Silicon-based fluoride acceptor groups for radiopharmaceuticals

Abstract

TIFF2025525111000074.tif118131 The present invention relates to novel silicon-based fluoride acceptor groups (SiFA groups) of the following formulas (Ia, Ib, Ic) (wherein R 1 and R 2 are each a linear or branched C3-C10 alkyl group, and R 3 is selected from (i) -OH or -O - , (ii) a sugar moiety or an amino sugar moiety, (iii) an amino acid moiety or an oligopeptide moiety, (iv) a PEG moiety, and combinations of two or more of (ii), (iii) and (iv)), and to compounds suitable for use in radiopharmacy containing such groups.

Description

Technical Field

[0001] The present invention relates to a novel silicon-based fluoride acceptor group (SiFA group) useful for the 18 F-labeling of target radiopharmaceuticals via a rapid and efficient isotope exchange reaction.

Background Art

[0002] WO2019 / 020831A1 describes dual-mode radiotracers and radiotherapy agents combining a silicon fluoride acceptor group with one or more chelate groups. WO2022 / 144463A1 also relates to compounds containing a silicon fluoride acceptor group together with a chelate containing a chelated radioactive or non-radioactive metal cation and thus suitable for use as radiotracers or radiotherapy agents. R. Koudih et al., Applied Radiation and Isotopes, 80, 2014, pages 146 - 150 disclose a method for the automated synthesis of N-succinimidyl 3-(di-tert-butyl 18 F]fluorosilyl)benzoate for the radiolabeling of peptides and proteins.

Summary of the Invention

[0003] Compared to the SiFA groups disclosed so far, especially the most frequently used p-(di-tert-butyl-(fluorosilyl)benzoic acid, the SiFA groups according to the present invention enable a) the development of more hydrophilic SiFA-based 18 F-labeled ligands with improved in vivo properties, such as reduced hepatobiliary excretion, decreased plasma protein binding, thus accelerated blood clearance and less non-specific binding, and b) facilitate the optimization of the structural requirements of target molecules (receptors, enzymes, etc.) according to structure-activity relationships, enabling the development of ligands with improved affinity if required.

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

[0005]

Chemical formula

[0006] In the formula, R 1 is a straight-chain or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group; R 2 is a straight-chain or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group; R 3 is (i) -OH or -O - , (ii) a sugar moiety or an amino sugar moiety, (iii) an amino acid moiety or an oligopeptide moiety, (iv) a PEG moiety as well as combinations of two or more of (ii), (iii) and (iv) selected from, The wavy line indicates the bond that attaches the above group to the remainder of the above compound.

[0007] R 3 When it is -O - , the substituent -C(=O)R 3 of the aromatic ring shown in the above formula is understood to be a deprotonated carboxylate group -C(=O)O - . In the present specification, the groups (Ia)-(Ic) are also referred to as SiFA groups according to the present invention.

[0008] Advantageously, such SiFA groups according to the invention can be used in compounds comprising a targeting moiety, for example, a receptor binding moiety, an enzyme binding substrate or enzyme inhibitor, or an antibody fragment or engineered antigen-binding construct such as a peptide, protein, or nanobody. Compounds comprising a SiFA group and a targeting moiety can be used as targeted radiopharmaceuticals.

[0009] Various aspects of the invention and their preferred embodiments are summarized in the following items. 1. A compound comprising a group selected from the groups of formula (Ia), (Ib) and (Ic), or a salt thereof:

[0010]

Chemical formula

[0011] In the formula, R 1 is a linear or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group, R 2 is a linear or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group, R 3 is (i) -OH or -O - , (ii) a sugar moiety or an amino sugar moiety, (iii) an amino acid moiety or an oligopeptide moiety, (iv) a PEG moiety, as well as combinations of two or more of (ii), (iii) and (iv) selected from, The wavy line indicates the bond that attaches the above group to the remainder of the above compound.

[0012] 2. The compound according to item 1 comprising a group of formula (Ia), or a salt of the compound. 3. The compound according to item 1, which is a compound of formula (IIa), (IIb) or (IIc), or a salt of said compound:

[0013] [Chemical formula]

[0014] wherein R 1 , R 2 , and R 3 are defined as in item 1, and R E is a group containing a targeting moiety. 4. The compound according to item 3, which contains a group of formula (IIa), or a salt of said compound.

[0015] 5. The compound or salt according to any one of items 1 to 4, wherein R 1 and R 2 are each a tert-butyl group. 6. The amino acid moiety as R 3 is derived from a hydrophilic amino acid containing an additional basic or acidic functional group in addition to an amino group and a carboxyl group, or the oligopeptide moiety as R 3 is derived from an oligopeptide having at least one hydrophilic amino acid containing an additional basic or acidic functional group in addition to an amino group and a carboxyl group. The compound or salt according to any one of items 1 to 5.

[0016] 7. The oligopeptide moiety as R 3 is a linear or branched moiety containing 2 to 10, preferably 2 to 5, more preferably 2 or 3 amino acid moieties. The compound or salt according to any one of items 1 to 6.

[0017] 8. The compound or salt according to item 6 or 7, wherein the hydrophilic amino acid is selected from lysine and glutamic acid. 9. The PEG moiety as R 3 has the formula -NH-(CH2-CH2-O) X -R P1 (wherein the nitrogen atom providing the open bond forms an amide bond -NH-C(O)- together with the carbon atom to which R 3 is bonded, X is an integer of 2 to 10, preferably 4 to 10, more preferably 8, and R P1 is selected from -CH2-COOH and -CH2-CH2-COOH) is a moiety of , the compound or salt according to any one of items 1 to 8.

[0018] 10. The sugar moiety or amino sugar moiety as R 3 is a residue derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers, the compound or salt according to any one of items 1 to 9.

[0019] 11. R 3 is -OH, a lysine moiety, a glutamic acid moiety, a residue derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomers, and the formula -NH-(CH2-CH2-O) X -R P1 is selected from the moiety of wherein the nitrogen atom providing the open bond forms an amide bond -NH-C(O)- together with the carbon atom to which R is bonded, X is an integer of 2 to 10, preferably 4 to 10, more preferably 8, and R 3 is selected from -CH2-COOH and -CH2-CH2-COOH, the compound or salt according to any one of items 1 to 10. P1 is selected from -CH2-COOH and -CH2-CH2-COOH, the compound or salt according to any one of items 1 to 10.

[0020] 12. R E is a targeting moiety selected from a receptor binding moiety, an enzyme binding substrate or enzyme inhibitor, a peptide, a protein, or an antibody fragment such as a nanobody or an engineered antigen-binding construct is included, the compound or salt according to any one of items 3 to 11.

[0021] 13.R E The compound or salt according to item 12, which comprises a targeting moiety selected from a receptor binding moiety and an enzyme binding substrate or enzyme inhibitor. 14. The compound or salt according to any one of items 3 to 13, wherein the targeting moiety is a peptide moiety.

[0022] 15. The targeting moiety is a receptor binding moiety, and by virtue of the receptor binding moiety, the compound of formula (IIa), (IIb) or (IIc) containing the targeting moiety or a salt thereof can function as a ligand for a receptor selected from gastrin-releasing peptide receptor (GRPR), C-X-C chemokine receptor type 4 (CXCR4), somatostatin receptor (SSTR), and cholecystokinin B receptor (CCK-2R). The compound or salt according to any one of items 3 to 14.

[0023] 16. The targeting moiety is a PSMA binding moiety, and by virtue of the PSMA binding moiety, the compound of formula (IIa), (IIb) or (IIc) or a salt thereof can function as a ligand for prostate-specific membrane antigen (PSMA). The compound or salt according to any one of items 3 to 14.

[0024] 17.R E The targeting moiety contained in is -C(=O)R E which is directly bonded to the carbon atom of the carbonyl group in. The compound or salt according to any one of items 3 to 16. 18.R E The targeting moiety contained in is -C(=O)R E which is bonded to the carbon atom of the carbonyl group in via a linker group. The compound or salt according to any one of items 3 to 16.

[0025] 19.R E which further comprises a chelating moiety, or a chelate moiety formed by the chelating moiety and a chelated radioactive or non-radioactive metal cation. The compound or salt according to any one of items 3 to 16.

[0026] 20. The compound or salt according to item 19, wherein the chelate-forming moiety is a moiety derived from DOTA or DOTAGA. 21. The compound or salt according to item 19 or 20, wherein the chelated metal cation is a radioactive metal cation.

[0027] 22. R E The targeting moiety contained in is bonded to the carbon atom of the carbonyl group in -C(=O)R E via a linker group, and the chelate-forming moiety or chelate moiety is part of the linker group. The compound or salt according to any one of items 19 to 21.

