oligopeptide moiety. Among amino acid moiety and oligopeptide moiety, amino acid moiety is preferred. As discussed above, preferably amino acid moiety is hydrophilic amino acid moiety, and preferably oligopeptide moiety comprises one or more hydrophilic amino acid moieties.

[0176] According to the present invention, other exemplary compounds of formula (IIa), (IIb) and (IIc) and their salts can be illustrated by the following formula (IIIa) and their salts:

[0177] R S –(R A1 )a –R T1 (IIIa)

[0178] R S –R A2 (R CH1 )–(R A3 ) b –R T1 (IIIb)

[0179] R S –(R A4 ) c –R CH2 –(R A5 ) d –R T1 (IIIc)

[0180] R S –R A6 (R CH3 )–(R A7 ) e –R CH4 –(R A8 ) f –R T1 (IIId)

[0181] In these formulas, R S represents a group of formula (Ia), (Ib) or (Ic) as discussed herein, preferably a group of formula (Ia). T1 refers to a targeting moiety as discussed herein, e.g., a gastrin releasing peptide receptor (GRPR) binding moiety, a CXC chemokine receptor type 4 (CXCR4) binding moiety, a somatostatin receptor (SSTR) binding moiety, a cholecystokinin B receptor (CCK-2R) binding moiety, or a PSMA binding moiety, including examples of these binding moieties disclosed herein.

[0182] For example, according to the above, preferred examples of compounds of formula (IIIa) to (IIId) are those wherein R S is a compound of formula (Ia) or a salt of such a compound, wherein R 1 and R 2 Each is tert-butyl, and wherein R 3 Selected from -OH, -O - , amino acid moieties and oligopeptide moieties, more preferably selected from amino acid moieties and oligopeptide moieties. Among amino acid moieties and oligopeptide moieties, amino acid moieties are preferred. Also as discussed above, preferably the amino acid moieties are hydrophilic amino acid moieties, and preferably the oligopeptide moieties comprise one or more hydrophilic amino acid moieties.

[0183] Furthermore, in formula (IIIa):

[0184] If there is more than one group R A1 , then the group R A1 Each occurrence independently represents the combination of two adjacent groups (e.g. R S , another group R A1 or R T1 ) forms a divalent group of an amide bond -NH-C(O)-. Preferably, R A1 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom involved in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / parts contained in the compound of formula (IIIa), each group R A1 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A1 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0185] The variable a represents an integer from 0 to 4, for example, 0, 1, 2, or 3.

[0186] In formula (IIIb):

[0187] As discussed in this article, R CH1 represents a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation, including the examples of chelating moieties disclosed herein, such as moieties derived from DOTA or DOTAGA. It will be understood from formula (IIIb) that R CH1 is connected to R A2 The unit price part. CH1 and R A2 They are connected to each other via an amide bond -NH-C(O)-.

[0188] The group R A2 represents a trivalent group, which is S and R CH1 and R A3 (if present) or R T1 To form an amide bond -NH-C(O)-. Preferably, R A2 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom participating in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / moieties contained in the compound of formula (IIIb), R A2 It can be selected from compounds that provide functional groups suitable for forming amide bonds. For example, the group R A2 It may be a group that provides two coupling groups -NH- and one coupling group -C(O)-.

[0189] If there is more than one group RA3 , then the group R A3 In each occurrence, it is independently expressed as R A2 and another group R A3 (if present) or R T1 A divalent group that forms an amide bond -NH-C(O)-. Preferably, R A3 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom participating in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / parts contained in the compound of formula (IIIb), each group R A3 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A3 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0190] The variable b represents an integer from 0 to 4, for example, 0, 1, 2, or 3.

[0191] In formula (IIIc):

[0192] If there is more than one group R A4 , then the group R A4 In each occurrence, it is independently expressed as R S and R CH2 A divalent group that forms an amide bond -NH-C(O)-. Preferably, R A4 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom participating in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / parts contained in the compound of formula (IIIc), each group R A4 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A4 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0193] The variable c represents an integer from 1 to 4, for example 1, 2 or 3, preferably 1 or 2.

[0194] As discussed in this article, R CH2 represents a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation, including the examples of chelating moieties disclosed herein, such as moieties derived from DOTA or DOTAGA. It will be understood from formula (IIIc) that R CH2 is connected to R A4 and R A5 (if present) or R T1The divalent part of R CH2 It is connected to its adjacent group through an amide bond -NH-C(O)-.

[0195] If there is more than one group R A5 , then the group R A5 In each occurrence, it is independently expressed as R CH2 and R T1 A divalent group that forms an amide bond -NH-C(O)-. Preferably, R A5 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom participating in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / parts contained in the compound of formula (IIIc), each group R A5 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A5 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0196] The variable d represents an integer from 0 to 4, for example 0, 1, 2 or 3, preferably 0, 1 or 2.

[0197] In formula (IIId):

[0198] As discussed in this article, R CH3 represents a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation, including the examples of chelating moieties disclosed herein, such as moieties derived from DOTA or DOTAGA. It will be understood from formula (IIId) that R CH3 is connected to R A4 The unit price part. CH3 and R A4 They are connected to each other via an amide bond -NH-C(O)-.

[0199] Group R A6 Represents R S , R CH3 and R A7 A trivalent group that forms an amide bond -NH-C(O)-. Preferably, R A6 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom participating in an amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / moieties contained in the compound of formula (IIId), R A6 It can be selected from compounds that provide functional groups suitable for forming amide bonds. For example, the group R A6 It may be a group that provides two coupling groups -NH- and one coupling group -C(O)-.

[0200] If there is more than one group R A7 , then the group R A7 In each occurrence, it is independently expressed as R A6 and R CH4 A divalent group that forms an amide bond -NH-C(O)-. Preferably, R A7 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom involved in an amide bond. Those skilled in the art will appreciate that, taking into account the desired arrangement of groups / parts contained in the compound of formula (IIId), each group R A7 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A7 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0201] The variable e represents an integer from 1 to 4, for example 1, 2 or 3, preferably 1 or 2.

[0202] As discussed in this article, R CH4 represents a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated metal cation, including the examples of chelating moieties disclosed herein, such as moieties derived from DOTA or DOTAGA. It will be understood from formula (IIId) that R CH4 is connected to R A7 and R A8 (if present) or R T1 The divalent part of R CH4 It is connected to its adjacent group through an amide bond -NH-C(O)-.

[0203] If there is more than one group R A8 , then the group R A8 In each occurrence, it is independently expressed as R CH4 and R T1 A divalent group that forms an amide bond -NH-C(O)-. Preferably, R A8 Contains 2 to 8 carbon atoms, excluding any carbonyl carbon atom involved in the amide bond. Those skilled in the art will appreciate that, with due regard to the desired arrangement of groups / parts contained in the compound of formula (IIId), each group R A8 can be independently selected among compounds that provide functional groups suitable for forming amide bonds. For example, the group R A8 It may be a group providing a coupling group -NH- and a coupling group -C(O)-, a group providing two coupling groups -NH-, or a group providing two coupling groups -C(O)-.

[0204] The variable f represents an integer from 0 to 4, for example 0, 1, 2 or 3, preferably 0, 1 or 2.

[0205] As described above, the compounds according to the present invention encompass compounds or salts thereof comprising a group selected from formula (Ia), (Ib) and (Ic), as well as compounds of formula (IIa), (IIb) or (IIc) (including formula (IIa') to (IIc') and (IIIa) to (IIId)) or salts of these compounds. The salt is preferably a pharmaceutically acceptable salt, i.e., a salt formed with a pharmaceutically acceptable anion or cation. The salt can be formed, for example, by protonating an atom (e.g., a nitrogen atom) with an easily protonated lone pair of electrons with an inorganic or organic acid, or by separating the proton from an acidic group (e.g., a carboxyl group) by neutralization with a base. Other charged groups that may be present in the compounds of the present invention and that can provide a compound in the form of a salt include groups that are always charged, such as quaternary ammonium groups comprising ammonium cations, wherein the nitrogen is substituted with four organic groups, or charged chelate complexes.

[0206] If the salt form contains a positively charged form of the compound, exemplary anions that can be present as counterions in the salt form of the compound of the present invention can be mentioned, for example, anions selected from the group consisting of chloride, bromide, iodide, sulfate, nitrate, phosphate (e.g., phosphate, hydrogen phosphate or dihydrogen phosphate), carbonate, bicarbonate or perchlorate; acetate, trifluoroacetate, propionate, butyrate, valerate, 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 (toluenesulfonate), 2-naphthalenesulfonate, 3-phenylsulfonate or camphorsulfonate. Since trifluoroacetic acid is often used in the synthesis of peptides, trifluoroacetate is a representative salt provided when forming a compound containing a peptide structure. Such trifluoroacetates can be converted, for example, into acetates during their work-up.

[0207] Exemplary cations that may be present as counterions in the salt form of the compound of the invention may be, for example, cations selected from the group consisting of 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), if the salt form comprises a negatively charged form of the compound.

[0208] The compounds according to the present invention contain SiFA groups, as shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc), wherein the fluorine atom F is attached to the Si atom via a direct covalent bond. It will be understood that the F may be 18 F (i.e. radioactive fluorine isotope) or 19F (non-radioactive fluorine isotope, also called "cold fluorine").

[0209] As mentioned above, the SiFA group according to the present invention can achieve 19 F and 18 Therefore, the present invention further provides a method for preparing a radiolabeled compound, which comprises reacting a compound comprising a group selected from the group consisting of formula (Ia), (Ib) and (Ic) or a salt thereof, or a compound of formula (IIa), (IIb) or (IIc) or a salt thereof (wherein the fluorine attached to the Si atom by a direct covalent bond is [ 19 F] fluorine) and [ 18 F] fluoride reacts to convert [ 19 F] Fluorine 18 F] Fluorine exchange step. 18 Sources of fluoride and its use in SiFA groups 19 F to 18 Devices for F isotope exchange are known to those skilled in the art and can be used in the methods of the invention described herein. For example, reference can be made to C. et al., Appl. Sci. 2012, 2(2), 277-302 (https: / / doi.org / 10.3390 / app2020277) or A. Wurzer et al., EJNMMI Radiopharm. Chem. 6, 4 (2021) (https: / / doi.org / 10.1186 / s41181-021-00120-5). It will be understood that the information provided above regarding preferred embodiments of the groups of formula (Ia), (Ib) and (Ic) or compounds of formula (IIa), (IIb) or (IIc) continues to apply in the context of this method.

[0210] In this regard, another aspect of the present invention is the use of a group of formula (Ia), (Ib) or (Ic) as defined above (including any preferred embodiments thereof) as a silicon-based fluoride acceptor group for the 19 F] Fluorine 18 F] Uses of fluorine isotope exchange.

[0211] Another aspect of the present invention is the use of a group of formula (Ia), (Ib) or (Ic) as defined above (including any preferred embodiments thereof) as a silicon-based fluoride acceptor group for targeting radiopharmaceuticals [ 18 F] labeling, for example, a targeted radiopharmaceutical of a compound of formula (IIa), (IIb) or (IIc) as defined above, or a salt thereof (including any preferred embodiment thereof), comprising [ 18 F] fluorine as the fluorine atom shown in the formula.

[0212] According to the above, the compounds according to the present invention encompass radiolabeled compounds and non-radiolabeled compounds. The radiolabeled compounds of the present invention are compounds containing a radioactive component, such as [ 18 F] fluorine atom as the fluorine atom shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc), or, if the compound comprises a chelate moiety, the chelate moiety comprises a chelated radioactive metal cation. Preferably, the radiolabeled compound according to the present invention is one in which the fluorine atom shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc) is [ 18 F] fluorine compounds. The non-radiolabeled compounds according to the present invention are compounds that do not contain radioactive components, in particular, do not contain [ 18 F] fluorine compounds that also do not contain chelated radioactive metal cations.

[0213] As another aspect, the present invention provides a pharmaceutical composition, typically a radiopharmaceutical composition, comprising a compound according to the present invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent. The compound according to the present invention contained in the radiopharmaceutical composition is typically a radiolabeled compound.

[0214] Compositions comprising a non-radiolabeled compound according to the invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent, may be provided, for example as a precursor composition of a radiopharmaceutical composition. In a related aspect, the invention provides a kit comprising a non-radiolabeled compound according to the invention containing no radioactive component, optionally in combination with a pharmaceutically acceptable excipient, and instructions for radiolabeling the compound.

[0215] In another aspect, the invention provides a diagnostic composition comprising a compound according to the invention, typically a radiolabeled compound according to the invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent. In a related aspect, the invention provides a compound according to the invention, typically a radiolabeled compound according to the invention, or a radiopharmaceutical composition as discussed above, for use in an in vivo method for diagnosing a disease or condition. The diagnostic method preferably involves nuclear diagnostic imaging, for example by positron emission tomography (PET) or single photon emission computed tomography (SPECT). According to the invention, the fluorine atom shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc) is [ 18 [F] fluorine radiolabeled compounds are preferred radiolabeled compounds suitable for PET.

[0216] For example, the diagnostic method may include administering a radiolabeled compound according to the present invention to an individual, and detecting the compound in the individual, or monitoring the distribution of the compound in the individual, thereby detecting or monitoring the disease or condition to be diagnosed. The individual may be a human or an animal, and preferably a human. Alternatively, the diagnostic method may also include adding the radiolabeled compound according to the present invention to a sample, such as a physiological sample obtained from an individual in vitro or in vitro, and detecting the compound in the sample.

[0217] The above diagnostic methods are intended to identify diseases or conditions in the human or animal body. An example of a disease or condition is cancer. If the compound according to the invention is a compound of formula (IIa), (IIb) or (IIc), it will be understood that the disease or condition is usually a compound related to the group R E Diseases or conditions associated with the target structures of the included targeting moieties. For example, the presence or increased presence of the target structure in an individual may indicate the disease or condition. In particular, the target structures of interest (e.g., the target structures discussed above as examples) may be overexpressed in human diseases (e.g., cancer).

[0218] In another aspect, the invention provides a therapeutic composition comprising a compound according to the invention, typically a radiolabeled compound according to the invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent. In a related aspect, the invention provides a compound according to the invention, typically a radiolabeled compound according to the invention, or a radiopharmaceutical composition as discussed above, for use in a method of treating a disease or condition. The method is preferably a method of treating a disease or condition by radioligand therapy. As an example of a radiolabeled compound according to the invention that can be used for radioligand therapy, mention may be made of a compound comprising a chelate moiety, wherein the chelated metal cation is 177 Lu cation.

[0219] For example, the method of treatment may comprise administering to a subject a radiolabeled compound according to the invention. The subject may be a human or an animal, and is preferably a human.

[0220] The above-mentioned methods of treatment are intended to treat diseases or conditions of the human or animal body. An example of a disease or condition is cancer. If the compound according to the invention is a compound of formula (IIa), (IIb) or (IIc), it will be understood that the disease or condition is usually a compound related to the group R E The targeting moiety encompassed herein is a target structure associated with a disease or disorder.

[0221] It will be appreciated that the suitability for therapeutic and diagnostic applications is not mutually exclusive. That is, the compounds according to the invention may be suitable for both applications. For example, 177Compounds containing Lu cations can be used for therapeutic and diagnostic imaging applications. In addition, compounds of the invention containing chelating groups and SiFA groups are suitable as radioactive hybrid (rh) ligands. Such rh ligands can be used alternatively [ 18 F] fluoride (e.g. for PET) or radioactive metal (e.g. for PET 68 Ga cations, or for radiotherapy 177 Lu cation) labeling. When the rh ligand is [ 18 F]fluoride labeling, the cold (non-radioactive) metal cation can (but does not have to) be complexed by a chelator moiety elsewhere in the molecule, and when it is labeled with the corresponding radioactive metal cation, the cold [ 19 F] fluorine. Therefore, 18 The F-labeled peptide and the corresponding radioactive metal-labeled analog may have the same chemical structure and therefore have the same in vitro and in vivo properties, thereby enabling the production of structurally identical theranostic tracers whose in vivo properties are comparable to those of diagnostic and therapeutic tracers (e.g. 18 F / 177 Lu analogs) are identical.

[0222] Thus, according to this method, the compounds according to the invention include radiolabeled compounds in which the SiFA group is 18 F-labeled, and there is a chelate moiety containing a chelated non-radioactive cation (e.g. nat Lu or nat Ga), and radiolabeled compounds wherein a chelate moiety is present and contains a chelated radioactive cation (e.g. 177 Lu or 68 Ga), and the SiFA group is not useful 18 F mark (therefore carrying 19 F). Likewise, the present invention provides such compounds according to the invention for use in a combined method for in vivo diagnosis and therapy of a disease or condition, wherein the method firstly involves administering a compound according to the invention, wherein the SiFA group is used 18 F-labeled, and the chelating group contains a chelated non-radioactive cation (e.g. nat Lu or nat Ga), and subsequently administering a compound wherein the chelating group contains a chelated radioactive cation and the SiFA group is not used 18 F-labeled compounds.

[0223] In a related aspect, the compounds according to the invention can be used in an imaging method, which may include administering a ligand compound to an individual, detecting the compound in the individual at different time points after injection, and monitoring the distribution of the compound in the body, with the purpose of calculating the dose distribution before or during treatment. The individual can be a human or an animal, and is preferably a human. This imaging method can be relied upon to calculate the dose distribution before or during treatment of a disease or condition of the human or animal body by radioligand therapy.

[0224] As mentioned above, compositions provided by the invention can comprise pharmaceutically acceptable carrier, excipient and / or diluent.The example of suitable pharmaceutical carrier, excipient and / or diluent is well-known in the art, and comprises phosphate buffered saline solution, amino acid buffer solution (with or without saline), water for injection, emulsion such as oil / water emulsion, various types of wetting agents, sterile solution etc.This composition can be prepared by well-known conventional method.

[0225] In this specification, many documents are cited, including not only scientific journal articles, but also patent applications and manufacturer manuals (see, for example, the list of references in this regard below). The disclosure of these documents, although not considered relevant to the patentability of the present invention, is incorporated herein by reference in its entirety. More specifically, all references are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. Example

[0226] In the following, the synthesis of the SiFA group according to the invention and the evaluation of its basic properties in comparison with the current gold standard p-(di-tert-butyl-(fluorosilyl)benzoic acid ((4-SiFA)benzoic acid, (4-SiFA)Bz) are illustrated using various model peptides. Furthermore, the performance of the SiFA group is exemplified by its use in compounds according to the invention comprising a variety of targeting carriers for application in the field of radiopharmaceuticals.

[0227] 1. Comparative evaluation of the chemical properties of various SIFA moieties based on model peptides (MPs)

[0228] Initially, each prosthetic group was coupled to three different model peptides (MP, Table 1) to investigate the structural influence of the novel SiFA building blocks on the labeling properties, stability and lipophilicity of the model peptides compared to the gold standard. Since similar trends were observed for the three series, the modifiability of the in vitro properties was investigated only by extending series a (X-Gly-Lys, see Table 2), providing differences in HSA binding strength within a region distinguishable by high performance affinity chromatography (HPAC) methods.