[0028] 23. The fluorine bonded to the Si atom via a direct covalent bond is 18 F] fluorine. The compound or salt according to any one of items 1 to 22. 24. The fluorine bonded to the Si atom via a direct covalent bond is 19 F] fluorine. The compound or salt according to any one of items 1 to 22.

[0029] 25. The compound or salt according to any one of items 1 to 24 for use as a medicine. 26. A radiopharmaceutical composition comprising the compound or salt according to any one of items 1 to 24, optionally in combination with a pharmaceutically acceptable excipient.

[0030] 27. The compound or salt according to any one of items 1 to 24, or the radiopharmaceutical composition according to item 26, for use in an in vivo method for diagnosing a disease or disorder.

[0031] 28. The compound, salt or radiopharmaceutical composition for use according to item 27, wherein the diagnostic method involves nuclear medicine imaging. 29. The compound, salt or radiopharmaceutical composition for use according to item 27 or 28, wherein the diagnostic method involves positron emission tomography (PET).

[0032] 30. A compound, salt or radiopharmaceutical composition for use according to item 27 or 28, wherein the diagnostic method involves SPECT. 31. Use of 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 treating a disease or disorder via radioligand therapy.

[0033] 32. A method for preparing a radiolabeled compound, comprising reacting a compound or salt according to any one of items 1 to 22, in which the fluorine bonded to the Si atom via a direct covalent bond is 19 F] fluorine, with 18 F] fluoride to exchange 19 F] fluorine for 18 F] fluorine.

[0034] 33. Use of a group of formula (Ia), (Ib) or (Ic) as defined in any one of items 1 or 5 to 11 as a silicon-based fluoride acceptor group for 19 F] fluorine isotope exchange with 18 F] fluorine.

[0035] 34. Use of a group of formula (Ia), (Ib) or (Ic) as defined in any one of items 1 or 5 to 11 as a silicon-based fluoride acceptor group for 18 F] labeling of a target radiopharmaceutical.

[0036] As described above, the compounds of the present invention include compounds containing a group selected from the groups of formula (Ia), (Ib) and (Ic), and compounds of formula (IIa), (IIb) or (IIc). Further, salts of these compounds, typically pharmaceutically acceptable salts, are also included in the present invention. Thus, unless the contrary is indicated, any reference herein to a compound of the present invention includes compounds containing a group selected from the groups of formula (Ia), (Ib) and (Ic) (and preferred embodiments of these formulas disclosed herein) and salts thereof, and compounds of formula (IIa), (IIb) or (IIc) (and preferred embodiments of these formulas disclosed herein) and salts thereof. Similarly, unless a specific stereochemistry of the compounds under consideration is indicated in a specific context, any racemate, enantiomer, or diastereomer of any chiral compound of the present invention is also included.

[0037] In a general aspect, the present invention provides a compound containing a group selected from the groups of formula (Ia), (Ib) and (Ic), or a salt of such a compound:

[0038]

Chemical formula

[0039] wherein R 1 is a straight-chain or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group, R 2 is a straight-chain or branched C3-C10 alkyl group, preferably a branched C3-C10 alkyl group, more preferably a tert-butyl group, R 3 is (i) -OH or -O - , (ii) an amino acid moiety or an oligopeptide moiety, (iii) a sugar moiety or an amino sugar moiety, (iv) a PEG moiety, and combinations of two or more of (ii), (iii) and (iv) selected from The wavy line indicates the bond that attaches the above group to the remainder of the above compound.

[0040] As a further general aspect, the present invention provides a compound of formula (IIa), (IIb) or (IIc) or a salt of said compound:

[0041]

Chemical formula

[0042] In the above formula, R 1 , R 2 , and R 3 are as defined for the groups of formula (Ia), (Ib) and (Ic), including any preferred embodiments thereof, and R E is a group containing a targeting moiety. As will be understood by those skilled in the art, the targeting moiety contained in R E may be attached directly (i.e., by a direct covalent bond) to the carbon atom of the carbonyl group that forms a bond with R E in the above formula, or optionally via a linker group to this carbon atom. The group R E containing the targeting moiety enables the compound of formula (IIa), (IIb) or (IIc) or a salt thereof to bind to a target structure, for example a target structure that is overexpressed in a human disease such as cancer. Thus, the compounds or salts according to the invention containing the group R E are suitable for use as target radiopharmaceuticals, particularly for in vivo applications in humans.

[0043] Among the groups of formula (Ia), (Ib) and (Ic), the group of formula (Ia) is preferred. Thus, in the above, a compound as a compound according to the invention containing a group of formula (Ia), wherein R 1 and R 2 are each a tert-butyl group, or a salt of such a compound is even more preferred.

[0044] Similarly, among the compounds of formulas (IIa), (IIb) and (IIc) and their salts, the compounds of formula (IIa) and their salts are preferred. Therefore, in the above, R 1 and R 2 are each a tert-butyl group, and the compound (IIa) as a compound of the present invention, or a salt of such a compound, is more preferred.

[0045] In the above formulas (Ia), (Ib) and (Ic) and (IIa), (IIb) and (IIc), R 3 is selected from (i) -OH or -O - , (ii) an amino acid moiety or an oligopeptide moiety, (iii) a sugar moiety or an amino sugar moiety, (iv) a PEG moiety, and combinations of two or more of (ii), (iii) and (iv).

[0046] As is understood, when R 3 is -OH or -O - , the substituent -C(=O)R 3 having R 3 is a carboxyl group -C(=O)OH or a deprotonated carboxylate group -C(=O)O - . As exemplary counterions of the deprotonated carboxylate group, reference can be made to the following cations that can exist as counterions in the salt form of the compounds according to the present invention, for example ammonium ions or alkali metal cations. Therefore, the compounds of the present invention include carboxylic acids, or carboxylates in the form of their salts, for example ammonium salts or alkali metal salts of carboxylic acids.

[0047] Furthermore, R 3 may be an amino acid moiety or an oligopeptide moiety, among which the amino acid moiety is preferred. As will be understood by those skilled in the art, an amino acid moiety is a group that can be derived from an amino acid, i.e., a compound containing an amino group -NH2 and a carboxyl group -COOH in the same molecule. Unless otherwise indicated in a specific context, the amino acids from which an amino acid moiety can be derived may have one or more additional functional groups in addition to the amino group and the carboxyl group. Specific amino acid moieties are typically identified by the name of the amino acid from which they can be derived, such as a lysine moiety, a glutamic acid moiety, etc. Unless otherwise indicated in a specific context, the amino acids from which an amino acid moiety can be derived are preferably α - amino acids. R 3 contained in or R 3 If the amino acid moiety provided by R

[0048] R 3 is an amino acid moiety, it will be further understood that the amino acid moiety can be derived from an amino acid using one of its functional groups, typically its amino group, to form a bond, preferably an amide bond -NH - C(O)- with the carbon atom to which R 3 is attached. Thus, the amino acid moiety as R 3 preferably forms an amide bond with the carbon atom to which R 3 is attached.

[0049] R 3 If R

[0050] is an amino acid moiety, the amino acid moiety is preferably derived from a hydrophilic amino acid containing additional hydrophilic functional groups such as basic or acidic functional groups in addition to the amino group and the carboxyl functional groups. Such moieties may be referred to herein as "hydrophilic amino acid moieties" for brevity. For example, the additional hydrophilic functional groups of a hydrophilic amino acid can be selected from -NH2, -COOH, -NH - C(=NH)-NH2, -C(=O)NH2, and -NH - C(=O)-NH2. Of these, -NH2 and -COOH are preferred. 3When it is an amino acid moiety, the amino acid moiety is more preferably 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. A moiety selected from a lysine moiety and a glutamic acid moiety is even more preferred, and a lysine moiety is most preferred.

[0051] R 3 When it is an oligopeptide moiety, this moiety can be a linear or branched oligopeptide moiety. Preferably, the oligopeptide moiety is a moiety that can be derived from an oligopeptide containing or consisting of 2 to 10, more preferably 2 to 5, even more preferably 2 or 3 amino acid moieties. The amino acids providing the amino acid moieties of the oligopeptide moiety can each independently be a natural amino acid or a synthetic amino acid at each occurrence. The amino acid moieties are linked via an amide bond -C(O)-NH-. This includes the possibility that the amide bond is formed via a functional group in the side chain of the amino acid. The oligopeptide moiety is derived from an oligopeptide by using one of the functional groups of the amino acid moieties constituting it, typically an amino group, to form a bond, preferably R 3 It will be further understood that it can be derived by forming an amide bond -NH-C(O)- with the carbon atom to which it is attached. Thus, R 3 The oligopeptide moiety as R 3 preferably forms an amide bond with the carbon atom to which it is attached.

[0052] Unless otherwise indicated in a specific context, the amino acids from which the amino acid moieties contained in the oligopeptide can be derived may have one or more additional functional groups in addition to the amino group and the carboxylic acid group. Also in this context, a specific amino acid moiety is typically identified by the name of the amino acid from which it can be derived, such as a lysine moiety, a glutamic acid moiety, etc. Unless otherwise indicated in a specific context, the amino acids from which the amino acid moieties can be derived are preferably α - amino acids. When the amino acid moieties constituting the oligopeptide can be derived from chiral amino acids, the L - configuration is preferred.

[0053] R 3 When R is an oligopeptide moiety, one or more of the amino acid moieties constituting the oligopeptide moiety are preferably derived from hydrophilic amino acids containing additional hydrophilic functional groups such as basic or acidic functional groups in addition to the amino group and the carboxyl functional group. As described above, the hydrophilic amino acids may be natural amino acids or synthetic amino acids. Such moieties may be referred to herein as "hydrophilic amino acid moieties" for brevity. For example, the additional hydrophilic functional groups of the hydrophilic amino acids can be selected from -NH2, -COOH, -NH - C(=NH)-NH2, -C(=O)NH2, and -NH - C(=O)-NH2. Of these, -NH2 and -COOH are preferred. The additional hydrophilic functional groups can also be used to form a bond, typically an amide bond, with an adjacent amino acid moiety in the oligopeptide.

[0054] Therefore, R 3When it is an oligopeptide moiety, one or more of the amino acid moieties constituting the oligopeptide moiety are more preferably 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. A moiety selected from a lysine moiety and a glutamic acid moiety is even more preferable, and a lysine moiety is most preferable.

[0055] R 3 When R is a sugar moiety or an amino sugar moiety, a moiety derivable from a monosaccharide is preferable, and this monosaccharide may be a monosaccharide in which a hydroxy group is replaced with an amino group. R 3 When R is a sugar moiety or an amino sugar moiety, the sugar moiety or the amino sugar moiety is derived from a sugar or an amino sugar, for example, using a hydroxy group of the sugar or the amino sugar, R 3 together with the carbon atom to which it is attached, by forming an ester bond -O-C(O)-, or using the amino group of the amino sugar, R 3 It will be further understood that it can be derived by forming an amide bond -NH-C(O)- together with the carbon atom to which it is attached. Among the sugar moiety and the amino sugar moiety, the amino sugar moiety is preferable. The amino sugar moiety preferably forms an amide bond together with the carbon atom to which R 3 is attached.

[0056] R 3 Examples of the sugar moiety or the amino sugar moiety as R 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-fructopyranose.

[0057] R 3The polyethylene glycol (PEG) moiety as such preferably has the formula -(CH2-CH2-O) X -(wherein X is an integer from 2 to 10, preferably from 4 to 10, more preferably 8) and comprises a moiety containing a group of the formula

[0058] More preferably, the PEG moiety has the formula -NH--(CH2-CH2-O) X -R P1 wherein the nitrogen atom providing the open bond forms an amide bond -NH-C(O)- together with the carbon atom to which R is attached, X is an integer from 2 to 10, preferably from 4 to 10, more preferably 8, and R 3 is selected from -CH2-COOH and -CH2-CH2-COOH. P1 As an example of a combination of two or more of (ii), (iii) and (iv) as can be R

[0059] according to the above, reference may be made to the combination of an amino acid moiety which forms an amide bond together with the carbon atom to which R 3 is attached and an amino sugar moiety which forms an amide bond -NH-C(O)- with the carboxy group of the amino acid moiety using its own amino group. As another example, reference may be made to the combination of an oligopeptide moiety which forms an amide bond together with the carbon atom to which R 3 is attached and an amino sugar moiety which forms an amide bond -NH-C(O)- with the carboxy group of the oligopeptide moiety using its own amino group. 3 Among the options for R

[0060] discussed above, R 3 is the group -OH, -O 3 - ​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 a hydrophilic amino acid moiety, and the oligopeptide moiety preferably contains one or more hydrophilic amino acid moieties.

[0061] Therefore, in the above, the compound of the present invention preferably is a compound containing a group of formula (Ia) (wherein R 1 and R 2 are each a tert-butyl group, and R 3 is selected from -OH, -O - , an amino acid moiety, and an oligopeptide moiety, more preferably an amino acid moiety and an oligopeptide moiety), or a salt of such a compound. Among the amino acid moiety and the oligopeptide moiety, the amino acid moiety is preferred. As also discussed above, the amino acid moiety is a hydrophilic amino acid moiety, and the oligopeptide moiety preferably contains one or more hydrophilic amino acid moieties.

[0062] Therefore, for example, a compound of the present invention containing a group of formula (Ia) (wherein R 1 and R 2 are each a tert-butyl group, and R 3 is selected from -OH, -O - , and a hydrophilic amino acid moiety such as a lysine moiety), or a salt of such a compound is preferred.

[0063] The group R E in the compound of formula (IIa), (IIb) or (IIc) or a salt thereof contains a targeting moiety. The group R EThe presence enables the compounds of formula (IIa), (IIb) or (IIc) further comprising a SiFA group according to the present invention or salts thereof to bind to the target structure. Therefore, the compounds of the present invention or salts thereof can be used as target radiopharmaceuticals, particularly target radiopharmaceuticals for in vivo applications in humans such as functional molecular imaging in vivo. This includes radiolabeled compounds of formula (IIa), (IIb) or (IIc) or salts thereof that can be directly used as target radiopharmaceuticals, for example, compounds in which the SiFA group according to the present invention is 18 labeled with F, and non-radiolabeled compounds that are useful precursors that can be radiolabeled before being used as target radiopharmaceuticals.

[0064] In the compounds of formula (IIa), (IIb) and (IIc) and salts thereof, the targeting moiety contained in R E may be directly bonded to, for example, the carbon atom of the carbonyl group in -C(=O)R E of formula (IIa), (IIb) and (IIc). In this case, R E may be a targeting moiety, that is, R E may consist of a targeting moiety. When the targeting moiety is directly bonded to the carbon atom of the carbonyl group in a substituent having R E , it is preferred that the carbonyl group and the targeting moiety form an amide bond -C(O)-NH-, and the -NH- coupling group of the amide bond is provided by the targeting moiety.

[0065] Alternatively, the group R E may further comprise, for example, a linker group, and the targeting moiety contained in R E may be bonded to the carbon atom of the carbonyl group in -C(=O)R E of formula (IIa), (IIb) and (IIc) via the linker group. In the latter case, the linker group typically is R Eis directly attached (i.e., via a direct covalent bond) to the carbon atom of the carbonyl group in the substituent having, and the targeting moiety is typically directly attached to a linker group. As will be understood by those skilled in the art, the presence of a linker group can, for example, facilitate the coupling of the SiFA group to the targeting moiety or prevent the SiFA group from interfering with the targeting function of the targeting moiety contained in R E and may be useful. When such a linker group is present and is attached to the carbon atom of the carbonyl group in the substituent having R E , it is preferred that the carbonyl group and the linker group form an amide bond -C(O)-NH-, and the -NH- coupling group of the amide bond is provided by the linker group. Further, it is also preferred that the targeting moiety contained in R E and the linker group form an amide bond -C(O)-NH-.

[0066] When the linker group has a branched-chain structure, more than one, for example two, targeting moieties may be attached thereto. However, typically, the group R E contains one targeting moiety.

[0067] Thus, the group R E can consist of a linker group and a targeting moiety. In this case, the group R E in formulas (IIa), (IIb) and (IIc) may have the structure -L-R T , where L is the linker group contained in R E , and R T is the targeting moiety contained in R E , and this structure results in compounds of formulas (IIa’), (IIb’) and (IIc’) shown below or salts thereof, among which the compounds of formula (IIa’) are more preferred. As will be understood, R 1 , R 2 and R 3is as defined above for formulas (IIa), (IIb) and (IIc), including any preferred embodiments. For the linker group L in formulas (IIa’), (IIb’) and (IIc’), it is also preferred that the linker and the carbonyl group -C(O)- to which it is attached form an amide bond -C(O)-NH-, and the -NH- coupling group in the amide bond is provided by the linker L. Further, the linker L and R T are preferably attached to each other via an amide bond -C(O)-NH-. Formulas (IIa’), (IIb’) and (IIc’) are each preferred embodiments of formulas (IIa), (IIb) and (IIc). Thus, unless otherwise indicated in a specific context, any reference to formulas (IIa), (IIb) and (IIc) herein includes formulas (IIa’), (IIb’) and (IIc’).