[0229] Table 1: Structure, purity and yield of the studied model peptides (MPs) comprising the dipeptide ac and various SiFA groups, namely the gold standard (4-SiFA)Bz (R1), (3-SiFA)Bz (R2), the newly developed (5-SiFA)Ip (R3) and the latter’s modified amino acid conjugates (HO-L-Lys-(5-SiFA)Ip (R4) and (HO-L-Glu-(5-SiFA)Ip (R5)).

[0230]

[0231]

[0232] **Comparative data

[0233] Table 2: Structure, purity and yield of model peptides (MP) studied as an extension of Lys series a.

[0234]

[0235]

[0236] 1.1 Model peptide (MP) 18 F Mark

[0237] The radiochemical conversion (RCC, n ≥ 3) of reaction mixture samples was determined by thin layer chromatography (TLC) analysis and the decay-corrected radiochemical yield (RCY, n ≥ 3) was evaluated after cartridge purification. 18 Isotope exchange efficiency of F labeling (see figure).

[0238] All derivatives showed good RCC and RCY in the range of about 60-80% with a molar activity of 3.1±1.8 GBq / μmol. A very similar trend can be observed for the values ​​of (4-SiFA)Bz- and (5-SiFA)Ip-derivatives, while the two values ​​of (3-SiFA)Bz- tended to decrease slightly, and the values ​​of X-(5-SiFA)Ip-derivatives tended to increase slightly, where X = -L-Lys-OH, -L-Glu-OH, -Gal6N or -PEG8-OH.

[0239] Model peptide (MP) 18 RCC and RCY trends of F-labeled reactions:

[0240] (3-SiFA)Bz-MP<(4-SiFA)Bz-MP~(5-SiFA)Ip-MP <X-(5-SiFA)Ip-MP

[0241] 1.2 Relative radiochemical conversion (rRCC)

[0242] To more precisely compare the relative reactivity of various SiFA model peptides in isotope exchange reactions, competitive 18 F labeling was carried out. In this paper, the corresponding (4-SiFA)Bz-MP was selected as an internal reference. Equal amounts of the test compound and the reference compound were added as a solution to an anhydrous 18 F]F solution. After 5 minutes at room temperature, the sample was analyzed by radio-RP-HPLC. The relative radiochemical conversion (rRCC) was calculated by peak integration and expressed as the ratio of the test compound to the reference compound [%]. The conclusion is that rRCC can more precisely compare the reactivity compared to the standard RCC determined in separate experiments (see Figure 1 A-C).

[0243] Figure 1 A-C show the radiochemical conversion (RCC, n ≥ 3) and radiochemical yield (RCY, n ≥ 3) of the 18 F labeling reaction (5 minutes, room temperature, molar activity = 3.1 ± 1.8 GBq / μmol) of the model peptides. The model peptides are divided into Lys-, Asp- and Tyr-series and are described in A, B and C respectively.

[0244] Thus, as Figure 2 shown in A-C, by comparing rRCC, the ranking order corresponding to RCC ((3-SiFA)Bz-MP < (4-SiFA)Bz-MP ∼ (5-SiFA)Ip-MP < X-(5-SiFA)Ip-MP) can be better distinguished, and the following ranking can be obtained:

[0245] (3-SiFA)Bz-MP < (4-SiFA)Bz-MP < (5-SiFA)Ip-MP < X-(5-SiFA)Ip-MP

[0246] (∼75% < 100% < 125% < 150–250%)

[0247] Figure 2 A-C show the relative reactivity represented by rRCC, which is normalized to the conversion of the corresponding (4-SiFA)Bz-MP, which was determined (n = 3) by the precursor mixture of equimolar amounts of the test compound and its (4-SiFA)Bz-counterpart (shown at the top of each series A, B and C, and the data are divided into Lys-, Asp- and Tyr-series respectively). Quality control by HPLC showed that the Gal6N-derivative formed two unidentified by-products (∼5–10%), which were added to the test compound integral and are estimated to occur due to keto- and enol tautomerism of the sugar moiety.

[0248] Therefore, in this context, it could be assessed whether new (5-SiFA)Ip-derivatives and X-(5-SiFA)Ip-derivatives exhibit better labeling properties, in particular increased reactivity, leading to higher RCY.

[0249] 1.3 Determination of n-octanol-water partition coefficient (logD 7.4 )

[0250] During the development of alternative SiFA-analogues, the substitution pattern of the aromatic moiety is of particular importance in terms of its effect on lipophilicity. Since the 4-SiFA-Bz-moieties used to date exhibit a strong lipophilic character, which is also a major factor in the properties of SiFA-ligand conjugates, it would be particularly interesting if newly developed SiFA-moieties could yield more negative logD 7.4 The excellent hydrophilicity indicated by the values ​​of 2.5 and 1.3 would be of interest. Assuming that a better differentiation in the properties of the various prosthetic groups was observed, small model peptides were investigated. The corresponding logD 7.4 Value (n≥8) such as Figure 3 shown.

[0251] Figure 3 AC Display 18 The n-octanol-water partition coefficient (logD 7.4 , n≥8), the model peptides are divided into Lys-, Asp- and Tyr-series and are described in A, B and C, respectively.

[0252] Figure 3 The results in AC show that the (4-SiFA)Bz-derivatives have only a modest change in lipophilicity compared to the (3-SiFA)Bz-derivatives. In contrast, the negative charge near the aromatic moiety introduced by the (5-Sifa)Ip-motif and the additional carboxylic acid itself within the X-(5-Sifa)Ip-motif (where X = -L-Lys-OH, -L-Glu-OH, -Gal6N or -PEG8-OH as variable hydrophilic modifiers that are easily conjugated to the additional carboxylic acid via peptide chemistry) leads to a greatly increased hydrophilicity.

[0253] 1.4 High-performance affinity chromatography (HPAC) for determination of human serum albumin (HSA) binding

[0254] The binding strength of SiFA-MPs to human serum albumin (HSA) was investigated using high performance affinity chromatography (HPAC). The corresponding gold standard ((4-SiFA)Bz-MP) showed - as expected from published and in-house data - rather strong HSA binding. This is associated with a relatively slow and unfavorable blood clearance in vivo.

[0255] If Figure 4 AC, only minor differences in HSA binding were observed when comparing the (3-SiFA)Bz-derivatives and (5-SiFA)Ip-derivatives with the (4-SiFA)Bz-derivatives. Figure 4 A and Figure 5 As shown, by conjugating other modifiers to the (5-SiFA)Ip-moiety, HSA binding can be greatly reduced. In the latter figure, it is clearly depicted that in particular HO-L-Lys-(4a), HOOC-PEG8-(6a) and Gal6N(7a)-modifiers are expected to be valuable tools for further optimization of two key parameters that are crucial for the desired fast pharmacokinetics, namely reduced HSA binding and improved hydrophilicity.

[0256] Figure 4 AC shows HSA binding of SiFA-MPs, which are divided into Lys-, Asp-, and Tyr-series according to HPAC and depicted in A, B, and C, respectively.

[0257] Figure 5 The logD of Lys-series a is shown 7.4 Comparison of values ​​with HSA binding.

[0258] Therefore, it can be concluded that the X-(5-SiFA)Ip-part can not only serve as 18 F-labeling can also serve as an HSA binding moiety, where HSA binding can be easily tuned over a wide range of binding strengths by conjugating appropriate modifiers of choice to additional carboxylic acids of the newly developed (5-SiFA)Ip-moiety, thereby precisely adjusting the pharmacokinetic properties of the ligand to the in vivo requirements.

[0259] 1.5 Under different conditions [ 18 Determination of the chemical stability of F]F-Si bonds

[0260] In order to determine the various MP 18 The chemical stability of the F]F-Si bond will 18 Aliquots of F-labeled MPs were incubated under three different conditions to simulate the stability in blood in vivo (pH 7.4, 37°C), the stability of the SiFA-radioactive hybrids used by our group, and the stability of the 177 The stability of Lu labeling protocol (pH 5.5, 90°C) and the reactivity of reverse isotope exchange in aqueous medium (1 mM NaF solution) were investigated. 18 The kinetics of F defluorination were determined by sampling over a 2-hour period (t = 0, 30, 60, 90, and 120 min) and monitoring the complete 18The proportion of F-labeled peptides. Intact under three different conditions 18 The corresponding calculated half-life of F-labeled MP (n=3) is as follows Figure 6 As described by AC.

[0261] Figure 6 Show full 18 The half-life of F-labeled MPs (n=3) was divided into subsets A: pH 7.4, 37°C (simulated blood conditions), B: pH 5.5, 90°C (SiFA-radioactive hybrids), and 177 Lu labeling scheme, and C: NaF (1 mM in H2O, pH 6.5, room temperature (reverse isotope exchange)); * indicates no half-life is given as the stability of intact MP after 2 h is >95% due to imprecise regression (R2<<90%).

[0262] It is noteworthy that previous in vitro and in vivo experience confirmed that the stability of (4-SiFA)Bz-derivatives is sufficient. As shown by the data shown below, the peptide sequence (Asp-MP compared to Tyr-MP and Lys-MP) and even the positioning of the same amino acids ((5-SiFA)Ip-Gly-L-Lys-OH compared to (5-SiFA)Ip-L-Lys-Gly-OH) appear to have a significant impact on the observed half-life of the intact MP. Moreover, in terms of standard deviation, the corresponding (4-SiFA)-Bz-MP, (3-SiFA)-Bz-MP and (5-SiFA)Ip-MP in one MP-series mostly showed similar stabilities, while X-(5-SiFA)Ip-MP (represented by white bars) was determined to be less stable. These findings are consistent with the results of the present study. 18 The F labeling results were in good agreement, indicating that the more reactive derivatives with higher (r)RCC and RCY also showed faster 18 However, although the stability of X-(5-SiFA)Ip-MP is inferior to the corresponding (4-SiFA)Bz-MP, it can be concluded that the stability of the new compound appears to be within a feasible range for in vivo applications.

[0263] 2. Comparative evaluation of the chemical properties of various SIFA-moieties using carrier-based ligands as an example

[0264] In the following, example data for several carrier-based ligands are shown to demonstrate the advantages of the novel (5-SiFA)Ip-based building blocks.

[0265] 2.1. Gastrin-releasing peptide receptor (GRPR) ligands

[0266] Table 3: Comparison of the gold standard (4-SiFA)Bz-fraction with the (3-SiFA)Bz-fraction and the novel (5-SiFA)Ip-fraction, consensus peptide sequence Lu-DOTAGA-D-Dap(R x )-EDA-DOTA-[α-Me-Trp 8 Structure, HSA binding, and GRPR affinity (IC) of the radiohybrid GRPR ligand of MJ9 50 ) and the n-octanol-water partition coefficient (logD 7.4 , n = 6, 177 Lu-labeled compounds).

[0267]

[0268]

[0269] **Comparative data

[0270] As shown in Table 3, the modification change from (4-SiFA)Bz-compound to (3-SiFA)Bz-compound resulted in only a modest improvement in HSA binding and a negligible change in hydrophilicity. In fact, the (5-SiFA)Ip-derivative showed an ideal, significant reduction in HSA binding and a significant increase in hydrophilicity.

[0271] Furthermore, the introduction of additional charged groups in the (5-SiFA)Ip-moiety is expected to have a possible effect on receptor affinity. Whether this effect is a positive or negative influence on affinity needs to be studied individually for each target and may be adjusted through structure-activity relationships in subsequent development steps. Therefore, the loss of affinity caused by the initial use of a novel (5-SiFA)Ip-moiety in a single compound does not necessarily constitute a permanent limitation for the entire set of ligands. However, the results suggest that the use of a (5-SiFA)Ip-moiety or possibly another modifiable X-(5-SiFA)Ip-moiety instead of a (4-SiFA)Bz-moiety to effectively compensate for the high lipophilicity and strong HSA binding in the structural vicinity of the t-Bu2FSi-Ar group is a promising step.

[0272] CXC chemokine receptor type 4 (CXCR4) ligand

[0273]

[0274] Structures of radiohybrid CXCR4 ligands, which share Pentixafor as lead structure, modified with either the gold standard (4-SiFA)Bz-moiety or the novel (5-SiFA)Ip-moiety attached to the chelator via an EDA linker.

[0275] Figure 7 A and B show the HSA binding and n-octanol-water partition coefficient (log D 7.4 , n = 8, 18 F labeled compounds) the lead structures were modified with either the gold standard (4-SiFA)Bz-moiety or the novel (5-SiFA)Ip-moiety attached to the chelator via an EDA linker.

[0276] Derivatives of the well-known CXCR4 ligand Pentixafor described above show the same expected trend, i.e. a significant reduction in lipophilicity with the (5-SiFA)Ip-moiety attached instead of the standard (4-SiFA)Bz-moiety. This effect is even pronounced in the presence (and not dominated by) installation of lipophilic amino acids (i.e. Nal and Tyr) in the pharmacophore along with the 4-Abz linker-moiety. HSA binding does not seem to be affected by changes in the prosthetic group, which may indicate a dominant interaction of the aromatic amino acids of the pharmacophore towards HSA.

[0277] 2.3. Somatostatin receptor (SSTR) ligands

[0278] Similar to the CXCR4 ligands shown above (derived from Pentixafor as shown in 2.2 above), the cyclic octapeptide Octreotate (TATE) constitutes a rather lipophilic pharmacophore. Therefore, it is not surprising that the (4-SiFA)Bz-conjugate is also observed to have high lipophilicity, consisting of the pharmacophore and the prosthetic group, which are already lipophilic alone (Table 4, entries 1, 2).

[0279] In contrast, the hydrophilicity of the two (5-SiFA)Ip-derivatives increased by 1.2-1.5 log units compared to the corresponding (4-SiFA)Bz-conjugates (Table 4, entries 3, 4). Interestingly, the installation of the carboxylic acid directly on the SiFA-moiety (Table 4, entry 4) resulted in a significant increase in hydrophilicity (Table 4, entry 1) compared to the (4-SiFA)Bz-derivatives in which the carboxylic acid was transferred to the linker. This finding clearly demonstrates the excellent efficiency and practicality of the novel (5-SiFA)Ip-moiety. In addition, additional modifications can be combined with the (5-SiFA)-moiety to achieve a higher increase in hydrophilicity (Table 4, entry 3).

[0280] Similar to the CXCR4 ligands mentioned above, HSA binding was barely affected by the modifications studied, as the interaction with HSA appeared to be dominated by the strongly binding aromatic amino acids within the cyclic pharmacophore.

[0281] Table 4: Total natGa-DOTATATE was used as the pharmacophore to compare the structure, HSA binding, SSTR affinity (IC) of the modified radiohybrid SSTR ligands using the gold standard (4-SiFA) Bz-moiety and the novel (5-SiFA) Ip-moiety. 50 ) and the n-octanol-water partition coefficient (logD 7.4 , n = 6, 18 F labeled compound).

[0282]

[0283]

[0284] **Comparative data

[0285] 2.4. Cholecystokinin B receptor (CCK-2R) ligand

[0286] Another example is composed of ligands for CCK-2 receptors. Again, similar to CXCR4 and SSTR ligands, the pharmacophore contains several lipophilic aromatic amino acids (Nal, Trp and Tyr). Therefore, high HSA binding is expected, as well as high lipophilicity. The conjugation of the hydrophilic DOTA chelator with the Lu complex yields the reference compound Lu-DOTA-MGS5, which compensates the lipophilicity to a logD value of -2.25 (8D). Not surprisingly, the introduction of the (4-SiFA) Bz-part or the (3-SiFA) Bz-part via the trifunctional linker D-Tap results in a sharp deterioration in hydrophilicity, with a logD value increase of about 2-2.5. In contrast, this shift can be effectively minimized by using the novel (5-SiFA) Ip-part. In summary, another example reinforces the importance of the second carboxylic acid directly attached to the aromatic unit within the (5-SiFA) Ip-part to minimize the lipophilicity increased by the introduction of the SiFA-based auxiliary group.

[0287]

[0288] Structures of CCK-2R ligands, i.e. reference compounds sharing the same pharmacophore, compared with the gold standard (4-SiFA)Bz-moiety, (3-SiFA)Bz-moiety and the novel (5-SiFA)Ip-moiety nat Lu-DOTA-MGS5 and its radioactive hybrid derivatives.

[0289] Figure 8 AD shows CCK-2R ligands (i.e., reference compounds sharing the same pharmacophore, modified comparatively with the gold standard (4-SiFA)Bz-moiety, (3-SiFA)Bz-moiety, and the novel (5-SiFA)Ip-moiety linked via the trifunctional linker - D-Tap-nat CCK-2R affinity (IC 50 , n = 3), internalization of reference F11N (n = 3) (%), HSA binding (HPAC) and n-octanol-water partition coefficient (logD 7.4 , n≥6, 177 Lu-labeled compounds).

[0290] 2.5. Prostate-specific membrane antigen (PSMA) ligand

[0291] Further studies were performed using ligands directed against prostate-specific membrane antigen (PSMA). Table 5 summarizes the data for simplified ligands containing the EuK-binding motif attached to different SiFA-parts, namely (4-SiFA)Bz- (first synthesized by Wirtz (1) but independently re-evaluated here), (3-SiFA)Bz- and (5-SiFA)Ip-). Almost equal values ​​were observed for HSA binding.

[0292] The IC 50 The values ​​provide a positive example of structure-activity relationship, where transfer of the silyl group of the aromatic moiety is clearly beneficial for the superior affinity. A simple transfer of the silyl group from the para position (PSMA-1) to the meta position (PSMA-2) resulted in a more than 20-fold increase in affinity, which could be further improved by two-fold by attachment of a carboxylic acid (PSMA-3).

[0293] Furthermore, using this data set, another example was found illustrating that an additional carboxylic acid directly attached to the SiFA-moiety greatly increases the hydrophilicity, as a difference of about one log unit was observed comparing entries 1 and 2 to entry 3.

[0294] Table 5: Structure, HSA binding, PSMA affinity (IC) of EuK-based small molecule PSMA ligands compared with the gold standard (4-SiFA)Bz-moiety, (3-SiFA)Bz-moiety, and novel (5-SiFA)Ip-moiety 50 ) and the n-octanol-water partition coefficient (logD 7.4 , n≥6).

[0295]

[0296]

[0297] **Comparative data

[0298] Determination 18 F]F-PSMA-3 in vivo data and compared them with previously published [ 18 F]F,nat The data of Ga-rhPSMA-7.3 (2) were compared with Fig. 9 ), not only verified the effect on pharmacokinetics, but also, by comparing bone uptake, specifically indicated the corresponding [ 18 F] Stability of F-Si bond.

[0299] Fig. 9 Show compounds [ 18 F]F, nat Ga-rhPSMA-7.3 (n=4) and [ 18 F] Biodistribution of F-PSMA-3 (n=5) in male tumor-bearing CB17-SCID mice 1 hour post-injection (pi). Data are expressed as percentage of injected dose per gram (% ID / g), mean ± SD. [ 18 F]F, nat Data on Ga-rhPSMA-7.3 have been published previously by our group (2).

[0300] like Fig. 9 As shown, 18 F]F, nat Compared with 0.96% ID / g of Ga-rhPSMA-7.3, 18 F]F-PSMA-3 showed faster blood clearance already 1 hour after injection, with a blood value of 0.55% ID / g.