[0068]

Chemical Formula

[0069] Unless otherwise indicated, any general reference to the targeting moiety included in R E or any general reference to the targeting moiety herein relates to all targeting moieties in all conformations of the compounds of formulas (IIa), (IIb), and (IIc) or their salts, and the compounds of formulas (IIa’), (IIb’), and (IIc’) or their salts as their preferred embodiments, as discussed above. Thus, it includes, for example, a targeting moiety directly attached to a carbonyl group in a substituent containing R E , or a targeting moiety attached via a linker group, for example, the targeting moiety R T in formulas (IIa’), (IIb’) and (IIc’).

[0070] A group R containing a targeting moiety in the compounds of formulas (IIa), (IIb), and (IIc) or their salts E(and in the compounds of formula (IIa'), (IIb'), and (IIc') or salts thereof, the targeting moiety is R T represented by R E as a specific embodiment of the group -L-R T ) enables the compound or salt to bind to the target structure. Thus, the compounds of the invention having the group -R E or -L-R T or salts thereof can be used as target radiopharmaceuticals, particularly target radiopharmaceuticals for in vivo applications in humans such as functional molecular imaging in vivo. A wide variety of targeting moieties are known in the field of radiopharmacy, and these enable a compound or salt containing such a targeting moiety to bind to the target structure of interest. In the context of the present invention, the targeting moiety contained in R E or the targeting moiety R T can be used. Such targeting moieties are also referred to as targeting vectors or biological targeting moieties. It will be understood that the target structure of interest is generally a biological target structure, more specifically a biological target structure associated with a disease or disorder, such as a target structure overexpressed in a human disease such as cancer. Furthermore, it will be understood that a compound containing a targeting moiety generally binds preferentially to the target structure of interest, for example, compared to other sites in the body of a patient to whom the compound is administered.

[0071] Compounds containing a targeting moiety, i.e., particularly compounds of formula (IIa), (IIb), and (IIc) or salts thereof, or compounds of formula (IIa'), (IIb'), and (IIc') or salts thereof, generally bind to the corresponding target structure with a high affinity as indicated by an IC50 in the low nanomolar range, preferably 50 nM or less, more preferably 10 nM or less, even more preferably 5 nM or less. Here, the maximum half-inhibitory concentration (IC50) is defined as a quantitative measure of the molar concentration of a compound according to the invention containing a targeting moiety required to inhibit the binding of a radiolabeled reference ligand to the receptor by 50% in vitro.

[0072] R E As exemplary targeting moieties included in R, reference can be made to receptor-binding moieties, enzyme-binding substrates or enzyme inhibitors, peptides, proteins, or antibody fragments such as nanobodies or engineered antigen-binding constructs. Among these exemplary moieties, targeting moieties selected from receptor-binding moieties, enzyme-binding substrates and enzyme inhibitors are preferred.

[0073] For example, R E The targeting moiety included in may be a peptide targeting moiety, i.e., a moiety composed of amino acid units, for example, 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 combining linear and cyclic portions.

[0074] Typically, when the targeting moiety is the receptor-binding moiety mentioned above, the presence of the targeting moiety in the compound of the present invention or its salt enables the compound or salt to act as a ligand for the relevant receptor. Similarly, when the targeting moiety is a portion that binds to the prostate-specific membrane antigen (PSMA-binding portion) mentioned above, the presence of the targeting moiety in the compound of the present invention or its salt enables the compound or salt to act as a ligand for PSMA.

[0075] R E When the targeting moiety included in R is the receptor-binding moiety or enzyme-binding substrate according to the above, the compound of the present invention containing the targeting moiety can generally bind to the receptor or enzyme with high affinity. In this context, high-affinity binding preferably means that a compound containing a receptor-binding moiety or enzyme-binding substrate exhibits an IC50 in the low nanomolar range, preferably 50 nM or less, more preferably 10 nM or less, and even more preferably 5 nM or less. For the sake of clarity, here, the maximum half-inhibitory concentration (IC50) is defined as a quantitative measure of the molar concentration of the compound according to the present invention containing a receptor-binding moiety or enzyme-binding substrate, respectively, required to inhibit the binding of a radioactive reference ligand to the receptor by 50% in vitro.

[0076] As a target structure of the purpose, R E Exemplary receptors for the targeting moiety contained in include gastrin-releasing peptide receptor (GRPR), C-X-C chemokine receptor type 4 (CXCR4), somatostatin receptor (SSTR), cholecystokinin B receptor (CCK-2R), and prostate-specific membrane antigen (PSMA). Thus, exemplary receptor-binding moieties as the targeting moiety include a gastrin-releasing peptide receptor (GRPR) binding moiety, a C-X-C chemokine receptor type 4 (CXCR4) binding moiety, a somatostatin receptor (SSTR) binding moiety, or a cholecystokinin B receptor (CCK-2R) binding moiety.

[0077] R E Examples of suitable SSTR binding moieties as the targeting moiety contained in R include Tyr 3 -octreotate (or Tyr 3 ,Thr 8 -octreotide, TATE, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-OH), Thr 8 -octreotide (ATE), Phe 1 ,Tyr 3 -octreotide (TOC, H-D-Phe-cyclo(L-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-L-Thr-ol), Nal 3 -octreotide (NOC, H-D-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 (H-L-Cpa-cyclo(D-Cys-L-Aph(Hor)-D-Aph(Cbm)-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2), BASS (H-L-Phe(4-NO2)-cyclo(D-Cys-L-Tyr-D-Trp-L-Lys-L-Thr-L-Cys)-D-Tyr-NH2), and KE121 (cyclo(D-Dab-L-Arg-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe)), more preferably TATE or JR11, and most preferably TATE. A portion that can be derived from a receptor agonist or receptor antagonist can be mentioned. As will be understood by those skilled in the art, the receptor-binding portion as the targeting portion can be obtained from the exemplary receptor agonists or antagonists listed above, using a functional group contained in the receptor agonist or antagonist, such as a carboxyl group or an amino group, to generate a coupling group that binds the targeting portion to the remainder of the compound of the present invention. Preferably, these receptor agonists or receptor antagonists use an amino group contained therein, such as an amino group in a phenylalanine unit that is optionally substituted, to form an amide bond -C(O)-NH- with the remainder of the compound of the present invention to provide the targeting portion.

[0078] Specifically, as an exemplary SSTR-binding portion suitable as the targeting portion, reference can be made to one of the following formulas (wherein the wavy line indicates a bond that binds the group to the remainder of the compound of the present invention):

[0079]

Chemical formula

[0080] R E As an exemplary CXCR4-binding portion suitable as the targeting portion contained in B1 R, reference can be made to the portion of the following formula (wherein R

[0081] [Chem.]

[0082] R E As an exemplary PSMA binding moiety suitable as a targeting moiety contained in R, the following formula:

[0083] [Chem.]

[0084] (wherein, m is an integer from 2 to 6, preferably from 2 to 4, more preferably 2, n is an integer from 1 to 6, preferably from 2 to 4, more preferably 2 or 4, R 1P is CH2, NH or O, preferably NH, R 3P is CH2, NH or O, preferably NH, R 2P is C or P(OH), preferably C, The wavy line indicates a bond that attaches the group to the remainder of the compound of the present invention). Typically, the PSMA binding moiety is attached to the remainder of the compound of the present invention via an amide bond -NH-C(O)-, and thus the group -NH- or the group -C(O)-, more preferably the group -NH-, is further provided at the position indicated by the dashed line in the above formula, and it is preferred that this group forms part of such an amide bond. More preferably, the PSMA binding moiety has the following formula:

[0085] [Chem.]

[0086] (wherein, m is an integer from 2 to 6, preferably from 2 to 4, more preferably 2, n is an integer from 1 to 6, preferably from 2 to 4, more preferably 2 or 4, The wavy line is the part that indicates the bond connecting the group to the rest of the compound of the present invention). Typically, a more preferred PSMA binding moiety is bonded to the rest of the compound of the present invention via an amide bond -NH-C(O)-, and thus the group -NH- or the group -C(O)-, more preferably the group -NH-, is further provided at the position indicated by the dashed line in the above formula, and it is preferred that this group forms part of such an amide bond.

[0087] R E As an exemplary GRPR binding moiety suitable as a targeting moiety included in R, reference can be made to the targeting moiety included in the modified GRPR antagonist peptide disclosed in WO2021 / 121735.

[0088] R E As a particularly preferred example of a GRPR binding moiety suitable as a targeting moiety included in R, the following group included in the GRPR antagonist RM2, namely -Pip-D-Phe-L-Gln-L-Trp-L-Ala-L-Val-Gly-L-His-L-Sta-L-Leu-NH2 (where Pip represents a 4-amino-1-carboxymethyl-piperidine residue in which the carboxyl group forms an amide bond with D-Phe) can be referred to.

[0089] R E As an exemplary CCK-2R binding moiety suitable as a targeting moiety included in R, reference can be made to the peptidomimetic amino acid polymer disclosed in WO2018 / 224665.

[0090] R E As a particularly preferred example of a CCK-2R binding moiety suitable as a targeting moiety included in R, the peptide group included in the ligand compound PP-F11 or PP-F11N, namely -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Met-L-Asp-L-Phe-NH2 and -D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-Phe-NH2, and -D-Glu-L-Ala-L-Tyr-Gly-L-Trp-L-(N-Me)Nle-L-Asp-L-1Nal-NH2 can be referred to.

[0091] In addition to the targeting moiety, the group R E may comprise a chelating moiety, or a chelate moiety formed by a chelating moiety and a chelated metal cation. When present, the chelating / chelate moiety typically forms part of a linker, such as the linker L mentioned above, which may be included in R E One or more, for example two, chelating / chelate moieties may form part of such a linker. The chelating / chelate moiety may be part of a linear linker structure or, for example, by providing a branch of a branched linker structure, may be part of a branched linker structure.

[0092] The chelating moiety is preferably diethylenetriamine pentamethylene phosphonic acid (EDTMP) and its derivatives, diethylenetriamine pentaacetic acid (DTPA) and its derivatives, bis(carboxymethyl)-1,4,8,11-tetraaza-bicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diamine tetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid (CPTA), N’-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]-amino]pentyl]-N-hydroxybutanediamide (DFO) and its derivatives, 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A), 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA or DOTA-GA), 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM), N,N’-dipyridoxylethylenediamine-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), hydroxyethyldiamine triacetic acid (HEDTA), 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 triethylenetetraminehexaacetic acid (TTHA), N,N’-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa), 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP), 1,4,7-triazacyclononane-1,4,7-tris[methylene(2-carboxyethyl)phosphinic acid (TRAP), 2-(4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (DO3AM), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethylphosphinic acid)] (DOTPI), S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid, hydrazinonicotinic acid (HYNIC), 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6-Eicosan-1,8-diamine (SarAr), 6-amino-6-methylperhydro-1,4-diazepine-N,N,N’,N’-tetraacetic acid (AAZTA) and its derivatives, such as (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA), pentadeca-1,4,7,10,13-penta-amino pentaacetic acid (PEPA), hexadeca-1,4,7,10,13,16-hexaamine-hexaacetic acid (HEHR), 4-{[bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD), N(4-{[bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-nona-1,4,7-triamine triacetic acid (BPAM), 1,2-[{6-(carboxylate)pyridin-2-yl}methylamine]ethane (DEDPA, H2DEDPA), deferoxamine (DFO) and its derivatives, deferiprone, (4-acetylamino-4-yl){2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}-heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (CP256) and its derivatives, such as YM103; tetraazacyclodecane-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 - (carboxylato)pyridin - 2 - yl}methylamino] - ethane (H2dedpa), N,N’ - bis(6 - carboxy - 2 - pyridylmethyl) - ethylenediamine - N,N’ - diacetic acid (H4octapa), N,N’ - bis(2 - hydroxy - 5 - sulfonylbenzyl) - N,N’ - bis - (2 - methylpyridyl)ethylenediamine (H6Sbbpen) and its derivatives, triethylenetetramine - N,N,N’,N’’,N’’’,N’’’ - hexaacetic acid (hexaacetic) (TTHA), 2 - aminomethylpiperidine triacetic acid (2 - AMPTA) and its derivatives, such as 2 - (N - (2 - hydroxybenzyl)aminomethyl)piperidine (2 - AMPTA - HB), derivatives of 2 - AMPTA further functionalized with additional functional groups suitable for conjugation with peptide structures, 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 - tetraazoundecane (N4) and its derivatives, which can be derived from chelating agents selected from these. Among these chelating agents, DOTA, DOTAGA, DOTAM, DO3AM, NOTA and NODAGA are preferred. DOTA and DOTAGA are most preferred.

[0093] As will be understood by those skilled in the art, the preferred chelating moiety is formed by the preferred chelating - forming moiety discussed above and a chelated metal cation. As will be further understood by those skilled in the art, the chelating moiety or chelate moiety in the compounds according to the invention can be readily 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 carboxyl groups, carboxamide groups, amino groups, or hydroxy groups, to form a chelating moiety bonded to the remainder of the compound, for example by generating a coupling group selected from -C(O)-, -NH-, and -O-. Preferably, the carboxyl group is used to generate a coupling group -C(O)- that bonds the chelating moiety or chelate moiety via an amide bond -C(O)-NH-.

[0094] The metal cations that can be chelated to the chelate moiety can be radioactive or non-radioactive metal cations. The metal cations that can be chelated to the chelate moiety are preferably 43 Sc 44 Sc 47 Sc 51 Cr 52m Mn 55 Co 57 Co 58 Co 52 Fe 56 Ni 57 Ni 62 Cu 64 Cu 67 Cu 66 Ga 68 Ga 67 Ga 89 Zr 90 Y 86 Y 94m Tc 99m Tc 97 Ru 105 Rh 109 Pd 111 Ag 110m In 111 In 113m In 114m In 117m Sn 121 Sn 127 Te 142 Pr 143 Pr147 Nd, 149 Gd, 149 Pm, 151 Pm, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 156 Eu, 157 Gd, 155 Tb, 161 Tb, 164 Tb, 161 Ho, 166 Ho, 157 Dy, 165 Dy, 166 Dy, 160 Er, 165 Er, 169 Er, 171 Er, 166 Yb, 169 Yb, 175 Yb, 167 Tm, 172 Tm, 177 Lu, 186 Re, 186g Re, 188 Re, 188 W, 191 Pt, 195 mPt, 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 cations of Th, and are selected from non-radioactive isotopes of any of these metals. The chelating cation is a complex cation, for example, a further coordination ligand other than the chelating group, for example 99m a metal ion having an oxo ligand in a chelate containing a Tc(V)-oxo core may be used.

[0095] a radioactive or non-radioactive cation of Ga or Lu, for example 177 Lu or68 Ga is particularly preferred as the chelating cation. According to the above, when the compound of the present invention contains a chelating moiety, or a chelate moiety formed by a chelating moiety and a chelating radioactive or non-radioactive metal cation, the chelating moiety is derived from DOTA or DOTAGA, and typically, by using the carboxyl groups contained in DOTA or DOTAGA to generate a coupling group -C(O)- that binds the chelating moiety to the remainder of the compound, the chelating cation of the chelate moiety is 177 Lu or 68 It is preferably a cation of Ga or Lu that may be radioactive or non-radioactive, such as a cation of Ga.

[0096] According to the above, the essential component of the group R in the compounds of formula (IIa), (IIb), (IIc) and their salts is E the targeting moiety represented by the group R in the compounds of formula (IIa’), (IIb’) and (IIc’) and their salts. The optional component of the group R in the compounds of formula (IIa), (IIb), (IIc) and their salts is a linker. Such a linker is preferably included as L in the preferred compounds of formula (IIa’), (IIb’), or (IIc’) and their salts, where, for example, -R T is represented by -L-R E . Another optional component of the group R is a chelating moiety, or a chelate moiety formed by a chelating moiety and a chelating radioactive or non-radioactive metal cation. When the chelating moiety / chelate moiety is included in R E , the linker, for example linker L, is also typically included in R E , and the chelating moiety / chelate moiety forms part of the linker. T The R E discussed above in formula (IIa), (IIb) and (IIc) E E E is also typically included in R, and the chelating moiety / chelate moiety forms part of the linker.

[0097] The R in formula (IIa), (IIb) and (IIc) discussed above EThe linker that may be included in, for example, the linker L in formulas (IIa’), (IIb’) and (IIc’) may have, for example, a linear or branched backbone structure. The linker may include one or more moieties that provide additional functionality in the compounds of the present invention, for example, a chelating moiety, or a chelate moiety formed by a chelating moiety and a chelated metal cation. Such moieties with additional functionality may be incorporated, for example, into the branched or linear backbone of the linker.

[0098] Examples of suitable moieties as linkers include amino acid moieties or oligoamide moieties. As described above, such amino acid moieties or oligoamide moieties as linkers may optionally include one or more additional moieties that provide additional functionality in the compounds of the present invention, for example, a chelating moiety, or a chelate moiety formed by a chelating moiety and a chelated metal cation.

[0099] For example, an amino acid moiety acting as a linker may, for example, R E a coupling group -NH- for forming an amide bond with the carbonyl group to which it is attached, and, for example, R E a targeting moiety included in, for example, R T a coupling group -C(O)- for forming an amide bond with, and here, the -NH- coupling group in the amide bond is provided by the targeting moiety. As another example, the amino acid moiety may, for example, R E a coupling group -NH- for forming an amide bond with the carbonyl group to which it is attached, and, for example, R E a coupling group -C(O)- for forming an amide bond with the targeting moiety included in, and an additional functional group such as an additional carboxy group or an additional amino group.