[0301] Obviously, 18 The low renal values ​​of [F]F-PSMA-3 (67.1 ± 13.9% ID / g) cannot be directly compared because, in the absence of the hydrophilic DOTAGA chelate, this derivative appears to be insufficiently hydrophilic, which leads to hepatobiliary excretion as indicated by increased accumulation in the liver (7.2 ± 4.8% ID / g) and intestine (17.7 ± 1.6% ID / g).

[0302] Although the pharmacokinetics of these derivatives differ significantly, resulting in unequal plasma half-lives and thus deviations from the derivatives' internal [ 18 F]F-Si bonds are exposed to incubation conditions, but the bone uptake values ​​(assuming that the main component is the cleavage of [ 18 F]fluoride) reflects the reactivity trend of the model peptide in the above in vitro study results ( Fig.10 ).

[0303] Fig.10 [ is shown as part of different SiFA-moieties [(4-SiFA)Bz-, (3-SiFA)Bz-, terminal (5-SiFA)Ip- and bridged-(5-SiFA)Ip-] 18Comparison of in vitro and in vivo data on the reactivity and stability of the F]F-Si bond: A: Lys-series model peptides (MP) in anhydrous [ 18 F] Reactivity under F labeling conditions, expressed as relative radiochemical conversion (rRCC); B: Lys series complete [ 18 F]F labeled MP half-life; C: Lys-series 19 F{ 29 Si}NMR spectra chemical shifts [ppm]; D: Ligand [ 18 F]F, nat Ga-rhPSMA-7.3 and [ 18 F] The cumulative activity of F-PSMA-3 1 hour after injection (%ID / g). 18 F]F, nat Data on Ga-rhPSMA-7.3 have been published previously by our group (2).

[0304] like Fig.10 As shown in A, the in vitro results of the Lys-MP series showed a trend in reactivity, with the relative radiochemical conversion (rRCC) of (3-SiFA)Bz-MP being similar to the normalized value of (4-SiFA)Bz-MP, the rRCC of the terminal (5-SiFA)Ip-derivative being slightly higher by 1.3-fold, and the rRCC of the bridged (5-SiFA)Ip-derivative being significantly higher by about 2.6-fold.

[0305] It was also found that the increase in reactivity was accompanied by a decrease in stability ( Fig.10 B), MP 18 The half-life of the [F]F-Si bond was decreased by 15% upon terminal attachment of the (5-SiFA)Ip-moiety and divided by a factor of 4.0 upon attachment of the (5-SiFA)Ip-moiety instead of the classical (4-SiFA)Bz-moiety in the bridging construct, respectively.

[0306] Furthermore, there appears to be an increase in reactivity and decrease in stability associated with smaller 19 Correlation of F NMR negative shift ( Fig.10 C), which indicates that the electron density at the fluorine atom is low.

[0307] Although in vitro data on PSMA ligands ( Fig.10 AC) was not determined, but the data found for MP appear to be positive for PSMA ligands [ 18 The in vivo stability trend of the F]F-Si bond has predictive value, as indicated by the cumulative activity in bone, which is mainly due to the dissociation of [18 F] fluoride ( Fig.10 D) In ​​[ 18 F]F-PSMA-3 used a terminal (5-SiFA)Ip-moiety, which resulted in a bone uptake of 1.16±0.22% ID / g. 18 F]F, nat The (4-SiFA)Bz-moiety used in Ga-rhPSMA-7.3 demonstrated higher stability with a bone uptake of 0.38±0.32% ID / g (2).

[0308] However, despite the fact that 18 F] fluoride release was increased, but clinical translation of the (5-SiFA)Ip-fraction seems feasible, comparing the findings on bone uptake with published data on [ 18 The results of F]F-SiFAlin-TATE (femur: 1.9 ± 0.6% ID / g, 60 minutes after injection (estimated by graph); 1.31 ± 0.31% ID / g at 90 minutes after injection) (3) were compared. 18 F]F-SiFAlin-TATE and [ 68 The first clinical results of a direct comparison of Ga]Ga-DOTA-TOC have yielded a favorable “signature” conclusion (4). In this study, it was found that [ 18 The bone uptake of F]F-SiFAlin-TATE was slightly higher than that of non-fluoridated [ 68 Ga]Ga-DOTA-TOC(SUV max :1.2±0.5 vs. 0.7±0.2; SUV max :0.6±0.3 vs. 0.4±0.1). Therefore, it can be considered that a certain instability of SiFA-compounds is controllable in clinical translation.

[0309] 3. Conclusion

[0310] The purpose of this study is to develop and investigate new 18 F-labeled prosthetic groups that retain the beneficial labeling properties and adequate stability of the gold standard (4-SiFA)Bz-moiety, but instead offer an alternative through modification that results in ligands with superior pharmacokinetic properties.

[0311] The highest priority requirement for this alternative is to drastically reduce the excessive lipophilicity caused by the tBu2FSi-Ar group used so far, which is a limiting factor. In addition, the SiFA-moiety displays a structural element that is also associated with strong HSA binding, and a simple and effective modulation of the binding strength plays a crucial role in optimizing the pharmacokinetics of the ligand. Both can be successfully achieved by developing the (5-SiFA)Ip-moiety and its easily modifiable derivatives.

[0312] 4. Materials and Methods

[0313] 4.1. General Information

[0314] Protected amino acid analogs were purchased from Bachem (Bubendorf, Switzerland), Carbolution Chemicals (St. Ingbert, Germany) or Iris Biotech (Marktredwitz, Germany). 2-Chlorotrityl chloride (2-CTC) resin was obtained from Sigma-Aldrich (Steinheim, Germany). Chelating agents DOTA, DOTA-GA and their derivatives were delivered by Chematech (Dijon, France). All necessary solvents and other organic reagents were purchased from Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Steinheim, Germany), Fluorochem (Hadfield, UK) or VWR (Darmstadt, Germany). Solid phase synthesis of peptides was performed manually using an Intelli-Mixer syringe oscillator (Neolab, Heidelberg, Germany). Analytical and preparative reverse phase high pressure chromatography (RP-HPLC) was performed using a Shimadzu gradient system (Shimadzu, Neufahrn, Germany), each equipped with a SPD-20A UV / Vis detector (220 nm). The analysis was performed using a MultoKrom 100C18 (150×4.6 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany) at a flow rate of 1 mL / min. The specific gradients and the corresponding retention times t are quoted in the text. R. Preparative RP-HPLC purification was performed using a MultoKrom 100C18 (250×20 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany) at a constant flow rate of 10 mL / min. Analytical and preparative radio-RP-HPLC were performed using a MultoKrom 100C18 (150×4.6 mm, 5 μm particle size) column or a Multokrom 100C18 (125×4.6 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany). The UV spectrometer was connected to a HERMLB 500NaI detector (Berthold Technologies, Bad Wildbad, Germany) or a Flowstar 2 LB 514 (Berthold Technologies, Bad-Wildbad, Germany) was used to detect radioactivity. Biotage SNAP cartridges (KP-C18-HS, ​​12 g) were used in Reverse phase high performance flash chromatography (RP-HPFC) was performed on a SP HPFC system (Biotage, Charlottesville, VA, USA). The eluents for all HPLC runs were water (solvent A) and acetonitrile (solvent B), both containing 0.1% trifluoroacetic acid. L Electrospray ionization mass spectra for the characterization of the substances were obtained on a CMS mass spectrometer (Advion, Harlow, UK). NMR spectra were recorded on a Bruker (Billerica, USA) AVHD-300, AVHD-400 or AVHD-500 spectrometer (300 K). Chemical shifts are expressed as δ values ​​[ppm] and are referenced to the residual proton signal of the deuterated solvent used or, in the absence of solvent signal, e.g. 19 F or 29 Si NMR spectra, shifts were calibrated against internal standards CFCl3 and tetramethylsilane, respectively. pH was measured using a SevenEasy pH meter (Mettler-Toledo, Giessen, Germany). A 2480 WIZARD 2 Activity quantification was performed using an automated g-counter (PerkinElmer, Waltham, USA) or a CRCR-55tR dose calibrator (Mirion Technologies, Ramsey, NJ, USA). Radioactive thin layer chromatography (TLC) was performed using a Scan-RAM detector (LabLogic Systems, Sheffield, UK).

[0315] 4.2. Solid-phase peptide synthesis

[0316] 4.2.1. General Procedure (GP)

[0317] Standard 2-CTC resin loading (GP1a)

[0318] 2-Chlorotrityl chloride (2-CTC) resin was loaded with Fmoc protected amino acid (AA) by stirring a solution of 2-CTC-resin (1.60 mmol / g) and Fmoc-AA-OH (1.5 eq.) in DMF with DIPEA (3.0 eq.) for 2 hours at room temperature. The remaining 2-chlorotriphenyl chloride was capped for 15 minutes by adding methanol (2 mL / g resin). The resin was then filtered and washed with DMF (8×5 mL / g resin and DCM (3×5 mL / g resin) and dried in vacuo. The final loading l of Fmoc-AA-OH was determined by the following equation:

[0319]

[0320] Standard H-Rink Amide Resin loading (GP1b)

[0321] H-Rink Amide Resin loading was achieved via an amide bond formation procedure (GP2). The equivalents used refer to the initial resin loading given by the manufacturer (1.0 equivalent = 0.5 mmol / g resin). Note: Except for the Dde-deprotection step, in each GP, when H-Rink amide was used - When using resin, use NMP instead of DMF.

[0322] Other 2-CTC resin loading options (GP1c)

[0323] The loading of 2-chlorotrityl chloride (2-CTC) resin (GP1a) was carried out by stirring a DCM solution of 2-CTC-resin (1.60 mmol / g) and R-CO2H (1.5 eq) with DIPEA (3.0 eq) overnight (18 hours) at room temperature. The remaining 2-chlorotrityl chloride was capped for 15 minutes by adding methanol (2 mL / g resin). The resin was then filtered, washed with DCM (8×5 mL / g resin) and dried in vacuo. The final loading of the compound was determined similarly to GP1a.

[0324] Formation of amide bonds via coupling with resin-bound amines (GP2a)

[0325] For conjugation of building blocks to resin-bound peptides, a mixture of TBTU (1.5 equiv.) and HOAt (1.5 equiv.) was used with DIPEA (4.5 equiv.) to pre-activate carboxylic acids (1.5 equiv.) or, in the case of pre-activated diaminopropionic acid and its derivatives, 2,4,6-trimethylpyridine (6.0 equiv.) as base in DMF (10 mL / g resin). After 10 min at room temperature, the solution was added to the swollen resin. If not otherwise stated in the respective synthetic schemes, the conjugation step was performed at room temperature for 2 h. After the reaction, the resin was washed with DMF (6×5 mL / g resin).

[0326] Formation of an amide bond by coupling with a resin-bound carboxylic acid (GP2b)

[0327] To conjugate the building blocks to the resin-bound peptide, the resin-bound carboxylic acid (1.0 equiv) was preactivated with a mixture of HATU (1.0 equiv) and HOAt (1.0 equiv) and DIPEA (3.0 equiv) in DMF (10 mL / g resin) for 30 min. Next, the free amine (3.0 equiv) dissolved in DMF was added to the preactivated resin. If not otherwise stated in the respective synthetic schemes, the conjugation step was performed at room temperature for 2 h. After the reaction, the resin was washed with DMF (6×5 mL / g resin).

[0328] Coupling of succinic anhydride with resin-bound amines to form amide bonds (GP2c)

[0329] To conjugate succinic anhydride to the resin-bound peptide with unprotected amine, a mixture of succinic anhydride (7.0 eq.) and DIPEA (7 eq.) in DMF (10 mL / g resin) was added to the resin. After 3 h at room temperature, the resin was washed with DMF (6 x 5 mL / g resin).

[0330] Urea bond formation via coupling with resin-bound amines (GP2d)

[0331] For binding motifs that deviate from the Glu-urea-Glu compound, the synthesis of Glu-urea-X compounds (such as Glu-urea-Lys) was carried out in a similar manner to the on-resin method. A solution of (S)-2-(1H-imidazole-1-carboxamido)pentanedioic acid di-tert-butyl ester in 1,2-dichloroethane (DCE, 5 mL / g resin) was added to the resin-bound peptide. The suspension was cooled on ice for 30 minutes, and TEA (3.0 equiv.) was added. The suspension was heated to 40°C and gently stirred overnight. After the reaction, the resin was washed with DMF (6×5 mL / g resin).

[0332] On-resin Fmoc-deprotection (GP3)

[0333] The resin-bound Fmoc-peptide was treated with 20% piperidine in DMF (v / v, 8 mL / g resin) for 5 min and then for 15 min. Afterwards, the resin was washed thoroughly with DMF (8 x 5 mL / g resin).

[0334] Dde-deprotection on resin without Fmoc-group (GP4a)

[0335] The Dde-protected peptide was dissolved in DMF (v / v, 5 mL / g resin) containing 2% hydrazine monohydrate and shaken for 20 minutes. After deprotection, the resin was washed with DMF (8×5 mL / g resin).

[0336] Dde-deprotection on resin in the presence of Fmoc-groups (GP4b)

[0337] In the presence of Fmoc-groups, peptides bound to 2-CTC resin were Dde-deprotected by addition of a solution of imidazole (0.92 g / g resin), hydroxylamine hydrochloride (1.26 g / g resin) in NMP (5.0 mL / g resin) and DMF (1.0 mL / g resin) for 3 h at room temperature (GP4b). - Dde-deprotection of the resin-bound peptide using the same amount of DCM instead of DMF. After deprotection, the resin was washed with DMF (8 x 5 mL / g resin).

[0338] Cleavage of peptide from resin with concomitant cleavage of acid-labile protecting groups (GP5a)

[0339] In order to cleave the peptide from the resin, with the cleavage of the acid labile protecting group (GP5a), the fully protected resin-bound peptide was dissolved in a mixture of TFA / TIPS / water (v / v / v; 95 / 2.5 / 2.5) and vibrated for 30 minutes. The solution was filtered out and the resin was treated in the same manner for another 30 minutes. The two filtrates were combined and stirred at room temperature for another 1-24 hours. The product was monitored by HPLC to form. After removing TFA under a nitrogen stream, the residue was dissolved in a mixture of tert-butyl alcohol and water and freeze-dried.

[0340] The peptide was cleaved from the resin while retaining the acid-labile protecting groups (GP5b)

[0341] To cleave the peptide (GP5b) from the resin while retaining the acid labile protecting groups, the fully protected resin-bound peptide was dissolved in a mixture of 1,1,1,3,3,3-hexafluoro-2-propanol / DCM (v / v; 1 / 4) and shaken for 1 hour. The solution was filtered off and the resin was treated in the same manner for another 1 hour. The two filtrates were combined and concentrated under a stream of nitrogen. The residue was dissolved in a mixture of tert-butyl alcohol and water and freeze-dried.

[0342] On-resin Allyl- / Alloc-deprotection (GP6)

[0343] The allyl- / alloc-protected resin-bound peptide was dissolved in a mixture of phenylsilane (24 eq.) and Pd(PPh3)4 (0.1 eq.) in DCM (5 mL / g resin) and kept in the dark for 20 min during the reaction. The solution was filtered off and the resin was treated in the same manner for another 20 min. To remove residual black palladium, the resin was washed alternately with DMF containing sodium diethyldithiocarbamate (0.5 wt.%, 5 mL / g resin) and DMF containing 0.5% DIPEA (5 mL / g resin), 3×5 min for each solution. The resin was then further washed with DMF (8×5 mL / g resin).

[0344] p-Nosyl-protected (GP7)

[0345] The resin-bound peptide was dissolved in a solution of p-nitrobenzenesulfonyl chloride (5.0 equiv.) and 2,4,6-trimethylpyridine (10.0 equiv.) in NMP (10 mL / g resin) and shaken at room temperature for 30 min. After deprotection, the resin was washed with NMP (6×10 mL / g resin).

[0346] p-Nosyl-deprotection (GP8)

[0347] A solution of DBU (5.0 eq.) in NMP (10 mL / g resin) was added to the p-Nosyl protected resin-bound peptide. After 5 min incubation, β-mercaptoethanol (10 eq.) was added and shaken at room temperature for 15 min. This procedure was repeated once. The resin was then washed with NMP (6 x 10 mL / g resin).

[0348] N-methylation (GP9)

[0349] The resin was suspended in a solution of PPh3 (0.3 M in anhydrous THF, 5.0 eq.) and MeOH (10 eq.), and the resin was shaken at room temperature for 1 min. Thereafter, DIAD (5.0 eq.) was added, and the reaction mixture was shaken at room temperature for 30 min. After repeating the above procedure, the resin was washed with NMP (6×10 mL / g resin).

[0350] Amide bond formation in solution (GP10)

[0351] To conjugate the building blocks to the unbound peptide, the carboxylic acid (1.1 eq.) was preactivated with DIPEA (3.0 eq.) as base in DMF (10 mL / g resin) using a mixture of HATU (1.1 eq.) and HOAt (1.1 eq.). After 5 min at room temperature, the mixture was added to the free amine peptide dissolved in DMF. If not otherwise specified in the respective synthetic scheme, the conjugation step was performed at room temperature for 2 h. After the reaction, the solvent was removed under reduced pressure.

[0352] Fmoc-deprotection in solution (GP11)

[0353] Unbound Fmoc-peptide was treated with 20% piperidine in DMF (v / v) for 20 min, and then the solvent was removed under reduced pressure.

[0354] Cyclization of Side-Chain Protected Peptides in Solution (GP12)

[0355] To a solution of HATU (0.1 eq.) and DIPEA (6.0 eq.) in DMF (100 μL / μmol Pep) was added dropwise Pep. (1.0 eq.) in DMF (100 μL / μmol) and HATU (3.0 eq.) in DMF (100 μL / μmol Pep) respectively under vigorous stirring. After the addition was complete, the reaction was stirred for an additional 15 minutes before the solvent was removed under reduced pressure.

[0356] Removal of Acid-Labile Side Chain Protecting Groups in Solution (GP13)

[0357] The peptide was dissolved in a solution of TFA and water (95:5) (v:v) and stirred for 1-2 hours, then the solvent was removed under a stream of nitrogen. When carrying a Trt-protecting group, a solution of TFA / H2O / TIPS (v / v / v=95:2.5:2.5) was used.

[0358] Allyl Deprotection in Solution (GP14)

[0359] The allyl protected peptide was dissolved in a mixture of phenylsilane (24 eq.) and Pd(PPh3)4 (0.1 eq.) in DCM (5 mL / g resin) and kept dark for 1 hour during the reaction at room temperature. The solvent was removed under reduced pressure. Unless otherwise stated, residual Pd that would induce additional side chain deprotection was quenched by adding TFA / H2O (v / v=95 / 5).

[0360] Acm-deprotection with disulfide bond formation (GP15)

[0361] The resin-bound Cys(Acm)-containing peptide was incubated with Tl(TFA)3 (4.0 equiv.) in DMF (8 mL / g resin). After 45 min at room temperature, the solution was discarded and the procedure was repeated once with fresh solution. The resin was then washed with DMF (6×5 mL / g resin).