[0100] R E Regarding the oligoamide moiety as an exemplary linker included in R EIt is similarly preferred that the carbonyl group -C(O)- to which it is attached and the like form an amide bond -C(O)-NH-, where the -NH- coupling group in the amide bond is provided by the oligoamide moiety. Further, it is preferred that the oligoamide moiety and the targeting moiety contained in R E form an amide bond -C(O)-NH-. T As understood by those skilled in the art, the oligoamide moiety contains two or more, for example 2 to 10, preferably 2 to 8, more preferably 2 to 6 subunits that are linked to each other via an amide bond -C(O)-NH-. For example, each of the subunits may be formed by 7 to 30 atoms. If one of the subunits provides more than two, for example three, coupling groups selected from -C(O)- and -NH- suitable for forming an amide bond -C(O)-NH-, the oligoamide moiety may be a branched-chain moiety.

[0101] As understood by those skilled in the art, subunits suitable for a linear or branched-chain oligoamide linker are, for example,

[0102] - a unit that provides a coupling group -NH- and a coupling group -C(O)-, which may be derived from, for example, an amino acid, - a unit that provides two coupling groups -NH-, which may be derived from, for example, a diamino compound or a compound containing two amino groups together with one or more additional functional groups, such as an amino acid containing a side chain having an additional terminal amino group, - a unit that provides two coupling groups -C(O)-, which may be derived from, for example, a dicarboxylic acid or a compound containing two carboxy groups together with one or more additional functional groups, such as an amino acid containing a side chain having an additional terminal carboxy group, and a chelating agent containing 2, 3 or 4 carboxy groups or carboxamide groups, two of which provide the coupling group -C(O)-. ​- A unit providing two coupling groups -NH- and one coupling group -C(O)-, which may be derived from an amino acid, for example, containing a side chain having a terminal amino group, and - A unit providing two coupling groups -C(O)- and one coupling group -NH-, which may be derived from an amino acid, for example, containing a side chain having a terminal carboxy group may be selected from.

[0103] The oligoamide moiety having a branched-chain structure acting as a linker L typically contains a terminal subunit that forms only one amide bond -C(O)-NH- with an adjacent unit. As an example, units derived from a chelating agent containing two, three or four carboxy groups or carboxamide groups, one of which provides the coupling group -C(O)- can be mentioned.

[0104] Thus, for example, according to the above, preferred compounds of the present invention are compounds of formula (IIa) or formula (IIa') wherein R E , L and R T are each defined as above, including any preferred embodiments of their definitions, R 1 and R 2 are each a tert-butyl group, R 3 is selected from -OH, -O - , an amino acid moiety, and an oligopeptide moiety, more preferably an amino acid moiety and an oligopeptide moiety), or a salt of such a compound. Among the amino acid moiety and the oligopeptide moiety, the amino acid moiety is preferred. As discussed above, the amino acid moiety is a hydrophilic amino acid moiety and the oligopeptide moiety preferably contains one or more hydrophilic amino acid moieties.

[0105] Further exemplary compounds of formulas (IIa), (IIb) and (IIc) according to the present invention and their salts can be represented by the following formula (IIIa) and their salts: R S -(RA1 ) a -R T1 (IIIa) R S -R A2 (R CH1 )-(R A3 ) b -R T1 (IIIb) R S -(R A4 ) c -R CH2 -(R A5 ) d -R T1 (IIIc) R S -R A6 (R CH3 )-(R A7 ) e -R CH4 -(R A8 ) f -R T1 (IIId).

[0106] In these formulas, R S is a group of formula (Ia), (Ib) or (Ic) discussed herein, preferably a group of formula (Ia). R T1 is a targeting moiety discussed herein, for example, a gastrin-releasing peptide receptor (GRPR) binding moiety, a C-X-C 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, for example, an example of these binding moieties disclosed herein.

[0107] For example, according to the above, preferred examples of the compounds of formulas (IIIa) to (IIId) are those in which R S is a group of formula (Ia) (wherein R 1 and R 2 are each a tert-butyl group and R 3 is -OH, -O -, an amino acid moiety, and an oligopeptide moiety, more preferably selected from an amino acid moiety and an oligopeptide moiety), or a salt of such a compound. Among the amino acid moiety and the oligopeptide moiety, the amino acid moiety is preferred. As discussed above, the amino acid moiety is a hydrophilic amino acid moiety, and the oligopeptide moiety preferably contains one or more hydrophilic amino acid moieties.

[0108] Furthermore, in formula (IIIa): Group R A1 When there are more than one group R A1 present, for each occurrence independently, two adjacent groups (e.g., R S , another group R A1 , or R T1 ) are divalent groups that form an amide bond -NH-C(O)-. Preferably, R A1 contains 2 to 8 carbon atoms and does not contain the carbonyl carbon atom involved in the amide bond. It will be understood by those skilled in the art that each group R A1 can be independently selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIIa). For example, the group R A1 can be a group that provides a coupling group -NH- and a coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0109] The variable a is an integer from 0 to 4, for example 0, 1, 2, or 3. In formula (IIIb): R CH1 is a chelating moiety as discussed herein, including moieties derived from examples of chelating moieties disclosed herein, such as DOTA or DOTAGA, or a chelate moiety formed by a chelating moiety and a chelated metal cation. As understood from formula (IIIb), R CH1 is a monovalent moiety bonded to R A2 . R CH1 and RA2 are bonded to each other via an amide bond -NH-C(O)-.

[0110] Group R A2 is R S and R CH1 and, if present, R A3 or R T1 is a trivalent group that forms an amide bond -NH-C(O)- with. Preferably, R A2 contains 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. It will be understood by those skilled in the art that R A2 can be selected from compounds that provide functional groups suitable for the formation of an amide bond, taking fully into account the desired arrangement of the groups / portions contained in the compound of formula (IIIb). For example, group R A2 can be a group that provides two coupling groups -NH- and a coupling group -C(O)-.

[0111] Group R A3 is, when more than one group R A3 is present, for each occurrence independently, R A2 and, if present, another group R A3 or R T1 is a divalent group that forms an amide bond -NH-C(O)- with. Preferably, R A3 contains 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. Each group R A3 can be independently selected from compounds that provide functional groups suitable for the formation of an amide bond, taking fully into account the desired arrangement of the groups / portions contained in the compound of formula (IIIb). It will be understood by those skilled in the art that, for example, group R A3 can be a group that provides a coupling group -NH- and a coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0112] The variable b is an integer from 0 to 4, for example 0, 1, 2 or 3. In formula (IIIc): Group R A4 When there are more than one group R A4 present, for each occurrence independently, R S and R CH2 is a divalent group that forms an amide bond -NH-C(O)- with. Preferably, R A4 contains 2 to 8 carbon atoms and does not contain the carbonyl carbon atom involved in the amide bond. Each group R A4 can be independently selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIIc). For example, the group R A4 can be a group that provides a coupling group -NH- and a coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0113] The variable c is an integer from 1 to 4, for example 1, 2 or 3, preferably 1 or 2. R CH2 is a chelating moiety discussed herein, including moieties derived from examples of chelating moieties disclosed herein, such as DOTA or DOTAGA, or a chelate moiety formed by a chelating moiety and a chelated metal cation. As understood from formula (IIIc), R CH2 is R A4 , and when present, R A5 or R T1 and is a divalent moiety bonded to. R CH2 is bonded to its adjacent group via an amide bond -NH-C(O)-.

[0114] Group R A5 When there are more than one group R A5 present, for each occurrence independently, R CH2 and R T1 is a divalent group that forms an amide bond -NH-C(O)- with. Preferably, R A5contains from 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. Each group R A5 It will be understood by those skilled in the art that it can be independently selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIIc). For example, the group R A5 can be a group that provides the coupling group -NH- and the coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0115] The variable d is an integer from 0 to 4, such as 0, 1, 2 or 3, preferably 0, 1 or 2. In formula (IIId): R CH3 is a chelating moiety discussed herein, including moieties derived from examples of chelating moieties disclosed herein, such as DOTA or DOTAGA, or a chelate moiety formed by a chelating moiety and a chelated metal cation. As understood from formula (IIId), R CH3 is a monovalent moiety bonded to R A4 . R CH3 and R A4 are bonded to each other via the amide bond -NH-C(O)-.