[0362] 4.2.2. Synthesis of SiFA-based structural units

[0363] 4-(Di-tert-butylfluorosilyl)benzoic acid ((4-SiFA)Bz-OH)

[0364] (Prepared according to Wurzer et al. with minor modifications (5))

[0365]

[0366] ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (i)

[0367] To a stirred solution of 4-bromobenzyl alcohol (4.68 g, 25.0 mmol, 1.0 eq.) in anhydrous DMF (70 mL) was added imidazole (2.04 g, 30.0 mmol, 1.2 eq.) and TBDMSCl (4.52 g, 30.0 mmol, 1.2 eq.) and the resulting mixture was stirred at room temperature (rt) for 16 h. The mixture was then poured into ice-cold H2O (250 mL) and extracted with Et2O (5×50 mL). The combined organic portions were washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), dried, filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (silica, 5% EtOAc / petroleum ether) to give i (7.18 g, 95%) as a colorless oil. RP-HPLC (HPLC (50% to 100% B in 15 min): t R = 15 minutes. K' = 7.43.

[0368] Di-tert-butyl[4-((tert-butyldimethylsilyloxy)methyl)phenyl]fluorosilane (ii)

[0369] Under -78 ℃ of magnetic stirring, tBuLi pentane solution (7.29mL, 1.7mol / L, 12.4mmol 2.4 equivalents) was added to a dry THF (15mL) solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (i) (1.56g, 5.18mmol, 1.0 equivalents). After stirring the reaction mixture at -78 ℃ for 30 minutes, the obtained suspension was added dropwise to a cooled (-78 ℃) solution of di-tert-butyldifluorosilane (1.12g, 6.23mmol, 1.2 equivalents) in dry THF (10mL) over 30 minutes. The reaction mixture was allowed to warm to room temperature over 12 hours and then hydrolyzed with saturated aqueous NaCl solution (100mL). The organic layer was separated and the aqueous layer was extracted with ether (3×50mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a light yellow oil ii (1.88 g, 95%). It was used in the subsequent reaction without further purification. RP-HPLC (50% to 100% B in 20 min): t R = 19 minutes. K' = 9.67.

[0370] 4-(Di-tert-butylfluorosilyl)benzyl alcohol (iii)

[0371] A catalytic amount of concentrated aqueous HCl (0.5 mL) was added to a suspension of ii (1.88 g, 4.92 mmol, 1.0 equiv) in methanol (50 mL). The reaction mixture was stirred at room temperature for 18 hours, and then the solvent and volatiles were removed under reduced pressure. The residue was redissolved in ether (40 mL), and the solution was washed with saturated aqueous NaHCO3. The aqueous layer was extracted with ether (3×50 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give a light yellow oil iii (1.29 g, 98%) which solidified. The product was used without further purification. RP-HPLC (50% to 100% B in 15 minutes): t R =8.2 minutes. K' =3.61.

[0372] 4-(di-tert-butylfluorosilyl)benzoic acid ((4-SiFA)Bz-OH, iv)

[0373] At room temperature, 5.8 g KMnO4 (36.7 mmol, 1.5 eq) was dissolved in H2O and added to a solution of iii (6.61 g, 24.6 mmol, 1.0 eq), tert-butyl alcohol (65 mL), dichloromethane (9 mL) and 1.25 M NaH2PO4·H2O buffer (36 mL) at pH 4.0-4.5. After stirring the mixture for 25 minutes, it was cooled on ice for 10 minutes and then an excess of KMnO4 (7.8 g, 49.2 mmol, 2.0 eq) was added. The reaction mixture was stirred on ice for 2 hours and then warmed to room temperature for 30 minutes. The reaction was then quenched by adding a saturated Na2SO3 aqueous solution (50 mL). After the addition of a 2M HCl aqueous solution, all MnO2 dissolved. The resulting solution was extracted with ether (3×100 mL). The combined organic layers were washed with saturated aqueous NaHCO 3 solution, dried over MgSO 4 , filtered, and concentrated under reduced pressure to give a white solid, which was purified by recrystallization from Et 2 O / n-hexane (1:3, 12 h) to give iv (2.57 g, 37%). 1 H NMR (300MHz, CDCl3): δ [ppm] = 8.10 (d, 2H 3 J( 1 H, 1 H)=8.1Hz; H m ),7.74(d,2H, 3 J( 1 H, 1 H)=8.1Hz; H o ),1.07(s,18H;CCH3); 13 C{ 1 H}NMR (101MHz, DMSO-D6): δ [ppm] = 167.2 (s; COOH), 138.3 (d, 2 J( 13 C, 19 F)=14Hz; C p ),133.8(d, 3 J( 13 C, 19 F)=4Hz; C m ),132.1(s;C i ),128.3(s;C o ),26.9(s;CCH3),19.7(d, 2 J( 13 C, 19 F) = 12 Hz; CCH3); 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.2;29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.1 (d, 1 J( 19 F, 29 Si)=299Hz).RP-HPLC (50% to 100% B in 15 minutes): t R = 8.5 minutes. K' = 3.78. ESI-MS (positive): calculate the monoisotopic mass (C 15 H 23 FO2Si): ​​282.15; Found: m / z = 283.2 [M + H] + ,265.2[M-H2O+H] + .

[0374]

[0375] Route 1: Synthesis of (4-SiFA)Bz-OH(iv): a) TBDMSCl, imidazole, room temperature, 16 hours (DMF); b) tBuLi, di-tert-butyldifluorosilane, -78°C to room temperature, overnight (THF); c) HCl, room temperature, 18 hours (methanol); d) KMnO4, 0° to room temperature, 2.5 hours (DCM / tBuOH / NaH2PO4·H2O buffer).

[0376] 3-(Di-tert-butylfluorosilyl)benzoic acid ((3-SiFA)Bz-OH)

[0377]

[0378] Di-tert-butylfluoro(3-methylphenyl)silane(i)

[0379] A solution of 342mg 3-bromo-toluene (2.0mmol, 1.0 equivalent) in 6mL dry THF was cooled to -78°C, and 2.59mL tBuLi (4.40mmol, 1.6M in pentane, 2.2 equivalents) was added dropwise, and stirred at -78°C for 30 minutes. Then at -78°C, the reaction mixture was added to a 4.0mL THF solution of 397mg di-tert-butyldifluorosilane (2.20mmol, 1.1 equivalents), and stirred overnight, and allowed to warm to room temperature under pressure control. The reaction was stopped by adding 40mL saline. The aqueous layer was extracted with Et2O (3×20mL), and the combined organic phase was dried with MgSO4, and the solvent was removed under reduced pressure to obtain a yellow oily crude product. The mixture was used for the next step without further purification.

[0380] 3-(di-tert-butylfluorosilyl)benzoic acid ((3-SiFA)Bz-OH, ii)

[0381] To a solution of the complete crude product (i) (assumed: 2.0 mmol, 1.0 eq.) in 6.4 mL tBuOH / DCM (v / v=7 / 1) was added 8.1 mL NaH2PO4·H2O solution (20.0 mmol, 1.25 M in H2O, 10.0 eq.). To the solution was added 1.89 g KMnO4 (12.0 mmol, 6.0 eq.) at room temperature, the reaction was carefully heated stepwise to 75°C and stirred for 24 hours. The reaction was quenched by the addition of saturated Na2SO3 aqueous solution (15 mL). Concentrated HCl aqueous solution (5 mL) was added to completely dissolve the MnO2. The solution was extracted with Et2O (3×40 mL), the combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by HPFC and lyophilized to give 140 mg 3-(di-tert-butylfluorosilyl)benzoic acid (0.5 mmol, 25% for 2 steps) as a colorless solid. 1 H NMR (400MHz, CDCl3): δ [ppm] = 8.36 (s, 1H; H Ar-2 ),8.16(dt,1H, 3 J( 1 H, 1 H)=7.8Hz, 4 J( 1 H, 1 H)=1.6Hz; H Ar-6 ),7.86(dt,1H, 3 J( 1 H, 1 H)=7.4Hz, 4 J( 1 H, 1 H)=1.3Hz; H Ar-4 ),7.51(t,1H, 3 J( 1 H, 1 H)=7.6Hz; H Ar-5 ),1.08(s,18H;CCH3); 13 C{ 1 H}NMR (101MHz, DMSO-D6): δ [ppm] = 167.3 (s; COOH), 137.8 (d, 3 J( 13 C, 19 F)=4Hz; C Ar-4 ),134.1(d, 3 J( 13 C, 19F)=4Hz; C Ar-2 ),133.1(d, 2 J( 13 C, 19 F)=14Hz; C Ar-3 ),130.7(s;C Ar-6 ),130.1(s;C Ar-5 ),128.2(s;C Ar-1 ),26.9(s;CCH3),19.7(d, 2 J( 13 C, 19 F) = 12 Hz; CCH3); 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.3; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si)=298Hz).RP-HPLC (50% to 100% B in 15 minutes): t R = 9.2 minutes. K' = 4.17. ESI-MS (positive): calculate the monoisotopic mass (C 15 H 23 FO2Si): ​​282.15; Found: m / z = 283.3 [M + H] + , 266.3 [M–H2O+H] + .

[0382]

[0383] Route 2: Synthesis of (3-SiFA)Bz-OH (ii): a) tBu2SiF2, tBuLi, -78°C to room temperature, overnight (THF) b) KMnO4, 75°C, 24 hours (DCM / tBuOH / NaH2PO4·H2O buffer).

[0384] 3-(Di-tert-butylfluorosilyl)-5-((allyloxy)carbonyl)benzoic acid (AllO-(5-SiFA)Ip-OH)

[0385]

[0386] Di-tert-butyl(3,5-dimethylphenyl)fluorosilane(i)

[0387] A solution of 4.54 g 1-bromo-3,5-dimethylbenzene (25.1 mmol, 1.0 eq) in 73.1 mL dry THF was cooled to -78 ° C, and 34.7 mL tBuLi (55.5 mmol, 1.6 M in pentane, 2.2 eq) was added dropwise and stirred at -78 ° C for 30 minutes. The reaction mixture was then added to a solution of 5.0 g di-tert-butyldifluorosilane (27.7 mmol, 1.1 eq) in 49.1 mL THF at -78 ° C and stirred overnight while warming to room temperature under pressure control. The reaction was stopped by adding 100 mL of brine. The aqueous layer was extracted with Et2O (3×100 mL), the combined organic phases were dried with MgSO4, and the solvent was removed under reduced pressure to give 6.6 g di-tert-butyl (3,5-dimethylphenyl) fluorosilane (24.8 mmol, 99%) in the form of a colorless solid. 1 H NMR (500MHz, CDCl3): δ [ppm] = 7.19 (s, 2H; H o ),7.04(s,1H;H p ), 2.33 (s, 6H; CH3), 1.06 (s, 18H; CCH3). RP-HPLC (50% to 100% B in 15 min, 100% B in 10 min): t R = 16.4 minutes. K' = 8.21.

[0388] 5-(di-tert-butylfluorosilyl)isophthalic acid ((5-SiFA)Ip-OH, ii)

[0389] To a solution of 1.1 g of di-tert-butyl(3,5-dimethylphenyl)fluorosilane (i) (4.0 mmol, 1.0 equiv) in 16.8 mL of tBuOH / DCM (v / v=3.5 / 1) was added 16.0 mL of NaH2PO4·H2O solution (40.0 mmol, 2.5 M in H2O, 10.0 equiv). 7.6 g of KMnO4 (48.0 mmol, 12.0 equiv) was added to the solution at room temperature, and the reaction was carefully heated to 75°C stepwise and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous Na2SO3 solution (50 mL). Concentrated aqueous HCl solution (10 mL) was added to completely dissolve MnO2. The solution was extracted with Et2O (3×100 mL), the combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure to give a colorless solid ii (1.3 g, 4.0 mmol, 100%). 1 H NMR (400MHz, DMSO-D6): δppm=8.53(t,1H, 4 J( 1 H, 1 H)=1.7Hz; H Ar-2),8.32(d,2H, 4 J( 1 H, 1 H)=1.6Hz; H Ar-4,-6 ),1.03(s,18H;CH3); 13 C{ 1 H}NMR (101MHz, DMSO-D6): δ [ppm] = 166.5 (s; COOH), 137.9 (d, 3 J( 13 C, 19 F)=4Hz; C Ar-4,-6 ),134.0(d, 2 J( 13 C, 19 F)=14Hz; C Ar-5 ),131.4(s;C Ar-2 ),130.8(s;C Ar-1,-3 ),26.8(s;CCH3),19.7(d, 2 J( 13 C, 19 F) = 12 Hz; CCH3); 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.1; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si)=299Hz).RP-HPLC (50% to 100% B in 15 minutes): t R = 5.7 minutes. K' = 2.20. ESI-MS (positive): calculate the monoisotopic mass (C 16 H 23 FO4Si): 326.13; Found: m / z = 327.2 [M + H] + , 309.2[M-H2O+H] + .

[0390] 3-(di-tert-butylfluorosilyl)-5-((allyloxy)carbonyl)benzoic acid (AllO-(5-SiFA)Ip-OH, iii)

[0391] A suspension of 1.0 g 5-(di-tert-butylfluorosilyl)isophthalic acid (ii) (3.1 mmol, 1.0 eq.) and 1.3 g KCO (9.2 mmol, 3.0 eq.) in 300 mL DMF was cooled to 0 ° C, and a 10.0 mL DMF solution of 185.0 mg allyl bromide (132.0 μL, 1.5 mmol, 0.5 eq.) was slowly added over 20 minutes. The mixture was stirred at room temperature overnight. Subsequently, the mixture was filtered, and all volatiles of the filtrate were removed under reduced pressure. The residue was dissolved in 100 mL HCl (1 M), and the aqueous layer was extracted with EtO (3 × 200 mL). The combined organic phases were dried with MgSO, and the solvent was removed under reduced pressure. The crude product was purified by HPFC and freeze-dried to give a colorless solid iii (250.9 mg, 684.6 mmol, 19%). 1 H NMR (400MHz, DMSO-D6): δ [ppm] = 8.57 (t, 1H, 4 J( 1 H, 1 H)=1.5Hz; H Ar-6 ),8.36(t,1H, 4 J( 1 H, 1 H)=1.5Hz; H Ar-2 ),8.34(t,1H, 4 J( 1 H, 1 H)=1.5Hz; H Ar-4 ),6.07(ddt,1H, 3 J( 1 H, 1 H)=17.3,10.7,5.5Hz; CH2–CH=CH2),5.41(dd,1H, 3 J( 1 H, 1 H)=17.2Hz, 2 J( 1 H, 1 H)=1.7Hz; CH2–CH=CH2(E)),5.30(dd,1H, 3 J( 1 H, 1 H)=10.3Hz, 2 J( 1 H, 1 H)=1.6Hz; CH2–CH=CH2(Z)),4.85(d,2H, 3 J( 1 H, 1H)=5.6Hz; CH2–CH=CH2),1.03(s,18H;CCH3); 13 C{ 1 H}NMR (101MHz, DMSO-D6): δ [ppm] = 166.3 (COOH), 164.6 (CO-OAll), 138.3 (d, 3 J( 13 C, 19 F)=4Hz; C Ar-4 ),137.6(d, 3 J( 13 C, 19 F)=4Hz; C Ar-6 ),134.3(d, 2 J( 13 C, 19 F)=14Hz; C Ar-5 ),132.4(CH2–CH=CH2),131.2(C Ar-2 ),131.0(C Ar-1 ),129.7(C Ar-3 ),118.2(CH2–CH=CH2),65.6(CH2–CH=CH2),26.8(s;CCH3),19.7(d, 2 J( 13 C, 19 F) = 12 Hz; CCH3); 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.0; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si)=299Hz).RP-HPLC (50% to 100% B in 15 minutes): t R = 10.4 minutes. K' = 4.84.

[0392]

[0393] Route 3: Synthesis of AllO-(5-SiFA)Ip-OH (iii): a) tBu2SiF2, tBuLi, -78°C to room temperature, overnight (THF) b) KMnO4, 75°C, 24 hours (DCM / tBuOH / NaH2PO4·H2O buffer), c) Allyl-Br, K2CO3, 0°C to room temperature, overnight (DMF).

[0394] 4.2.3. Synthesis of model peptide (MP)

[0395] (4-SiFA)Bz-Gly-L-Lys-OH(1a)

[0396]

[0397] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (4-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (77%). 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.17; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.08 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (30% to 90% B in 15 minutes): t R =7.4 minutes. K' =3.16. ESI-MS (positive): calculate the monoisotopic mass (C 23 H 38 FN3O4Si): 467.26; Found: m / z = 468.4 [M+H] + .

[0398] (4-SiFA)Bz-Gly-L-Asp-OH(1b)

[0399]

[0400] 2-CTC-resin was loaded with Fmoc-L-Asp(tBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (4-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (86%). 19 F{ 29Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.17; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.08 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (30% to 90% B in 15 minutes): t R = 9.1 min. K' = 4.11. ESI-MS (positive): calculate the monoisotopic mass (C 21 H 31 FN2O6Si): 454.19; Found: m / z = 455.3 [M+H] + .

[0401] (4-SiFA)Bz-Gly-L-Tyr-OH(1c)

[0402]

[0403] 2-CTC-resin was loaded with Fmoc-L-Tyr(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (4-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (90%). 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –187.12; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (30% to 90% B in 15 minutes): t R = 10.2 minutes. K' = 4.73. ESI-MS (positive): calculate the monoisotopic mass (C 26 H 35 FN2O5Si): 502.23; Found: m / z = 503.3 [M + H] + .

[0404] (3-SiFA)Bz-Gly-L-Lys-OH(2a)

[0405]

[0406] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (3-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (95%). 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.90; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.98 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 11.3 minutes. K' = 5.35. ESI-MS (positive): calculate the monoisotopic mass (C 23 H 38 FN3O4Si): 467.26; Found: m / z = 468.5 [M+H] + .

[0407] (3-SiFA)Bz-Gly-L-Asp-OH(2b)

[0408]

[0409] 2-CTC-resin was loaded with Fmoc-L-Asp(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (3-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (79%). 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.90; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.98 (d, 1 J(19 F, 29 Si) = 298 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 10.3 minutes. K' = 4.79. ESI-MS (positive): calculate the monoisotopic mass (C 21 H 31 FN2O6Si): 454.19; Found: m / z = 455.4 [M+H] + .

[0410] (3-SiFA)Bz-Gly-L-Tyr-OH(2c)

[0411]

[0412] 2-CTC-resin was loaded with Fmoc-L-Tyr(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), (3-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid after lyophilization (77%). 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.86; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.99 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 8.8 minutes. K' = 3.94. ESI-MS (positive): calculate the monoisotopic mass (C 26 H 35 FN2O5Si): 502.23; Found: m / z = 503.8 [M + H] + .

[0413] (5-SiFA)Ip-Gly-L-Lys-OH(3a)

[0414]

[0415] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to resin-bound amino acids (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to free amines (GP2a). Allyl deprotection was performed (GP6), and the peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (25%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.66; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.96 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 9.6 minutes. K' = 4.39. ESI-MS (positive): calculate the monoisotopic mass (C 24 H 38 FN3O6Si): 511.25; measured: m / z = 512.1 [M+H] + .

[0416] (5-SiFA)Ip-Gly-L-Asp-OH(3b)

[0417]

[0418] 2-CTC-resin was loaded with Fmoc-L-Asp(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to resin-bound amino acids (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to free amines (GP2a). Allyl deprotection was performed (GP6), and the peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (38%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.65; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.94 (d, 1J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 8.6 minutes. K' = 3.83. ESI-MS (positive): calculate the monoisotopic mass (C 22 H 31 FN2O8Si): 498.18; Found: m / z = 499.1 [M+H] + .