[0116] The group R A6 is a trivalent group that forms an amide bond -NH-C(O)- with R S , R CH3 and R A7 . Preferably, R A6 contains from 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. R A6 It will be understood by those skilled in the art that it can be selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIId). For example, the group R A6 can be a group that provides two coupling groups -NH- and the coupling group -C(O)-.

[0117] Group R A7 When there is more than one group R A7 for each occurrence, independently, R A6 and R CH4 is a divalent group that forms an amide bond -NH-C(O)- with. Preferably, R A7 contains 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. Each group R A7 can be independently selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIId). For example, the group R A7 can be a group that provides a coupling group -NH- and a coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0118] The variable e is an integer from 1 to 4, for example 1, 2 or 3, preferably 1 or 2. R CH4 is a chelating moiety discussed herein, including moieties derived from examples of chelating moieties disclosed herein, such as DOTA or DOTAGA, or a chelate moiety formed by a chelating moiety and a chelated metal cation. As understood from formula (IIId), R CH4 is R A7 , and, when present, R A8 or R T1 is a divalent moiety bonded to. R CH4 is bonded to its adjacent group via an amide bond -NH-C(O)-.

[0119] Group R A8 When there is more than one group R A8 for each occurrence, independently, R CH4 and R T1 is a divalent group that forms an amide bond -NH-C(O)- with. Preferably, R A8contains from 2 to 8 carbon atoms and does not include the carbonyl carbon atom involved in the amide bond. Each group R A8 It will be understood by those skilled in the art that it can be independently selected from compounds that provide functional groups suitable for the formation of amide bonds, taking fully into account the desired arrangement of the groups / parts contained in the compound of formula (IIId). For example, the group R A8 can be a group that provides the coupling group -NH- and the coupling group -C(O)-, a group that provides two coupling groups -NH-, or a group that provides two coupling groups -C(O)-.

[0120] The variable f is an integer from 0 to 4, for example 0, 1, 2 or 3, preferably 0, 1 or 2. As described above, the compounds according to the invention include compounds containing a group selected from the groups of formula (Ia), (Ib) and (Ic) or salts thereof, and compounds of formula (IIa), (IIb) or (IIc) including formula (IIa’) to (IIc’) and (IIIa) to (IIId) or salts of said compounds. The salts are preferably pharmaceutically acceptable salts, i.e. salts formed with pharmaceutically acceptable anions or cations. The salts may be formed, for example, by protonation of an atom having a lone pair of electrons susceptible to protonation such as a nitrogen atom using an inorganic or organic acid, or by separation of a proton from an acidic group such as a carboxy group by neutralization using, for example, a base. Other charged groups that may be present in the compounds according to the invention and that may provide the compounds in salt form include continuously charged groups, for example, quaternary ammonium groups including ammonium cations in which nitrogen is substituted by four organyl groups, or charged chelate complexes.

[0121] When the salt form includes the positively charged form of the compound, exemplary anions that may be present as counterions to the salt form of the compound of the present invention include, for example, chloride ion, bromide ion, iodide ion, sulfate ion, nitrate ion, phosphate ion (such as phosphate, hydrogen phosphate, or dihydrogen phosphate, etc.), carbonate ion, bicarbonate or perchlorate ion; acetate ion, trifluoroacetate ion, propionate ion, butyrate ion, valerate ion, hexanoate ion, heptanoate ion, octanoate ion, cyclopentanepropionate ion, undecanoate ion, lactate ion, maleate ion, oxalate ion, fumarate ion, tartrate ion, malate ion, citrate ion, nicotinate ion, benzoate ion, salicylate ion or ascorbate ion; sulfonate ions, for example, methanesulfonate ion, ethanesulfonate ion, 2-hydroxyethanesulfonate ion, benzenesulfonate ion, p-toluenesulfonate ion (tosylate ion), 2-naphthalenesulfonate ion, 3-phenylsulfonate ion, or camphorsulfonate ion. Since trifluoroacetic acid is frequently used during peptide synthesis, trifluoroacetate salts are typical salts provided when compounds containing peptide structures are formed. Such trifluoroacetate salts may be converted to acetate salts, for example, during their processing.

[0122] When the salt form includes the negatively charged form of the compound, exemplary cations that may be present as counterions to the salt form of the compound of the present invention include, for example, alkali metal cations such as lithium ion, sodium ion or potassium ion, alkaline earth metal cations such as calcium ion or magnesium ion; and ammonium ions (including ammonium ions substituted by organic groups).

[0123] The compounds according to the invention contain a SiFA group in which a fluorine atom F is bonded to the Si atom via a direct covalent bond, as shown in formulas (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc). As will be appreciated, F may be 18 F (i.e., a radioactive fluorine isotope), 19 or F (a non-radioactive fluorine isotope, also referred to as "cold fluorine").

[0124] As described above, the SiFA group according to the invention enables a rapid and efficient isotope exchange reaction to be achieved between 19 F and 18 F. Thus, the invention further provides a method for the preparation of radiolabeled compounds, which comprises reacting a compound or a salt thereof containing a group selected from the groups of formulas (Ia), (Ib) and (Ic) in which the fluorine bonded to the Si atom via a direct covalent bond is 19 F] fluorine, or a compound of formula (IIa), (IIb) or (IIc) or a salt thereof with 18 F] fluoride to effect an exchange of 19 F] fluorine for 18 F] fluorine. Sources and devices of 19 F] fluoride that can be used for the isotope exchange of 18 F to 18 F in the SiFA group are known to those skilled in the art and can be utilized in the methods of the invention described herein. For example, reference can be made to C. Waengler 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 formulas (Ia), (Ib) and (Ic) or the compounds of formulas (IIa), (IIb) or (IIc) continues to apply in the context of this method.

[0125] In that range, a further aspect of the present invention includes any preferred embodiments of the group of formula (Ia), (Ib) or (Ic), the group of formula (Ia), (Ib) or (Ic) as defined above, 19 F] fluorine 18 for use as a silicon-based fluoride acceptor group for isotope exchange with fluorine.

[0126] A further aspect of the present invention includes any preferred embodiments of the group of formula (Ia), (Ib) or (Ic), the group of formula (Ia), (Ib) or (Ic) as defined above, a target radiopharmaceutical, for example, any preferred embodiments of a compound of formula (IIa), (IIb) or (IIc) or a salt thereof, as a fluorine atom shown in these formulas 18 F] fluorine-containing compound of formula (IIa), (IIb) or (IIc) as defined above or a salt thereof for use as a silicon-based fluoride acceptor group for 18 F] labeling of the target radiopharmaceutical.

[0127] According to the above, the compounds according to the present invention include radiolabeled compounds and non-radiolabeled compounds. The radiolabeled compounds of the present invention contain a radioactive constituent, for example, a 18 F] fluorine atom as a fluorine atom shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc), or when the compound contains a chelating moiety, a chelating moiety containing a chelated radioactive metal cation. Preferably, the radiolabeled compounds according to the present invention are compounds in which the fluorine atoms shown in formula (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc) are 18 F] fluorine. The non-radiolabeled compounds according to the present invention are compounds that do not contain a radioactive constituent, in particular 18 compounds that do not contain F] fluorine or a chelated radioactive metal cation.

[0128] In 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 generally a radiolabeled compound.

[0129] A composition comprising a non-radiolabeled compound according to the present invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent, can be provided, for example, as a precursor composition of a radiopharmaceutical composition. In a related aspect, the present invention provides a kit comprising a non-radiolabeled compound according to the present invention, which is optionally combined with a pharmaceutically acceptable excipient and does not contain a radioactive component, in combination with instructions for radiolabeling the compound.

[0130] In another aspect, the present invention provides a diagnostic composition comprising a compound according to the present invention, typically a radiolabeled compound according to the present invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent. In a related aspect, the present invention provides a compound according to the present invention, typically a radiolabeled compound according to the present invention, or a radiopharmaceutical composition discussed above, for use in a method for diagnosing a disease or disorder in vivo. The diagnostic method preferably involves nuclear medicine imaging diagnosis, for example, via positron emission tomography (PET) or single photon emission computed tomography (SPECT). The fluorine atoms shown in formulas (Ia), (Ib), (Ic), (IIa), (IIb) and (IIc) are 18 The radiolabeled compound according to the present invention in which the fluorine atom is [[[F]]] fluorine is a preferred radiolabeled compound suitable for use in PET.

[0131] For example, a diagnostic method may include administering a radiolabeled compound according to the present invention to a subject and detecting the compound in the subject or monitoring the distribution of the compound in the subject, thereby detecting or monitoring a disease or disorder to be diagnosed. The subject can be a human or an animal, preferably a human. Alternatively, a diagnostic method may also include adding a radiolabeled compound according to the present invention to a sample, for example, a physiological sample obtained from a subject, in vitro or ex vivo, and detecting the compound in the sample.