[0419] (5-SiFA)Ip-Gly-L-Tyr-OH(3c)

[0420]

[0421] 2-CTC-resin was loaded with Fmoc-L-Tyr(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to resin-bound amino acids (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to free amines (GP2a). Allyl deprotection was performed (GP6), and the peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (18%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.62; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 13.96 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 9.6 minutes. K' = 4.39. ESI-MS (positive): calculate the monoisotopic mass (C 27 H 35 FN2O7Si): 546.22; Found: m / z = 547.0 [M+H] + .

[0422] HO-L-Lys-(5-SiFA)Ip-Gly-L-Lys-OH(4a)

[0423]

[0424] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection (GP6) was performed and HL-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid with modified GP2 (pre-activated resin-coupled peptide was incubated with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (16%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.19; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 5.7 minutes. K' = 2.20. ESI-MS (positive): calculate the monoisotopic mass (C 30 H 50 FN5O7Si): 639.35; Found: m / z = 640.6 [M+H] + .

[0425] HO-L-Lys-(5-SiFA)Ip-Gly-L-Asp-OH(4b)

[0426]

[0427] 2-CTC-resin was loaded with Fmoc-L-Asp(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection (GP6) was performed and HL-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid with modified GP2 (pre-activated resin-coupled peptide was incubated with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (21%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.22; 29 Si 1 H}INEPT NMR (79MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R = 6.6 minutes. K' = 2.71. ESI-MS (positive): calculate the monoisotopic mass (C 28 H 43 FN4O9Si): 626.28; Found: m / z = 627.5 [M+H] + .

[0428] HO-L-Lys-(5-SiFA)Ip-Gly-L-Tyr-OH(4c)

[0429]

[0430] 2-CTC-resin was loaded with Fmoc-L-Tyr(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection (GP6) was performed and HL-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid with modified GP2 (pre-activated resin-coupled peptide was incubated with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (9%) after HPFC-based purification and lyophilization. 19 F{ 29 Si}NMR (376MHz, DMSO-D6): δ [ppm] = –186.28; 29 Si 1 H}INEPTNMR (79MHz, DMSO-D6): δ [ppm] = 14.06 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20% to 90% B in 15 minutes): t R =7.3 minutes. K' =3.10. ESI-MS (positive): calculate the monoisotopic mass (C 33 H 47 FN4O8Si): 674.31; Found: m / z = 675.5 [M+H] + .

[0431] HO-L-Glu-(5-SiFA)Ip-Gly-L-Lys-OH(5a)

[0432]

[0433] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection was performed (GP6), and HL-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid using modified GP2 (pre-activated resin-coupled peptide by incubation with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (12%) after HPFC-based purification and lyophilization. RP-HPLC (20% to 90% B in 15 min): t R = 6.7 minutes. K' = 2.76. ESI-MS (positive): calculate the monoisotopic mass (C 29 H 45 FN4O9Si): 640.29; Found: m / z = 640.7 [M+H] + .

[0434] HO-L-Glu-(5-SiFA)Ip-Gly-L-Asp-OH(5b)

[0435]

[0436] 2-CTC-resin was loaded with Fmoc-L-Asp(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection (GP6) was performed and HL-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid using modified GP2 (pre-activated resin-coupled peptide by incubation with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (23%) after HPFC-based purification and lyophilization. RP-HPLC (20% to 90% B in 15 min): t R= 7.5 minutes. K' = 3.21. ESI-MS (positive): calculate the monoisotopic mass (C 27 H 38 F3O 11 Si): 627.23; Found: m / z = 627.7 [M + H] + .

[0437] HO-L-Glu-(5-SiFA)Ip-Gly-L-Tyr-OH(5c)

[0438]

[0439] 2-CTC-resin was loaded with Fmoc-L-Tyr(OtBu)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection (GP6) was performed and HL-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid using modified GP2 (pre-activated resin-coupled peptide by incubation with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (15%) after HPFC-based purification and lyophilization. RP-HPLC (20% to 90% B in 15 min): t R = 8.3 minutes. K' = 3.66. ESI-MS (positive): calculate the monoisotopic mass (C 32 H 42 F3O 10 Si): 675.26; Found: m / z = 675.7 [M + H] + .

[0440] (5-SiFA)Ip-L-Lys-Gly-OH(3a*)

[0441]

[0442] 2-CTC-resin was loaded with Fmoc-Gly-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-L-Lys(Boc)-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection was performed (GP6), the peptide was cleaved from the resin with concomitant deprotection (GP5a), and isolated as a colorless solid (26%) after RP-HPLC-based purification and lyophilization. RP-HPLC (20% to 90% B in 15 minutes): t R =7.6 minutes. K' =3.27. ESI-MS (positive): calculate the monoisotopic mass (C 24 H 38 FN3O6Si): 511.25; Found: m / z = 511.6 [M + H] + .

[0443] HOOC-PEG8-(5-SiFA)Ip-Gly-L-Lys-OH(6a)

[0444]

[0445] To prepare the model peptide 6a, a combined liquid and solid phase peptide synthesis strategy was used. First, the dipeptide H-Gly-L-Lys(Boc)-OtBu·TFA was synthesized by pre-activating 178 mg Fmoc-Gly-OH (0.6 mmol, 1.2 eq.) with 82 mg HOAt (0.6 mmol, 1.2 eq.), 228 mg HATU (0.6 mmol, 1.2 eq.) and adding 510 μL DIPEA (3.0 mmol, 5.0 eq.) in 5 mL DMF. After 15 min at room temperature, 1 mL of a DMF solution of 169 mg HL-Lys(Boc)-OtBu (0.5 mmol, 1.0 eq.) was added and stirred at room temperature for 4 h. For subsequent Fmoc-deprotection with 30 vol. % piperidine in DMF, 2.5 mL piperidine was added to the solution. After 30 min, the solvent was removed under reduced pressure at 60°C. HPFC purification and subsequent lyophilization of the dipeptide gave 184 mg of a colorless solid (78%). RP-HPLC (10% to 90% B in 15 min): t R = 8.9 minutes. K' = 4.00. ESI-MS (positive): calculate the monoisotopic mass (C 17 H 33 N3O5): 359.24; Found: m / z = 359.8 [M+H] + .

[0446] 2-CTC-resin was loaded with Fmoc-NH-PEG8-CH2-CH2-COOH (GP1a). After Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection was performed (GP6), and H-Gly-L-Lys(Boc)-OtBu·TFA was coupled to the deprotected carboxylic acid with modified GP2 (pre-activated resin-coupled peptide was incubated with HOAt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (6.0 eq.) in DMF for 20 min, followed by addition of amino acids dissolved in DMF (1.5 eq.) at room temperature). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (25%) after RP-HPLC-based purification and lyophilization. RP-HPLC (20% to 90% B in 15 min): t R = 7.5 minutes. K' = 3.21. ESI-MS (positive): calculate the monoisotopic mass (C 43 H 75 FN4O 15 Si): 934.50; Found: m / z = 934.4 [M + H] + .

[0447] Gal6N-(5-SiFA)Ip-Gly-L-Lys-OH(7a)

[0448]

[0449] 2-CTC-resin was loaded with Fmoc-L-Lys(Boc)-OH (GP1a). After Fmoc-deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After another Fmoc-deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection was performed (GP6), and for the next coupling step, a modified version of GP2 was used, pre-activating the resin-coupled peptide by incubation with HOAt (1.5 eq.), TBTU (1.5 eq.), and DIPEA (6.0 eq.) in DMF for 20 min, followed by the addition of 6-amino-6-deoxy-1,2;3,4-di-O-isopropylidene-D-galactopyranoside (1.5 eq.) dissolved in DMF at room temperature. The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (17%) after RP-HPLC based purification and lyophilization. RP-HPLC (20% to 90% B in 15 min): t R = 5.8 minutes. K' = 2.26. ESI-MS (positive): calculate the monoisotopic mass (C 30H 49 FN4O 10 Si): 672.32; Found: m / z = 672.8 [M+H] + .

[0450] 4.2.4. Synthesis of support-based ligands

[0451] Synthesis of GRPR ligands

[0452] Fmoc-D-Dap(NH2)-EDA-DOTA(tBu)2-[α-Me-Trp 8 ]MJ9(PG)(1)

[0453]

[0454] All GRPR targeting compounds were purified by standard Fmoc-based SPPS (GP1b, GP2a, GP3) using H-Rink amide Resin (35-100 mesh particle size, 0.4-0.6mmol / g loading) synthesis. According to GP1b, Fmoc-L-Leu-OH loaded resin. Subsequently, amino acids Fmoc-Sta-OH, Fmoc-L-His (Trt) -OH, Fmoc-Gly-OH, Fmoc-L-Val-OH, Fmoc-L-Ala-OH, Fmoc-a-Me-L-Trp (Boc) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-D-Phe-OH and Fmoc-4-APipAc-OH were alternately coupled (GP2a) and Fmoc-deprotection (GP3). DOTA-di (tBu) -OH was coupled to resin according to GP2a. Fmoc-EDA-NH2 was coupled similarly to GP2b, and Fmoc-deprotection was carried out according to GP3. Fmoc-D-Dap(Dde)-OH was coupled on the resin (GP2a) using 2,4,6-trimethylpyridine (6.0 equiv) as a preactivated base. The side chain was Dde-deprotected (GP4b) while retaining Fmoc to complete the resin-bound precursor for the synthesis of the following GRPR ligands.

[0455] DOTAGA-D-Dap[(4-SiFA)Bz]-EDA-DOTA-[α-Me-Trp 8 ]MJ9(2)

[0456]

[0457] (4-SiFA)Bz-OH was coupled to the unprotected Dap-side chain. Subsequently, the Fmoc protecting group was removed (GP3) and DOTAGA(tBu)4 was coupled at room temperature for an extended time of 6 hours (modified GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (8%) after HPLC-based purification and lyophilization. RP-HPLC (10% to 90% B in 15 minutes): t R = 11.6 minutes. K' = 6.25. ESI-MS (positive): calculate the monoisotopic mass (C 118 H 183 FN 28 O 29 Si): 2505.0; Found: m / z = 1253.7 [M + 2H] 2+ ,836.3[M+3H] 3+ ,627.5[M+4H] 4+ .

[0458] DOTAGA-D-Dap[(3-SiFA)Bz]-EDA-DOTA-[α-Me-Trp 8 ]MJ9(3)

[0459]

[0460] (3-SiFA)Bz-OH was coupled to the unprotected Dap-side chain. Subsequently, the Fmoc protecting group was removed (GP3) and DOTAGA(tBu)4 was coupled for an extended time of 6 hours at room temperature (modified GP2a). The peptide was cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (7%) after HPLC-based purification and lyophilization. RP-HPLC (10% to 90% B in 15 minutes): t R = 11.3 minutes. K' = 6.06. ESI-MS (positive): calculated monoisotopic mass (C 118 H 183 FN 28 O 29 Si): 2505.0; Found: m / z = 836.3 [M + 3H] 3+ 、627.5[M+4H] 4+ .

[0461] DOTAGA-D-Dap[(5-SiFA)Ip]-EDA-DOTA-[α-Me-Trp 8 ]MJ9(4)

[0462]

[0463] AllO-(5-SiFA)Ip-OH was coupled to the unprotected Dap-side chain. Subsequently, the Fmoc protecting group was removed (GP3) and DOTAGA(tBu)4 was coupled at room temperature for an extended period of 6 hours (modified GP2a). The peptide was allyl deprotected (GP6), cleaved from the resin with concomitant deprotection (GP5a), and isolated as a colorless solid (5%) after HPLC-based purification and lyophilization. RP-HPLC (10% to 90% B in 15 minutes): t R = 10.6 min. K' = 5.63. ESI-MS (positive): calculate the monoisotopic mass (C 119 H 183 FN 28 O 31 Si): 2549.0; Found: m / z = 851.0 [M + 3H] 3+ 、638.5[M+4H] 4+ .

[0464] Synthesis of CXCR4 ligands

[0465] CPCR4(Circle[Gly-L-2Nal-L-Arg-N(Me)-D-Orn-D-Tyr])(1)

[0466]

[0467] 1 was synthesized using solid phase peptide synthesis according to the general procedure (GP). In short, Fmoc-Gly-OH was loaded on the resin (GP1a) and Fmoc was deprotected (GP3). Continuously, Fmoc-L-2Nal-OH, Fmoc-L-Arg(Pbf)-OH and Fmoc-D-Orn(Boc)-OH were coupled alternately according to the coupling steps of GP2a and the Fmoc-deprotection steps of GP3. p-Nosyl protection was performed according to GP7-9, followed by N-methylation and p-Nosyl deprotection. Fmoc-D-Tyr(tBu)-OH was coupled and Fmoc-deprotected according to GP2a and GP3. Similar to GP5b, the resin was cleaved while retaining the protecting group. In the last step, the peptide was cyclized (GP12) and the side chain was deprotected (GP13). 1 was obtained as a colorless solid (68.3%) and was used without further purification. RP-HPLC (10% to 90% B in 15 min): t R = 6.2 minutes, K' = 1.48. ESI-MS (positive): calculate the monoisotopic mass (C 36 H 47 N9O6): 701.36; Found: m / z = 702.6 [M + H] + .

[0468] H2N-Amba-CPCR4(2)

[0469]

[0470] Fmoc-Amba-OH was coupled to 1 according to GP10. After completion of the reaction, the solvent was removed under reduced pressure and Fmoc-deprotection was performed according to GP11. 2 was obtained after HPFC purification and lyophilization as a colorless solid (38%). RP-HPLC (10% to 90% B in 15 min): t R = 6.3 minutes, K' = 1.86. ESI-MS (positive): calculate the monoisotopic mass (C 44 H 54 N 10 O7): 834.42; Found: m / z = 835.4 [M+H] + .

[0471] (4-SiFA)Bz-EDA-DOTA(tBu)2-OH(3)

[0472]

[0473] DOTA-di(tBu)-OH was coupled to the resin as GP1c. Fmoc-EDA-NH2 was coupled analogously to GP2b and Fmoc-deprotected as GP3. (4-SiFA)Bz-OH was coupled as GP2a and cleaved from the resin with the protecting groups retained (GP5b). 3 was obtained after HPFC purification and lyophilization as a colorless solid (36%). RP-HPLC (10% to 90% B in 15 min): t R = 11.8 minutes, K' = 4.13. ESI-MS (positive): calculate the monoisotopic mass (C 41 H 71 FN6O8Si): 822.51; Found: m / z = 823.7 [M+H] + .

[0474] AllO-(5-SiFA)Ip-EDA-DOTA(tBu)2-OH(4)

[0475]

[0476] DOTA-di(tBu)-OH was coupled to the resin as GP1c. Fmoc-EDA-NH2 was coupled similarly to GP2b and Fmoc-deprotected as GP3. AllO-(5-SiFA)Ip-OH was coupled as GP2a and cleaved from the resin with the protecting groups retained (GP5b). After HPFC purification and lyophilization, 4 was obtained as a colorless solid (23%). RP-HPLC (10% to 90% B in 15 minutes): t R = 12.5 minutes, K' = 4.00. ESI-MS (positive): calculate the monoisotopic mass (C 45 H 75 F6O 10 Si): 906.53; Found: m / z = 907.6 [M + H] + .

[0477] (4-SiFA)Bz-EDA-DOTA-Amba-CPCR4(5)

[0478]

[0479] 2 was coupled to 3 according to GP10 and side chain deprotection was performed according to GP13. 5 was obtained after purification by RP-HPLC and lyophilization as a colorless solid (40%). RP-HPLC (10% to 90% B in 15 min): t R = 9.80 min, k' = 3.08. ESI-MS (positive): calculate the monoisotopic mass (C 77 H 107 FN 16 O 14 Si): 1526.79; Found: m / z = 1528.7 [M + H] + ,764.8[M+2H] 2+ .

[0480] (5-SiFA)Ip-EDA-DOTA-Amba-CPCR4(6)

[0481]

[0482] 2 was coupled with 4 according to GP10, followed by allylic and side chain deprotection according to GP14 and GP13, respectively. 6 was obtained after RP-HPLC purification and lyophilization as a colorless solid (19%). RP-HPLC (10% to 90% B in 15 min): t R = 9.00 min, K' = 3.09. ESI-MS (positive): calculate the monoisotopic mass (C 78 H 107 FN16 O16Si): 1570.78; Found: m / z = 1572.2 [M+H] + ,786.9[M+2H] 2+ .

[0483] Synthesis of SSTR ligands

[0484] Fmoc-D-Phe-cyclo[L-Cys-L-Tyr(tBu)-D-Trp(Boc)-L-Lys(Boc)-L-Thr(tBu)-L-Cys]-L-Thr(tBu)-2-CTC resin

[0485] (Fmoc-TATE(PG)-2-CTC resin)(1)

[0486]

[0487] The syntheses of all SSTR ligands described in this article started from the same resin-bound precursor, H-TATE(PG)-2-CTC resin. In the first step, 2-CTC resin was loaded with Fmoc-L-Thr(tBu)-OH (GP1a). Subsequently, peptide scaffolds were constructed by alternately coupling the corresponding Fmoc-protected amino acids (GP2a), namely Fmoc-L-Cys(Acm)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-D-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Cys(Acm)-OH and Fmoc-D-Phe-OH, and their consecutive Fmoc-deprotection (GP3). The linear peptide sequence, which was fully protected so far, was Acm-deprotected and cyclized (GP15). To confirm the identity of the precursor, a small portion of the resin sample was treated according to GP5a. RP-HPLC (10% to 90% B in 15 min): t R = 10.8 min. K' = 5.07. ESI-MS (positive): Fmoc-D-Phe-cyclo[L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys]-L-Thr-OH (C 64 H 74 N 10 O 14 Calculated monoisotopic mass of S2): 1270.5; Measured: m / z = 1273.4 [M+H] + .

[0488] (4-SiFA)Bz-EDA-DOTATATE(2)

[0489]

[0490] The resin (1) loaded with Fmoc-TATE (PG) was treated according to GP3 for Fmoc-deprotection. DOTA (tBu) 2 was coupled to the resin according to GP2a. Fmoc-EDA-NH 2 was coupled similarly to GP2b and Fmoc-deprotection was performed according to GP3. (4-SiFA) Bz-OH was coupled according to GP2a and the peptide was cleaved from the resin with concomitant cleavage of the acid-labile protecting group (GP5a). The product was obtained after RP-HPLC purification and lyophilization as a colorless solid (5%). RP-HPLC (10% to 90% B in 15 minutes): t R = 9.8 minutes, K' = 3.00. ESI-MS (positive): calculate the monoisotopic mass (C 82 H 117 FN 16 O 19 S2Si): ​​1740.8; Found: m / z = 1741.9 [M+H] + ,871.2[M+2H] 2+ ,581.2[M+3H] 3+ .

[0491] (4-SiFA)Bz-D-Dap(DOTATATE)(3)

[0492]

[0493] The resin (1) loaded with Fmoc-TATE (PG) was treated for Fmoc-deprotection according to GP3. DOTA (tBu) 2 was coupled to the resin according to GP2a. Fmoc-D-Dap-OtBu HCl was coupled analogously to GP2b and Fmoc-deprotection was carried out according to GP3. (4-SiFA) Bz-OH was coupled according to GP2a and the peptide was cleaved from the resin with concomitant cleavage of the acid-labile protecting group (GP5a). The product was obtained after RP-HPLC purification and lyophilization as a colorless solid (8%). RP-HPLC (10% to 90% B in 15 minutes): t R = 9.7 minutes, K' = 2.96. ESI-MS (positive): calculate the monoisotopic mass (C 83 H 117 FN 16 O 21 S2Si): ​​1784.8; Found: m / z = 1786.8 [M+H] + ,892.9[M+2H] 2+ .

[0494] (5-SiFA)Ip-EDA-DOTATATE(4)

[0495]

[0496] The resin (1) loaded with Fmoc-TATE (PG) was treated according to GP3 for Fmoc-deprotection. DOTA (tBu) 2 was coupled to the resin according to GP2a. Fmoc-EDA-NH 2 was coupled similarly to GP2b and Fmoc-deprotection was carried out according to GP3. (5-SiFA) Ip-OH was coupled according to GP2a. The peptide was allyl deprotected (GP6) and cleaved from the resin with concomitant cleavage of the acid-labile protecting group (GP5a). The product was obtained after RP-HPLC purification and lyophilization as a colorless solid (4%). RP-HPLC (10% to 90% B in 15 minutes): t R = 9.1 minutes, K' = 2.71. ESI-MS (positive): calculate the monoisotopic mass (C 83 H 117 FN 16 O 21 S2Si): ​​1784.8; Found: m / z = 1787.4 [M+H] + ,894.1[M+2H] 2+ .

[0497] (5-SiFA)Ip-D-Dap(DOTATATE)(5)

[0498]

[0499] The resin (1) loaded with Fmoc-TATE(PG) was treated for Fmoc-deprotection according to GP3 and DOTA(tBu)2 was coupled to the resin according to GP2a. Fmoc-D-Dap-OtBu·HCl was coupled analogously to GP2b and Fmoc-deprotection was carried out according to GP3. (5-SiFA)Ip-OH was coupled according to GP2a. The peptide was allyl deprotected (GP6) and cleaved from the resin with concomitant cleavage of the acid-labile protecting group (GP5a). The product was obtained after RP-HPLC purification and lyophilization as a colorless solid (9%). RP-HPLC (10% to 90% B in 15 minutes): t R = 9.0 min, K' = 2.67. ESI-MS (positive): calculate the monoisotopic mass (C 84 H 117 FN 16 O 23 S2Si): ​​1828.8; Found: m / z = 1832.0 [M+H] +,915.9[M+2H] 2+ ,611.0[M+3H] 3+ .

[0500] Synthesis of CCK-2R ligand

[0501] Fmoc-D-Dap-D-Glu(tBu)-L-Ala-L-Tyr(tBu)-Gly-L-Trp(Boc)-L-Nle-L-Asp(tBu)-L-1-Nal-NH2(1)

[0502]

[0503] 1 was synthesized using solid phase peptide synthesis following the general procedure (GP). Briefly, Fmoc-L-1-Nal-OH was coupled to preloaded H-Rink amide resin (GP1b) followed by Fmoc-deprotection (GP3). Then, Fmoc-L-Asp(tBu)-OH and Fmoc-L-Nle-OH were coupled accordingly (GP2a) and after each coupling step, the Fmoc-protecting group was cleaved (GP3). The free N-terminus of Nle was p-Nosyl protected (GP7), N-methylated (GP9) and p-Nosyl deprotected (GP8). Then, according to GP2a, Fmoc-L-Trp(Boc)-OH, Fmoc-Gly-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Ala-OH and Fmoc-D-glu(tBu)-OH were coupled, followed by Fmoc-deprotection (GP3), respectively. Fmoc-D-dap(Dde)-OH was coupled to the free amine using 2,4,6-trimethylpyridine as a base (GP2a), followed by Dde-deprotection and Fmoc-retention (GP4b). The resin-bound peptides were used for synthesis without further purification and analysis.

[0504] DOTA-rhCCK-52(DOTA-D-Dap[(4-SiFA)Bz]-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-1-Nal)(2)

[0505]

[0506] (4-SiFA)Bz-OH was coupled to 1 (GP2a), the Fmoc-protecting group was cleaved (GP3), and DOTA(tBu)3 was coupled (GP2a). The peptide was then cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (6%) after RP-HPLC-based purification and lyophilization. RP-HPLC (10% to 70% B in 15 min): t R = 14.5 minutes, K' = 6.25. ESI-MS (positive): calculate the monoisotopic mass (C 88 H 119 FN 16 O 22 Si): 1800.1; Found: m / z = 1800.3 [M + H] + ,900.3[M+2H] 2+ .

[0507] DOTA-rhCCK-53(DOTA-D-Dap[(3-SiFA)Bz]-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-1-Nal)(3)

[0508]

[0509] (3-SiFA)Bz-OH was coupled to 1 (GP2a), the Fmoc-protecting group was cleaved (GP3), and DOTA(tBu)3 was coupled (GP2a). The peptide was then cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (9%) after RP-HPLC-based purification and lyophilization. RP-HPLC (10% to 70% B in 15 min): t R = 14.3 minutes, K' = 6.15. ESI-MS (positive): calculate the monoisotopic mass (C 88 H 119 FN 16 O 22 Si): 1800.1; Found: m / z = 1800.5 [M + H] + ,900.3[M+2H] 2+ .

[0510] DOTA-rhCCK-54(DOTA-D-Tap[(5-SiFA)Ip]-D-glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-1-Nal)(4)

[0511]

[0512] AllO-(5-SiFA)Ip-OH was conjugated to 1 (GP2a), the Fmoc-protecting group was cleaved (GP3), DOTA(tBu)3 was coupled (GP2a), and the allyl-protecting group was cleaved (GP6). The peptide was then cleaved from the resin with concomitant deprotection (GP5a) and isolated as a colorless solid (5%) after RP-HPLC-based purification and lyophilization. RP-HPLC (10% to 70% B in 15 min): t R = 13.6 minutes, K' = 5.80. ESI-MS (positive): calculate the monoisotopic mass (C 88 H 119 FN 16 O 22 Si): 1800.1; Found: m / z = 1845.1 [M + H] + ,923.0[M+2H] 2+ .

[0513] Synthesis of PSMA ligand

[0514] (S)-5-(tert-Butoxy)-4-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopentanoic acid ((tBuO)EuE(OtBu)2) (prepared according to Wurzer et al. (5))

[0515]

[0516] (1H-imidazole-1-carbonyl)-L-glutamic acid di-tert-butyl ester (i)

[0517] A solution of 2.0 g (7.71 mmol, 1.0 eq.) of di-tert-butyl L-glutamic acid ester hydrochloride in 20 mL of DCM was cooled on ice for 30 min and then treated with 2.69 mL of TEA (19.28 mmol, 2.5 eq.) and 3.3 mg (0.3 mmol, 0.04 eq.) of DMAP. After stirring for an additional 5 min, 1.38 g (8.84 mmol, 1.1 eq.) of 1,1'-carbonyldiimidazole (CDI) dissolved in DCM was slowly added over 30 min. The reaction mixture was further stirred overnight and warmed to room temperature. The reaction was stopped with 8 mL of saturated NaHCO3, and washing steps with water (2×30 mL) and brine (2×30 mL) were performed simultaneously and dried over Na2SO4. The remaining solvent was removed in vacuo, and the crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamido)pentanedioate (i) was used without further purification.

[0518] 5-Benzyl-1-(tert-butyl)(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-glutamate (ii)

[0519] 2.72 g (7.71 mmol, 1.0 eq.) of crude product (S)-2-(1H-imidazole-1-carboxamido)pentanedioic acid di-tert-butyl ester (i) was dissolved in 20 mL of 1,2-dichloroethane (DCE) and cooled on ice for 30 minutes. 2.15 mL (15.42 mmol, 2.0 eq.) of TEA and 2.54 g (7.71 mmol, 1.0 eq.) of HL-Glu(OBzl)-OtBu·HCl were added to the solution, and the solution was stirred at 40°C overnight. The remaining solvent was evaporated, and the crude product was purified by flash chromatography on silica gel, with an eluent mixture containing ethyl acetate / hexane / TEA (v / v / v=500:500:0.8). After removal of the solvent, 5-benzyl-1-(tert-butyl)-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-glutamate (ii) was obtained as a colorless oil.

[0520] (tBuO)EuE(OtBu)2(iii)

[0521] To synthesize (tBuO)EuE(OtBu)2, 3.17 g (5.47 mmol, 1.0 eq) of 5-benzyl-1-(tert-butyl)-(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-glutamate (ii) was dissolved in 75 mL of ethanol and to this solution was added 0.34 g (0.57 mmol, 0.1 eq) of palladium on activated carbon (10%). The flask containing the reaction mixture was first purged with H2 and the solution was stirred at room temperature under light H2 pressure (balloon) overnight. The crude product was filtered through celite and the solvent was evaporated in vacuo. The product (iii) was obtained as a hygroscopic solid (84%). RP-HPLC (10% to 90% B in 15 min): t R = 11.3 minutes. ESI-MS (positive): calculate the monoisotopic mass (C 23 H 40 N2O9): 488.3; Found: m / z = 489.4 [M+H] + ,516.4[M+Na] + .

[0522]

[0523] Route 4: Synthesis of (tBuO)EuE(OtBu)2: a) DCI, TEA, DMAP, 0°C to room temperature, overnight (DCM); b) HL-Glu(OBzl)-OtBu·HCl, TEA, 0°C to 40°C, overnight (DCE); c) Pd / C (10%), H2, room temperature, overnight (EtOH).

[0524] (tBuO)KuE(OtBu)2 (prepared according to Weineisen et al. (6))

[0525]

[0526] 6-(Benzyloxy)carbonyl-1-(tert-butyl)(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-lysine ester (i)

[0527] 2.72 g (7.71 mmol, 1.0 eq.) of crude product (S)-2-(1H-imidazole-1-carboxamido)pentanedioic acid di-tert-butyl ester (see Synthesis of (tBuO)EuE(OtBu)2) was dissolved in 20 mL of 1,2-dichloroethane (DCE) and cooled on ice for 30 minutes. To the solution were added 2.15 mL (15.42 mmol, 2.0 eq.) of TEA and 2.87 g (7.71 mmol, 1.0 eq.) of HL-Lys(Z)-OtBu·HCl, and the solution was stirred at 40°C overnight. The remaining solvent was evaporated and the crude product was purified by flash chromatography on silica gel with an eluent mixture containing ethyl acetate / hexane / TEA (v / v / v=500:500:0.8). After removal of the solvent, a colorless oil (i) was obtained.

[0528] (tBuO)KuE(OtBu)2(ii)

[0529] To synthesize (tBuO)KuE(OtBu)2, 3.40 g (5.47 mmol, 1.0 eq) of (i) was dissolved in 75 mL of ethanol and 0.34 g (0.57 mmol, 0.1 eq) of palladium on activated carbon (10%) was added to the solution. The flask containing the reaction mixture was first purged with H2 and the solution was stirred overnight at room temperature under light H2 pressure (balloon). The crude product was filtered through celite and the solvent was evaporated in vacuo. The product (ii) was obtained as a hygroscopic solid (92%). RP-HPLC (10% to 90% B in 15 min): t R = 12.6 minutes. K' = 6.41. ESI-MS (positive): calculate the monoisotopic mass (C 24 H 45 N3O7): 487.6; Found: m / z = 488.3 [M + H]+ ,510.3[M+Na] + .

[0530]

[0531] Route 5: Synthesis of (tBuO)KuE(OtBu)2: a) HL-Lys(Z)-OtBu·HCl, TEA, 0°C to 40°C, overnight (DCE); b) Pd / C (10%), H2, room temperature, overnight (EtOH).

[0532] PSMA-1(1)

[0533]

[0534] (4-SiFA)Bz-OH (4.2 mg, 14.9 μmol, 1.0 eq.) was pre-activated with HOAt (2.0 mg, 14.9 μmol, 1.0 eq.), TBTU (4.8 mg, 14.9 μmol, 1.0 eq.) and DIPEA (4.5 eq.) in 1 mL DMF for 15 min at room temperature. For coupling, 500 μL of a DMF solution of (tBuO)KuE(OtBu)2 (1.0 eq.) was added to the pre-activated SiFA-building block and stirred at room temperature for 2 h. Next, the solvent was evaporated under reduced pressure at 60 °C. The residue was dissolved in 1 mL TFA / TIPS / DCM (v / v / v=95:2.5:2.5) and reacted at room temperature for 1 h. Subsequently, the volatiles were removed under a stream of nitrogen, and the dried crude product was purified by RP-HPLC and lyophilized to give a colorless solid (3.24 mg, 5.55 mmol, 37%). RP-HPLC (10% to 70% B in 15 min): t R = 11.7 minutes. K' = 5.57. ESI-MS (positive): calculate the monoisotopic mass (C 27 H 42 FN3O8Si): 583.3; Found: m / z = 583.8 [M+H] + .

[0535] PSMA-2

[0536]

[0537] (3-SiFA)Bz-OH (4.2 mg, 14.9 μmol, 1.0 equiv) was pre-activated for 15 minutes at room temperature with HOAt (2.0 mg, 14.9 μmol, 1.0 equiv), TBTU (4.8 mg, 14.9 μmol, 1.0 equiv) and DIPEA (4.5 equiv) in 1 mL DMF. For coupling, 500 μL of a DMF solution of (tBuO)KuE(OtBu)2 (1.0 equiv) was added to the pre-activated SiFA-building block and stirred at room temperature for 2 hours. Next, the solvent was evaporated under reduced pressure at 60 °C. The residue was dissolved in 1 mL TFA / TIPS / DCM (v / v / v=95:2.5:2.5) and reacted at room temperature for 1 hour. Subsequently, the volatiles were removed under a stream of nitrogen and the dried crude product was purified by RP-HPLC and lyophilized to give a colorless solid (7.92 mg, 13.57 μmol, 91%). RP-HPLC (10% to 70% B in 15 min): t R = 11.5 minutes. K' = 5.46. ESI-MS (positive): calculate the monoisotopic mass (C 27 H 42 FN3O8Si): 583.3; Found: m / z = 584.4 [M+H] + .

[0538] PSMA-3

[0539]

[0540] 2-CTC resin was loaded with Fmoc-L-Lys(Dde)-OH (GP1). The resin-bound amino acid was Fmoc-deprotected (GP3). According to GP7, a urea bond was formed on the resin with (S)-2-(1H-imidazole-1-carbamoyl)pentanedioic acid di-tert-butyl ester. The Lys-side chain was Dde-deprotected (GP4a) and AllO-(5-SiFA)Ip-OH was coupled (GP2a). The peptide was allyl deprotected (GP6) and then cleaved from the resin with deprotection of the acid-labile protecting group (GP5a). The cleaved dry crude product was purified by RP-HPLC and lyophilized to give a colorless solid (41%). RP-HPLC (10% to 70% B in 15 minutes): t R = 10.0 min. K' = 4.62. ESI-MS (positive): calculate the monoisotopic mass (C 28 H 42 F3O 10 Si): 627.3; Found: m / z = 627.8 [M+H] + .

[0541] rhPSMA-7.3

[0542]

[0543] The reference ligand rhPSMA-7.3 was prepared according to a published protocol (5). RP-HPLC (10% to 70% B in 15 min): t R = 10.0 min. K' = 4.67. ESI-MS (positive): calculate the monoisotopic mass (C 63 H 99 FN 12 O 25 Si): 1470.7; Found: m / z = 1471.4 [M+H] + ,736.7[M+2H] 2+ .

[0544] 4.3. Synthesis of cold metal complexes

[0545] 4.3.1. nat Ga-complex

[0546] nat Ga-SSTR ligand

[0547] SSTR ligand nat Ga complexation: Purified SSTR ligand containing chelator (2 mM in DMSO, 1.0 equiv) and nat Ga(NO3)3(20mM in H2O, 3.0 equivalents) The mixture was diluted with H2O to a final concentration of 1 mM and heated to 70°C for 1 hour. After cooling, the mixture was confirmed by RP-HPLC / ESI-MS. nat Formation of Ga chelates.

[0548] nat Ga-(4-SiFA)Bz-EDA-DOTATATE: RP-HPLC (10% to 90% B in 15 min): t R = 12.8 minutes, K' = 4.22. ESI-MS (positive): calculate the monoisotopic mass (C 82 H 115 FGaN 16 O 19 S2Si): ​​1808.1; Found: m / z = 1809.1 [M+H] + ,1206.7[2M+3H] 3+ ,904.7[M+2H] 2+ .

[0549] natGa-(4-SiFA)Bz-D-Tap(DOTATATE): RP-HPLC (10% to 90% B in 15 min): t R = 10.1 min, K' = 3.12. ESI-MS (positive): calculate the monoisotopic mass (C 83 H 115 FGaN 16 O 21 S2Si): ​​1852.2; Found: m / z = 1853.2 [M + H] + ,1235.3[2M+3H] 3+ ,927.0[M+2H] 2+ .

[0550] nat Ga-(5-SiFA)Ip-EDA-DOTATATE: RP-HPLC (10% to 90% B in 15 min): t R = 9.6 minutes, K' = 3.00. ESI-MS (positive): calculate the monoisotopic mass (C 83 H 115 FGaN 16 O 21 S2Si): ​​1851.6; Found: m / z = 1854.2 [M+H] + ,1236.6[2M+3H] 3+ ,927.3[M+2H] 2+ .

[0551] nat Ga-(5-SiFA)Ip-D-Dap(DOTATATE): RP-HPLC (10% to 90% B in 15 min): t R = 9.5 minutes, K' = 2.96. ESI-MS (positive): calculate the monoisotopic mass (C 84 H 115 FGaN 16 O 23 S2Si): ​​1895.7; Found: m / z = 1897.6 [M+H] + ,949.7[M+2H] 2+ .

[0552] nat Ga-CXCR4 ligand

[0553] nat Ga-(4-SiFA)Bz-EDA-DOTA-Amba-CPCR4: RP-HPLC (10% to 60% B in 15 min): t R= 14.4 minutes, K' = 5.26. ESI-MS (positive): calculate the monoisotopic mass (C 77 H 107 FGaN 16 O 14 Si): 1595.7; Found: m / z = 798.6 [M + 2H] 2+ .

[0554] nat Ga-(4-SiFA)Bz-EDA-DOTA-Amba-CPCR4: RP-HPLC (10% to 60% B in 15 min): t R = 13.8 minutes, K' = 5.00. ESI-MS (positive): calculate the monoisotopic mass (C 78 H 105 FGaN 16 O 16 Si): 1637.7; Found: m / z = 820.3 [M + 2H] 2+ .

[0555] 4.3.2. nat Lu-complex

[0556] nat Lu-GRPR ligand

[0557] GRPR ligands nat Lu complexation: The purified GRPR ligand containing the chelating agent (in 10 in H2O -3 M, 1.0 equivalent) and nat LuCl3 (in 20 mM in H2O, 2.5 equivalents) Dilute with H2O to a final concentration of 10 -4 M and heated to 95°C for 30 minutes. After cooling, the nat Formation of Lu chelates.

[0558] nat Lu-DOTAGA-D-Dap((4-SiFA)Bz)EDA-transDOTA-[α-Me-Trp 8 ]MJ9: RP-HPLC (10% to 90% B in 15 min): t R = 11.4 minutes, K' = 6.13. ESI-MS (positive): calculate the monoisotopic mass (C 118 H 180 FWf 28 O 29Si): 2677.0; Found: m / z = 951.0 [M + Lu + 3H] 3+ .

[0559] nat Lu-DOTAGA-D-Dap((3-SiFA)Bz)EDA-transDOTA-[α-Me-Trp 8 ]MJ9: RP-HPLC (10% to 90% B in 15 min): t R = 11.2 minutes, K' = 6.00; ESI-MS (positive): calculate the monoisotopic mass (C 118 H 180 FWf 28 O 29 Si): 2677.0; Found: m / z = 951.0 [M + Lu + 3H] 3+ .

[0560] nat Lu-DOTAGA-D-Dap((5-SiFA)Ip)EDA-transDOTA-[α-Me-Trp 8 ]MJ9: RP-HPLC (10% to 90% B in 15 min): t R = 10.5 min, K' = 5.56; ESI-MS (positive): calculate the monoisotopic mass (C 119 H 180 FWf 28 O 31 Si): 2721.0; Found: m / z = 965.5 [M + Lu + 3H] 3+ .

[0561] nat Lu-CCK-2R ligand

[0562] CCK-2R ligands nat Lu complexation: the response of CCK-2R ligands nat The Lu complex was prepared by dissolving 2 mM of the ligand (1.0 equivalent) in DMSO and 20 mM nat LuCl3 aqueous solution (2.5 equivalents) was prepared and heated to 95°C for 30 minutes. After cooling, the reaction was confirmed by RP-HPLC / ESI-MS. nat Formation of Lu chelates.

[0563] nat Lu-DOTA-rhCCK-52: RP-HPLC (10% to 90% B in 15 min): t R = 12.7 minutes, K' = 7.88. ESI-MS (positive): calculate the monoisotopic mass (C88 H 116 FWf 16 O 22 Si): 1972.0; Found: m / z = 1972.6 [M + H] + ,986.8[M+2H] 2+ .

[0564] nat Lu-DOTA-rhCCK-53: RP-HPLC (10% to 90% B in 15 min): t R = 12.5 minutes, K' = 7.74; ESI-MS (positive): calculate the monoisotopic mass (C 88 H 116 FWf 16 O 22 Si): 1972.0; Found: m / z = 1973.2 [M+H] + ,986.9[M+2H] 2+ .

[0565] nat Lu-DOTA-rhCCK-54: RP-HPLC (10% to 90% B in 15 min): t R = 14.1 min, K' = 8.86; ESI-MS (positive): calculate the monoisotopic mass (C 89 H 116 FWf 16 O 24 Si): 2016.1; Found: m / z = 1008.8 [M + 2H] 2+ .

[0566] 4.4. Radiolabeling

[0567] 4.4.1. 18 F Mark

[0568] [ 18 The two given steps of the [F]F labeling procedure have been previously optimized in our group by Daniel Di Carlo (unpublished data).

[0569] [ 18 F] Drying of fluoride aqueous solution

[0570] Will[ 18An aqueous solution of [F]fluoride (in vitro studies: 100-300 MBq, biodistribution studies: up to 1.7 GBq; about 0.6-2.0 GBq / mL when used; from Klinikum Rechts der Isar, Munich, Germany) was passed through a SAX cartridge (Sep-PakAccell Plus QMA Carbonate Plus Light, 46 mg, 40 μm, Waters), pre-treated with 10 mL of ultrapure water. The load was dried by flushing with 8 mL of anhydrous DMSO and then 10 mL of air. 18 For elution with an extraction efficiency of 78 ± 9%, a solution of 40 mg of ammonium formate in 500 μL of anhydrous DMSO was slowly passed through the cartridge, followed by 5 mL of air.

[0571] Use dry [ 18 F] Fluoride solution labeling of SiFA-modified peptides

[0572] For labeling, 125-500 μL of the eluted [ 18 F] Fluoride solution was added to a proportional amount of precursor solution (7.5-30nmol, 1mM in anhydrous DMSO). After 5 minutes at room temperature, a sample was taken to determine the radiochemical conversion (RCC) by thin layer chromatography (TLC). The labeled mixture was diluted with 10mL PBS* (pH 3, adjusted with 1M HCl aqueous solution) and passed through an OasisHLB Plus Light column (30mg, 30μM, freshly pretreated with 10mL EtOH and 10mL ultrapure H2O, Waters). Subsequently, 10mL PBS* and 10mL air were added. Elute with 300μL EtOH / PBS* (v / v=7:3) 18 A mixture of a F-labeled peptide and its chemically identical cold precursor. 18 The radiochemical purity of the F-labeled compounds was determined by radio-RP-HPLC and radio-TLC (silica gel 60F). 254 , mobile phase: MeCN / PBS (v / v=3:2), +10% NaOAc solution (2M in H2O), +1% TFA). The radiochemical yield (RCY) was determined using a dose calibrator and calculated taking into account decay correction. *Note: In subsequent stability studies, the PBS used for purification was replaced by ultrapure H2O. Only the PBS used for TLC was not replaced because TLC analysis after column-based purification showed that the free [ 18 F] The fluoride content is less than 1%.

[0573] 4.4.2. 125 I Mark

[0574] Reference compounds for GRPR-based assays [3-[ 125 I]I-tyr 6 ]MJ9 125 I Mark

[0575] IC 50 The reference ligand ([3-[ 125 I]I-tyr 6 ]MJ9) was prepared according to a previously published procedure (7) with minor modifications by our group. Briefly, 0.2 mg of the precursor ([tyr 6 ]MJ9) dissolved in 20 μL H2O and 280 μL TRIS buffer (25 mM TRIS HCl, 0.4 M NaCl, pH = 7.9). The solution was added to a 150 μg Iodo (1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril, surface-bound, Merck, Darmstadt, Germany) was added to a vial and 5.0 μL (16 MBq) [ 125 I] NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mm NaOH, Hartmann Analytic, Braunschweig, Germany). The reaction solution was incubated at room temperature for 15 min and purified by RP-HPLC. After purification, sodium ascorbate (0.1 M, H2O, 10 vol%) to prevent radiolysis. RP-HPLC (20%-35% B in 20 min): t R = 18.9 minutes, K' = 10.46 ([3-[ 125 I]I-tyr 6 ]MJ9).

[0576] Reference compounds for SSTR-based assays [ 125 I] I-TOC 125 I Mark

[0577] Iodination was performed similarly to a previously published procedure (8). 125 I labeling, 50-150 μg TOC was dissolved in 20 μL DMSO in a 1.5 mL Eppendorf reaction tube (Protein LowBind), and 280 μL TRIS buffer (25 mM TRIS-HCl, 0.4 mM NaCl, pH 7.5) was added. The solution was transferred to a plate coated with (150 μg) in a reaction tube (1.5 mL, Protein LowBind), and add 5.00 μL (10-20 MBq) [ 125 I] NaI solution (74 TBq / mmol, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany). After 15 min at room temperature, the The reaction was stopped by separation. The crude product was purified by analytical RP-HPLC [ 125 I] I-TOC. To prevent radiolysis, 10 vol% sodium ascorbate solution (100 mM in H2O) was added to the resulting product solution. RP-HPLC (20% to 50% B in 15 min): t R =8.2 minutes. K' =3.97 ([ 125 I]I-TOC).

[0578] Reference compounds for CXCR4-based assays [ 125 I]I-FC131 125 I Mark

[0579] Iodination was performed according to a previously published procedure (9). Prior to the iodination step, a reaction vial was coated by dissolving 1.5 mg of iodogen (1,3,4,6-tetrachloro-3R,6R-diphenylglycoluril, Pierce, Rockford, IL) in 1.0 mL of dry DCM and dispensing into 10 Eppendorf caps (100 μL of iodogen solution per cap). The DCM was evaporated under a stream of nitrogen and the iodogen-coated Eppendorf caps were stored at −20° C. under nitrogen until further use. To the reaction vial thus prepared, approximately 0.5 mg (0.5 μmol) of FC131 was added and dissolved in 20 μL of DMSO and 200 μL of Tris buffer (25 mM in H2O). To the solution was added 5 μL (23.1 MBq) [ 125 I] NaI (74 TBq / mmol, 3.1 GBq / mL 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany) and incubated at room temperature for 15 minutes. The crude product was separated from the unlabeled FC131 by analytical RP-HPLC to give the desired product. RP-HPLC (20%-40% B in 20 minutes); t R = 18.0 minutes, K' = 9.0 ([ 125 I]I-FC131).

[0580] Reference compounds for PSMA-based assays [ 125 I]I-BA-KuE’s[ 125I]I mark

[0581] Reference ligands for in vitro studies ([ 125 I]I-BA)KuE. For iodination, the peracetic acid solution used was freshly prepared by incubating 50 μL of acetic acid in 130 μL of 30 vol% H2O2 (in H2O) for 2 h at room temperature. Approximately 0.1 mg of the tination precursor Sn(n-Bu)3-BA-(tBuO)KuE(OtBu)2 was dissolved in 20 μL of peracetic acid, 5.0 μL of [ 125 I]NaI (20 ± 5MBq, 74TBq / mmol, 40mM in NaOH, Hartmann Analytic, Braunschweig, Germany), 20μL MeCN and 10μL acetic acid in a mixture. The reaction solution was incubated at room temperature for 15 minutes, diluted in 10mLH2O, and loaded on a Sep-Pak C18 Plus Short column (360mg, 55-105μm, Waters, pre-treated with 10mLMeOH and then 10mLH2O). After washing the column with 10mLH2O and then 10mL air, the peptide was eluted with 1.5mLEtOH / MeCN (v / v=1:1). The eluate was evaporated to dryness under a gentle nitrogen stream at 70°C and treated with 500μL TFA for 45 minutes. After removing TFA in a nitrogen stream, the crude product was purified by radio-RP-HPLC to obtain ([ 125 I]I-BA)KuE (10±2MBq). HPLC (20%-40% B in 20 minutes): t R =13.0 minutes.

[0582] 4.4.3. 177 Lu Marking

[0583] for 177 Lu labeling was performed using a previously published procedure (11) with slight modifications. The labeling precursor (1.0 nmol, 5 μL, 0.2 mM in DMSO) was added to 10 μL AcOH / NaOAc buffer (1.0 M in H2O, pH 5.5, 1.0 M). Subsequently, 10 to 110 MBq of 177 LuCl3(Specific activity(S A)>3000 GBq / mg, 740 MBq / mL, 0.04 M HCl, ITM, Garching, Germany), and the mixture was filled to 100 μL with 0.04 M HCl aqueous solution. The reaction mixture was heated at 90° C. for 20 minutes, and after the addition of sodium ascorbate (0.1 M in PBS), the radiochemical purity was determined using radio-HPLC and radio-TLC (0.1 M sodium citrate buffer and 1.0 M NH4OAc / DMF buffer (1 / 1; v / v)).

[0584] In vitro experiments

[0585] Cell culture

[0586] GRPR + Culture of PC-3 cells

[0587] GRPR + PC-3 cells (Merck, Darmstadt, Germany) were cultured at 37°C in a humidified 5% CO2 atmosphere in Dulbecco's modified eagle medium / Ham's F-12 (DMEM / F-12, v / v=1 / 1, with stabilized glutamine, Biochrom GmbH, Berlin, Germany) supplemented with fetal bovine serum (10%, FBS Superior, Biochrom GmbH, Berlin, Germany). Cells were harvested using a mixture of trypsin and ethylenediaminetetraacetic acid (0.05%, 0.02%) in PBS (Biochrom GmbH, Berlin, Germany). The cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Germany) to count cells.

[0588] Culture of Jurkat cells

[0589] hCXCR4-positive Jurkat human T-cell leukemia (Merck Millipore, Darmstadt, Germany) was cultured in RPMI 1640 medium (2.0 g / L NaHCO3, L-glutamine-free, low endotoxin, Biochrom, Berlin, Germany) containing 10% (v:v) FBS Superior (Biochrom GmBH, Berlin, Germany) and maintained in a humidified CO2 atmosphere (5%) at 37°C. For splitting, Jurkat suspension cells were harvested by centrifugation (1300 rpm, 3 minutes) and resuspended in culture medium. Depending on the growth rate of the cells, each cell culture was split approximately twice per week. The cells were counted using a Neubauer hemacytometer (Paul Marienfeld, All operations were performed under sterile conditions using the MSC-Advantage safety workbench from Thermo Fisher Scientific.

[0590] CHO / Sst2(a) cell culture

[0591] The cells were incubated at 37°C in a humidified atmosphere (5% CO2) using a HERAcell 150i-incubator from Thermo Fisher Scientific (Waltham, USA) in an incubator obtained from Greiner Bio-One GmbH (Frickenhausen, Germany). Stable Sst2(a)-transfected Chinese hamster ovary (CHO / Sst2(a)) cells were cultured in monolayers in cell culture flasks. DMEM / F12 GlutaMax medium supplemented with 10% FBS Superior (Biochrom GmbH, Berlin, Germany) was used as the nutrient medium. In addition, Dulbecco's PBS solution containing 0.05% trypsin and 0.1% EDTA (v / v) was applied to detach the cells for cell passaging. The cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Germany) to count the isolated cells. For optimal growth, cells were harvested at about 80% confluence. In addition, all manipulations under sterile conditions were completed using the MSC-Advantage safety workbench from Thermo Fisher Scientific.

[0592] AR42J cell culture

[0593] Rat pancreatic cancer cells AR42J expressing CCK-2R (CLS GmbH, Eppelheim, Germany) were incubated at 37°C in a humidified atmosphere (5% CO2) using a HERAcell 150i-incubator from Thermo Fisher Scientific (Waltham, USA) in a 4% CO2 incubator obtained from Greiner Bio-One GmbH (Frickenhausen, Germany). Cells were cultured in monolayers in cell culture flasks. RPMI 1640 medium was used as the nutrient medium, supplemented with 5 mM L-Glu, 5 mL non-essential amino acids (100×) and 10% FBS Superior (Biochrom GmbH, Berlin, Germany). In addition, Dulbecco's PBS solution containing 0.05% trypsin and 0.1% EDTA (v / v) was applied to separate cells for cell passage. The cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Germany) to count the isolated cells. For optimal growth, cells were harvested at about 80% confluence. In addition, all manipulations under sterile conditions were completed using the MSC-Advantage safety workbench from Thermo Fisher Scientific.

[0594] Culture of LNCaP cells

[0595] PSMA-positive LNCaP cells (ACC 256; DSMZ-German Collection of Microorganismsand Cell Cultures GmbH, Braunschweig, Germany) were cultured in Dulbecco's modified Eagle's medium / nutrient mixture F-12 and Glutamax (1:1) (DMEM-F12, Biochrom GmbH, Berlin, Germany) supplemented with fetal bovine serum (10%, FBS Superior, Biochrom GmbH, Berlin, Germany) and maintained at 37°C in a humidified CO2 atmosphere (5%). A mixture of trypsin and EDTA (0.05%, 0.02%) in PBS (Biochrom GmbH, Berlin, Germany) was used to harvest the cells. The cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Germany) to count cells.

[0596] 4.5.2. Affinity determination (IC 50 )

[0597] GRPR affinity studies

[0598] In order to determine the affinity of GRPR for PC-3 cells (IC 50 ), cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10 5 cells, 1 mL / well).

[0599] After removing the culture medium, the cells were washed once with 500 μL HBSS (Hank's balanced salt solution, Biochrom GmbH, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA, v / v)) and placed in 200 μL HBSS (1% BSA, v / v) for 9 minutes at room temperature for equilibration. Next, 25 μL of a solution containing HBSS (1% BSA, v / v) as a control or increasing concentrations of the corresponding compound (10 μL in HBSS (1% BSA, v / v)) was added to each well. -10 -10 -4 M)), followed by the addition of 25 μL [3-[ 125I]ID-Tyr 6 ]MJ9 (2.0 nM). Each concentration of all experiments was performed in triplicate. After incubation for 2 h at room temperature, the experiment was terminated by removing the medium and washing with 300 μL HBSS (1% BSA, v / v) successively. The medium from the two steps was combined into one fraction, representing free [3-[ 125 I]I-tyr 6 ]MJ9. Then, cells were lysed with 300 μL 1M NaOH for at least 15 min and combined with 300 μL NaOH in the following wash step. Bound and free 3-[ 125 I]ID-Tyr 6 - Quantification of MJ9. IC of each conjugate 50 The assay was repeated twice.

[0600] hCXCR4 affinity study

[0601] For receptor binding assays, Jurkat cells were counted, detached from the culture medium, and resuspended in HBSS (Hanks' balanced salt solution, + 1% BSA). 200 μL of the suspension (400.000 cells) were mixed with 25 μL of the reference radioligand [ 125 I] I-FC131 (400.000 cpm / 25 μL) and 25 μL of different concentrations (10 -4 -10 -10 M) competitor and 25 μL HBSS (1% BSA) (for control experiments). After 2 hours at 4-9°C, the culture was terminated by centrifugation (1300 rpm, 3 minutes). HBSS (containing 0.35 g / L NaHCO3, Ca 2+ , containing Mg 2+ The cell pellet was washed with 1% paraformaldehyde (without phenol red) and centrifuged twice for each step. The radioactivity of the supernatant / washing solution and the cell-bound fraction was determined using a gamma counter. The experiment was performed in triplicate, with n = 3 for each concentration. IC was calculated using GraphPad PRISM software (GraphPad software Inc., La Jolla, USA). 50 value.

[0602] SSTR affinity study

[0603] To determine the affinity of SSTR, CHO / Sst2(a) cells (1.0×10 5) were seeded into 24-well plates, and the cells were incubated with 1 mL of nutrient medium (DMEM / F12 GlutaMax medium supplemented with 10% FBS Superior) at 37°C in a humidified atmosphere (5% CO2).

[0604] After removing the culture medium, each well was washed with 300 μL HBSS (1% BSA, v / v). For cell assays, 200 μL of assay medium HBSS (1% BSA, v / v), [ 125 I] I-TOC (1 nM in HBSS (1% BSA), 25 μL, 0.3 pmol) and 25 μL increasing concentrations (10 -10 Up to 10 -4 The peptide of interest (20 μM) was added to the cells in triplicate. Thereafter, the assay was incubated for 1 hour at room temperature and the supernatant was collected. The cells were washed with 300 μL of ice-cold PBS and the collected fractions were combined. After lysing the cells with NaOH (300 μL, 1N) for 20 minutes, each well was washed with NaOH (300 μL, 1N) and the two fractions were combined. The radioactivity of the supernatant and lysed fractions was quantified using a γ-counter. The data obtained were evaluated by GraphPad PRISM software (GraphPad software Inc., La Jolla, USA), which calculated the half-maximal inhibitory concentration (IC 50 ).

[0605] CCK-2R affinity study

[0606] To determine the receptor affinity of various peptides, AR4-2J cells (2.0×10 5 ) were seeded into 24-well plates and incubated with 1 mL of nutrient medium (RPMI 1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS) at 37°C in a humidified atmosphere (5% CO2).

[0607] After removing the medium, each well was washed with 500 μL PBS. For cell assays, 200 μL nutrient medium (RPMI 1640, 5 mM L-Glu, 5 mL non-essential amino acids (100×), 10% FCS, 5% BSA), [ 177 Lu]Lu-DOTA-PP-F11N (25 μL, 0.3 pmol) and 25 μL increasing concentrations (10 -10 Up to 10 -4M) of the peptide of interest in triplicate. Thereafter, the assays were incubated at 37°C for 3 hours and the supernatants were collected. The cells were washed with 300 μL PBS and the collected fractions were combined. After lysing the cells with NaOH (300 μL, 1N) for 15 minutes, each well was washed with NaOH (200 μL, 1N) and the two fractions were combined. The radioactivity of the supernatant and lysed fractions was quantified using a γ-counter. The data obtained were evaluated by GraphPad PRISM software (GraphPad software Inc., La Jolla, USA), which calculated the half-maximal inhibitory concentration (IC 50 ).

[0608] PSMA affinity studies

[0609] For PSMA affinity (IC 50 ) assay, the corresponding ligand was diluted (serial dilution 10) in Hank's balanced salt solution (HBSS, Biochrom GmbH, Berlin, Germany) supplemented with 1% bovine serum albumin (BSA, Biowest, Nuaillé, France). -4 Up to 10 -10 M). In the case of metal complexing ligands, the crude reaction mixture was diluted similarly without further purification. Cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10 5 After removing the culture medium, the cells were carefully washed with 500 μL HBSS (1% BSA) and placed on ice for 15 minutes to equilibrate in 200 μL HBSS (1% BSA). Next, 25 μL of a solution containing HBSS (1% BSA, control) or increasing concentrations (10 μL in HBSS) was added to each well. -10 -10 -4 M) of the corresponding test ligand), followed by the addition of 25 μL [ 125 I]I-BA-KuE (2.0 nM) was used as a radiolabeled competitor in HBSS (1% BSA). For each concentration, the experiment was performed in triplicate. After incubation on ice for 60 min, the experiment was terminated by removing the culture medium and rinsing continuously with 200 μL HBSS (1% BSA). The media from both steps were combined into one portion and represented the amount of free radioligand. The cells were then lysed with 250 μL NaOH (1 M in H2O) for at least 15 min. After a washing step with NaOH (250 μL, 1 M H2O), the two portions representing the amount of bound ligand were combined. All collected portions were quantified in a γ-counter. IC was calculated using GraphPad PRISM software (GraphPad software Inc., LaJolla, USA)50 The entire PSMA affinity assay was performed at least three times for each ligand.

[0610] 4.5.3. Internalization studies

[0611] CCK-2R internalization study

[0612] To determine the internalization kinetics of various peptides, AR42J cells (3.0×10 5 ) were seeded into a 24-well plate coated with poly-L-lysine, and 1 mL of nutrient medium (RPMI 1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS) was added. Then, the cells were incubated at 37° C. in a humidified atmosphere (5% CO 2 ) for 24±2 hours.

[0613] On the day of the experiment, the culture medium was removed and each well was washed with culture medium (RPMI 1640, 5 mM L-Glu, 5 mL non-essential amino acids (100×)) (300 μL). Subsequently, 200 μL of nutrient medium (RPMI 1640, 5 mM L-Glu, 5 mL non-essential amino acids (100×), 10% FCS), 25 μL of 177 Lu]Lu labeled peptide (0.3pmol, n=6) and 25μL of nutrient medium (RPMI 1640, 5mM L-Glu, 5mL non-essential amino acids (100×), 10% FCS) were used for internalization studies (n=3), and 25μL of DOTA-PP-F11N (10μmol) were added for blocking studies (n=3). Thereafter, the assay was incubated in a humidified atmosphere (5% CO2) at 37°C for 6 hours. After incubation, the cells were placed on ice and the supernatant was collected. Then, the cells were washed with ice-cold medium (RPMI 1640, 5mM L-Glu, 5mL non-essential amino acids (100×)) (300μL), and the two parts were combined. In order to displace the peptide from the cell membrane, 300μL of ice-cold glycine buffer (1M, pH 2.2) was added, and the cells were incubated on ice for 15 minutes. Then, the supernatant was collected and the cells were washed with 300 μL of ice-cold glycine buffer (1M, pH 2.2). The two parts were combined. After lysing the cells with NaOH (300 μL, 1N) for 15 minutes, each well was washed with NaOH (200 μL, 1N) and the two parts were combined. The radioactivity of the supernatant, acid wash and lysate parts was quantified using a γ-counter.

[0614] 4.5.4. Determination of relative radiochemical conversion rate (rRCC)

[0615] In the first step, according to the above procedure (4.4.1[ 18F]F-labeled) dry Klinikum Rechts der Isar provided [ 18 For the competitive labeling reaction, 167 μL of dry [ 18 F] Fluoride solution (30-50 MBq) was added to 10 μL of an equimolar mixture of the test compound and the corresponding (4-SiFA)Bz-reference compound (5 nmol each in DMSO). After 5 min at room temperature, a sample was taken and immediately analyzed by radio-RP-HPLC. If necessary, the standard solvent gradient (10% to 90% B in 15 min) was modified to achieve baseline separation ((3-SiFA)Bz-Gly-LX vs. (4-SiFA)Bz-Gly-LX, where X = Tyr: 45% to 65% B in 15 min; X = Asp: 40% to 60% B in 15 min; X = Lys: 35% to 55% B in 15 min). In these cases, a mixture of the cold precursor and an approximately 3-fold excess of (3-SiFA)Bz-compound was analyzed with the corresponding gradient for unambiguous peak assignments. Relative radiochemical conversion (rRCC) was calculated by peak integration and expressed as the ratio of test compound to reference compound [%]. The experiment was repeated (n=3).

[0616] 4.5.5. Determination of n-octanol-water partition coefficient (log D 7.4 )

[0617] About 1MBq of [ 177 Lu]Lu labeled tracer or 0.5MBq [ 18 F]F labeled tracer was dissolved in 1 mL of n-octanol / PBS (v / v=1:1) in a reaction bottle (1.5 mL). After vigorous mixing of the suspension for 3 minutes at room temperature, the vial was centrifuged at 15000 g for 5 minutes (Biofuge 15, Heraus Sepatech, Osterode, Germany), and 100 μL aliquots of both layers were measured in a γ-counter. The experiment was repeated (n≥6).

[0618] 4.5.6. High Performance Affinity Chromatography (HPAC) Determination of Human Serum Albumin (HSA) Binding

[0619] HSA binding to PSMA ligands by HPAC was determined by HPLC according to previously published procedures (12). Chiralpak HSA columns (50 x 3 mm, 5 μm, H13H-2433, Daicel, Tokyo, Japan) were used at room temperature with a constant flow rate of 0.mL / min. Mobile phase A was a freshly prepared 50 mM NH4OAc aqueous solution (pH 6.9), and mobile phase B was isopropanol (HPLC grade, VWR). The applied gradient for all experiments was 100% A (0 to 3 minutes) followed by 80% A (3 to 40 minutes). Prior to the experiment, the column was calibrated using nine reference substances with HSA binding in the range of 13% to 99% known in the literature (12, 13). All substances were dissolved in a 1:1 mixture (v / v) of isopropanol and 50 mM NH4OAc aqueous solution (pH 6.9) at a final concentration of 0.5 mg / mL. Nonlinear regression was established using OriginPro2016G software (Northampton, USA).

[0620] Fig.11 An exemplary sigmoidal plot showing human serum albumin (HSA) binding versus retention time (t R The HSA binding values ​​shown in the table below are from the literature (Literature HSA [%]) (12, 13).

[0621] Table 6: Example table of reference compound data used for calibration: Log t R : Experimentally determined retention time t R Logarithmic value of HSA binding value; Literature HSA [%]: HSA binding value obtained from literature (12, 13). Log K HSA: Logarithmic value of HSA binding value.

[0622]

[0623] 4.5.7.[ 18 Determination of the stability of the F]F-Si bond ( 18 F defluorination half-life)

[0624] Under chemically simulated blood in vivo conditions (pH 7.4, 37°C) 18 F defluorination

[0625] According to the above procedure (4.4.1 18 F marker), from 200-300MBq [ 18 F] fluoride aqueous solution to begin labeling the test compound. 18F]F-labeled compounds (10 μL per vial, about 0.8-1.0 nmol, 2.5-5.0 MBq) were added to 90 μL of K2CO3 solution (3 mM in ultrapure H2O, pH 7.4 adjusted with formic acid) per vial. The pH of the incubation solution was controlled by a test strip (resolution: 0.5). After incubation at 37°C for 0, 30, 60, 90 and 120 min in separate reaction vials, the concentrations of the compounds were determined by radio-TLC (silica gel 60F 254 , mobile phase: MeCN / PBS (v / v=3:2), + 10% NaOAc solution (2M in H2O), + 1% TFA) to analyze the samples and distinguish the released [ 18 F] fluoride (fixed at baseline) and labeled test compounds. The experiment was repeated (n=3). 18 The ratio of F-labeled peptides was calculated 18 Half-life of defluorination of F. For the evaluation, GraphPad PRISM software (GraphPad software Inc., La Jolla, USA) was used.

[0626] Radioactive hybrids 177 Lu-labeled 18 F defluorination (pH 5.5, 90℃)

[0627] According to the above procedure (4.4.1 18 F marker), from 200-300MBq [ 18 F] fluoride aqueous solution to begin labeling the test compound. 18 F-labeled compound (10 μL per bottle, about 0.8-1.0 nmol, 2.5-5.0 MBq) was added to a solution of 80 μL of aqueous HCl (40 mM) and 10 μL of AcOH / NaOAc buffer (1.0 M in H2O, pH 5.5, 1.0 M) per bottle. The pH of the incubation solution was controlled by a test strip (resolution: 0.5). After incubation at 37°C for 0, 30, 60, 90 and 120 minutes in separate reaction bottles, the concentrations of the F-labeled compound were determined by radio-TLC (silica gel 60F 254 , mobile phase: MeCN / PBS (v / v=3:2), + 10% NaOAc solution (2M in H2O), + 1% TFA) to analyze the samples and distinguish the released [ 18 F] fluoride (fixed at baseline) and labeled test compounds. The experiment was repeated (n=3). 18 The ratio of F-labeled peptides was calculated 18 Half-life of defluorination of F. For the evaluation, GraphPad PRISM software (GraphPad software Inc., La Jolla, USA) was used.

[0628] In aqueous solution 18 F-to nat F isotope exchange (1 mM NaF, pH 6.5, room temperature)

[0629] According to the above procedure (4.4.1 18 F marker), from 200-300MBq [ 18 F] fluoride aqueous solution to begin labeling the test compound. 18 The F-labeled compound (10 μL per vial, about 0.8-1.0 nmol, 2.5-5.0 MBq) was added to a solution of 80 μL ultrapure H2O and 10 μL NaF solution (10 mM in H2O) per vial. The pH of the incubation solution was controlled by a test strip (resolution: 0.5). After incubation at 37°C for 0, 30, 60, 90 and 120 min in separate reaction vials, the pH values ​​were determined by radio-TLC (silica gel 60F 254 , mobile phase: MeCN / PBS (v / v=3:2), + 10% NaOAc solution (2M in H2O), + 1% TFA) to analyze the samples and distinguish the released [ 18 F] fluoride (fixed at baseline) and labeled test compounds. The experiment was repeated (n=3). 18 The ratio of F-labeled peptides was calculated 18 Half-life of defluorination of F. For the evaluation, GraphPad PRISM software (GraphPadsoftware Inc., La Jolla, USA) was used.

[0630] 4.6. Biodistribution studies

[0631] All animal experiments were performed in accordance with the general animal welfare regulations of Germany (German Animal Protection Act, amended on May 18, 2018, Art 141G v. March 29, 2017 I 626, approval number 55.2-1-54-2532-71-13) and institutional guidelines for the care and use of animals. To establish tumor xenografts, LNCaP cells (approximately 1.5 × 10 7 Cells) were suspended in 200 μL of a 1:1 mixture (v / v) of DMEM F-12 and Matrigel (BD Biosciences, Germany) and inoculated subcutaneously on the right shoulder of 6-8 week old CB17-SCID mice (Charles River, Sulzfeld, Germany). When the tumor grew to a diameter of 2-6 mm (4-20 weeks after inoculation), mice were used for experiments.

[0632] By adding about 2-5MBq (50-120pmol)177 Lu-labeled ligand or about 1-2 MBq (50-120 pmol) 18 F-labeled ligands were injected into the tail vein of male CB-17SCID mice bearing LNCaP tumors and sacrificed 1 hour or 24 hours after injection (pi). Selected organs were removed, weighed and measured in a γ-counter. All results were decay-corrected and given as percentage of injected dose per gram of tissue (%ID / g).

[0633] 5. References

[0634] 1.Wirtz M. Development of biomarkers for molecular imaging and endoradiotherapy of prostate cancer. PhD thesis, Technical University Munich. 2015.

[0635] 2. Wurzer A, Parzinger M, Konrad M et al., Preclinical comparison of four[18F,natGa]rhPSMA-7isomers: influence of the stereoconfiguration onpharmacokinetics. EJNMMI Research. 2020; 10:149.

[0636] 3.Niedermoser S,Chin J, C et al., In Vivo Evaluation of 18F-SiFAlin–Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical GoldStandard for Somatostatin Receptor Imaging with PET. J Nucl Med. 2015;56:1100.

[0637] 4. Ilhan H, Lindner S, Todica A, et al., Biodistribution and first clinical results of 18F-SiFAlin-TATE PET: a novel 18F-labeled somatostatin analog for imaging of neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2020;47:870-880.

[0638] 5. Wurzer A, DiCarlo D, Schmidt A, et al., Radiohybrid ligands: a novel tracer concept exemplified by 18F- or 68Ga-labeled rhPSMA-inhibitors. J Nucl Med. 2019:jnumed.119.234922.

[0639] 6. Weineisen M, Simecek J, Schottelius M, Schwaiger M, Wester H-J. Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI Research. 2014;4:63.

[0640] 7. Nakagawa T, Hocart SJ, Schumann M, et al., Identification of key amino acids in the gastrin-releasing peptide receptor (GRPR) responsible for high affinity binding of gastrin-releasing peptide (GRP). Biochem Pharmacol. 2005;69:579-593.

[0641] 8. Schottelius M, J,Hoffmann F,Willibald M,Schwaiger M,WesterHJ.Twins in spirit-episode I:comparative preclinical evaluation of[68Ga]DOTATATE and[68Ga]HA-DOTATATE.EJNMMI Res.2015;5:22.

[0642] 9.Osl T.Development of cyclic pentapeptide ligands for chemokinereceptor targeting,PhD thesis,Technical University Munich.2017.

[0643] 10.Vaidyanathan G,Zalutsky MR.Preparation of N-succinimidyl 3-[*I]iodobenzoate:an agent for the indirect radioiodination of proteins.NatProtoc.2006;1:707-713.

[0644] 11.Sosabowski JK,Mather SJ.Conjugation of DOTA-like chelating agentsto peptides and radiolabeling with trivalent metallic isotopes.NatProtoc.2006;1:972-976.

[0645] 12.Valko K,Nunhuck S,Bevan C,Abraham MH,Reynolds DP.Fast gradientHPLC method to determine compounds binding to human serumalbumin.Relationships with octanol / water and immobilized artificial membranelipophilicity.J Pharm Sci.2003;92:2236-2248.

[0646] 13.Yamazaki K,Kanaoka M.Computational prediction of the plasmaprotein-binding percent of diverse pharmaceutical compounds.J Pharm Sci.2004;93:1480-1494.

Claims

1. A compound comprising a group selected from the group consisting of formula (Ia), (Ib) and (Ic) or a salt thereof: in: R 1 is a linear or branched C3 to C10 alkyl group; R 2 is a linear or branched C3 to C10 alkyl group; R 3 Selected from (i) -OH or -O - , (ii) a sugar moiety or an amino sugar moiety, (iii) an amino acid portion or an oligopeptide portion, (iv) a PEG moiety; and a combination of two or more selected from (ii), (iii) and (iv); And a wavy line indicates the bond connecting the group to the rest of the compound.

2. The compound or salt of the compound according to claim 1, wherein the compound is a compound of formula (IIa), (IIb) or (IIc): Where R 1 , R 2 and R 3 As defined in claim 1, and R E is a group comprising a targeting moiety.

3. The compound or salt according to any one of claims 1 or 2, wherein as R 3 The amino acid moiety is derived from a hydrophilic amino acid which, in addition to the amino and carboxyl groups, contains an additional basic or acidic functional group, or wherein as R 3 The oligopeptide portion is derived from an oligopeptide having at least one hydrophilic amino acid which, in addition to the amino and carboxyl groups, also contains an additional basic or acidic functional group.

4. The compound or salt according to claim 3, wherein the hydrophilic amino acid is selected from lysine and glutamic acid.

5. The compound or salt according to any one of claims 1 to 4, wherein as R 3 The oligopeptide portion is a linear or branched portion comprising 2 to 10, preferably 2 to 5, and more preferably 2 or 3 amino acid portions.

6. The compound or salt according to any one of claims 1 to 5, wherein as R 3 The PEG moiety is a moiety of the formula -NH-(CH2-CH2-O)X-R P1 , The nitrogen atom providing the open bond to R 3 The carbon atom to which it is connected forms an amide bond -NH-C(O)-, X is an integer from 2 to 10, and R P1 Selected from -CH2-COOH and -CH2-CH2-COOH.

7. The compound or salt according to any one of claims 1 to 6, wherein as R 3 The sugar moiety or amino sugar moiety is a residue derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers.

8. A compound or salt according to any one of claims 2 to 7, wherein R E It comprises a targeting moiety selected from a receptor binding moiety, an enzyme binding substrate or enzyme inhibitor, a peptide, a protein or an antibody fragment or an engineered antigen binding construct.

9. A compound or salt according to any one of claims 2 to 8, wherein the targeting moiety is a peptide moiety.

10. A compound or salt according to any one of claims 2 to 9, wherein the targeting moiety is a receptor binding moiety that enables the compound of formula (IIa), (IIb) or (IIc) or its salt comprising the targeting moiety to act as a ligand for a receptor selected from the group consisting of gastrin releasing peptide receptor (GRPR), CXC chemokine receptor type 4 (CXCR4), somatostatin receptor (SSTR) and cholecystokinin B receptor (CCK-2R).

11. A compound or salt according to any one of claims 2 to 10, wherein R E It further comprises a chelating moiety or a chelate moiety formed by a chelating moiety and a chelated radioactive or non-radioactive metal cation.

12. The compound or salt of claim 11, wherein the chelated metal cation is a radioactive metal cation.

13. A compound or salt according to any one of claims 1 to 12, wherein the fluorine attached to the Si atom by a direct covalent bond is [ 18 F] fluorine.

14. A group of formula (Ia), (Ib) or (Ic) as defined in any one of claims 1 or 3 to 7 as a silicon-based fluoride acceptor group for [ 19 F] Fluorine 18 F] Uses of fluorine isotope exchange.

15. A group of formula (Ia), (Ib) or (Ic) as defined in any one of claims 1 or 3 to 7 as a silicon-based fluoride acceptor group for use in targeting radiopharmaceuticals [ 18 F] Purpose of the mark.

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