[0132] The diagnostic method mentioned above is for the purpose of identifying a disease or disorder in the body of a human or an animal. An example of a disease or disorder is cancer. When the compound according to the present invention is a compound of formula (IIa), (IIb) or (IIc), it will be understood that the disease or disorder is typically related to the target structure of the targeting moiety contained in the group R E For example, the presence or increased presence of a target structure in the body of a subject may indicate a disease or disorder. In particular, the target structure of interest, for example, the target structure discussed as an example above, may be overexpressed in human diseases such as cancer.

[0133] In a further aspect, the present invention provides a therapeutic composition comprising a compound according to the present invention, typically a radiolabeled compound according to the present invention, optionally in combination with a pharmaceutically acceptable carrier, excipient and / or diluent. In a related aspect, the present invention provides a compound according to the present invention, typically a radiolabeled compound according to the present invention, or a radiopharmaceutical composition discussed above, for use in a method of treating a disease or disorder. The method is preferably a method for treating a disease or disorder via radioligand therapy. As an example of a radiolabeled compound according to the present invention useful for radioligand therapy, reference can be made to a compound containing a chelate moiety in which the chelated metal cation is 177 a Lu cation.

[0134] For example, the treatment method may include administering the radiolabeled compound according to the present invention to a subject. The subject can be a human or an animal, preferably a human. The treatment method mentioned above is for the treatment of diseases or disorders in the body of a human or an animal. An example of the disease or disorder is cancer. When the compound according to the present invention is a compound of formula (IIa), (IIb) or (IIc), the disease or disorder will typically be related to the target structure of the targeting moiety contained in the group R E It will be understood that it is related to the target structure of the targeting moiety contained in the.

[0135] It will be understood that the suitability for therapeutic and diagnostic applications is not mutually exclusive, that is, the compounds according to the present invention may be suitable for both applications. For example, a compound containing a chelating 177 Lu cation can be used for both therapeutic imaging applications and diagnostic imaging applications. Furthermore, the compounds of the present invention containing a chelating group together with a SiFA group are suitable as radiohybrid (rh) ligands. Such rh ligands can alternatively be 18 F] fluoride (for example, in the case of PET) or a radioactive metal (for example, in the case of PET 68 Ga cation, or in the case of radiotherapy 177 Lu cation). When the rh ligand is 18 F] fluoride labeled, a cold (non-radioactive) metal cation can (but does not have to) form a complex with a chelator moiety at another position in the molecule, and when the rh ligand is labeled with the corresponding radioactive metal cation, cold 19 F] fluorine may be included. Therefore, 18 F-labeled peptides and the corresponding radioactively metal-labeled analogs have the same chemical structure and thus the same in vitro and in vivo properties, thereby having exactly the same in vivo properties as diagnostic and therapeutic tracers. Structurally identical seranostic tracers (for example 18 F / 177 Lu analogs) may be produced.

[0136] Thus, according to this approach, compounds according to the invention include those in which the SiFA group is 18 labeled with F and contains a chelate moiety containing a chelating non-radioactive cation (e.g., nat Lu or nat Ga), and those in which a chelate moiety is present and contains a chelating radioactive cation (e.g., 177 Lu or 68 Ga) and the SiFA group is 18 not labeled with F (and thus 19 has F). Similarly, the invention provides such compounds according to the invention for use in a hybrid method of in vivo diagnosis and therapy of a disease or disorder, where the method involves first administering a compound according to the invention in which the SiFA group is 18 labeled with F and the chelating group contains a chelating non-radioactive cation (e.g., nat Lu or nat Ga), and then administering a compound in which the chelating group contains a chelating radioactive cation and the SiFA group is 18 not labeled with F.

[0137] In related aspects, the compounds according to the invention can be used in an imaging method, which can include administering a ligand compound to a subject, detecting the compound in the subject, and monitoring the distribution of the compound in vivo at different time points after injection for the purpose of calculating the dose before or during a therapeutic treatment. The subject can be a human or an animal, preferably a human. Such an imaging method can also be utilized for calculating the dose before or during the therapeutic treatment of a disease or disorder of the body of a human or an animal via radioligand therapy.

[0138] As described above, the composition provided by the present invention may contain a pharmaceutically acceptable carrier, excipient and / or diluent. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline aqueous solution, amino acid buffer solution (with or without physiological saline), water for injection, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions and the like. Such compositions can be formulated by well-known conventional methods.

[0139] Several documents are cited herein, including not only papers in scientific journals but also patent applications and manufacturer's manuals (for this point, see, for example, the following list of references). The disclosures of these documents are considered not relevant to the patentability of the present invention, but the whole of them are incorporated herein by reference. More specifically, all the documents referred to are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

Brief Description of the Drawings

[0140]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Modes for Carrying Out the Invention

[0141] Examples Henceforth, the synthesis of SiFA groups according to the present invention, and their evaluation compared to p-(di-tert-butyl-(fluorosilyl)benzoic acid ((4-SiFA)benzoic acid, (4-SiFA)Bz), the current gold standard for their basic properties, are shown using various model peptides. In addition, the performance of SiFA groups is exemplified by their use in compounds according to the present invention containing various targeting vectors applied in the field of radiopharmacy.

Example

[0142] 1. Comparative evaluation of the chemical properties of various SiFA moieties based on model peptides (MP) First, each deficiency molecular family was coupled to three different model peptides (MP, Table 1) to examine the structural effects of the novel SiFA components on the labeling properties, stability, and lipophilicity of the model peptides in comparison to the gold standard. Since similar trends were observed in these three systems, the in vitro property modifiability was then examined only by the expansion of system a (X-Gly-Lys, see Table 2) that brings about differences in HSA binding affinity within the region distinguishable by the high-performance affinity chromatography (HPAC) method.

[0143]

Table 1

[0144]

Table 2

[0145] 1.1 18 F labeling 18 The efficiency of isotope exchange for F labeling was evaluated by determining the radiochemical conversion rate (RCC, n≧3) by analyzing samples of the reaction mixture by thin-layer chromatography (TLC), and the decay-corrected radiochemical yield (RCY, n≧3) after purification through a cartridge (see figure).

[0146] All derivatives showed good RCC and RCY in the range of approximately 60 - 80%, and the molar activity was 3.1 ± 1.8 GBq / μmol. It was observable that the (4-SiFA)Bz derivatives and (5-SiFA)Ip derivatives tended to have very similar values, but the values of both decreased slightly in the (3-SiFA)Bz derivatives and tended to increase slightly in the X-(5-SiFA)Ip derivatives (where X = -L-Lys-OH, -L-Glu-OH, -Gal6N or -PEG8-OH).

[0147] Using the model peptide (MP) 18 Trends regarding the RCC and RCY of the F-labeling reaction: (3-SiFA)Bz-MP < (4-SiFA)Bz-MP ~ (5-SiFA)Ip-MP < X-(5-SiFA)Ip-MP 1.2 Relative radiochemical conversion rate (rRCC) For a more accurate comparison of the relative reactivity of various SiFA model peptides in the isotope exchange reaction, competitive 18 F-labeling was performed. Here, the corresponding (4-SiFA)Bz-MP was selected as the internal reference. Equal amounts of the test compound and the reference compound were added as one solution to the anhydrous 18 F]F solution. After 5 minutes at rt, the sample was analyzed by radio RP-HPLC. The relative radiochemical conversion rate (rRCC) was calculated by peak integration and expressed as the ratio of the test compound to the reference compound [%]. It was concluded that rRCC enables a more accurate comparison of reactivity as opposed to the standard RCC determined in separately conducted experiments (see Figures 1A - C).

[0148] Figures 1A - C show the radiochemical conversion rate (RCC, n ≧ 3) and radiochemical yield (RCY, n ≧ 3) regarding the 18 F-labeling reaction (5 minutes, rt, molar activity = 3.1 ± 1.8 GBq / μmol) of the model peptides divided into Lys, Asp and Tyr series and shown in A, B and C respectively.

[0149] Thus, the order of the rankings corresponding to RCC ((3-SiFA)Bz-MP < (4-SiFA)Bz-MP ~ (5-SiFA)Ip-MP < X-(5-SiFA)Ip-MP) can be better distinguished by comparison of rRCC, as shown in FIGS. 2A to 2C, resulting in the following ranking: (3-SiFA)Bz-MP < (4-SiFA)Bz-MP < (5-SiFA)Ip-MP < X-(5-SiFA)Ip-MP (~75% < 100% < 125% < 150 - 250%) FIGS. 2A to 2C show the relative reactivity represented by rRCC (n = 3) normalized to the conversion rate of the corresponding (4-SiFA)Bz-MP, which was individually determined by labeling the test compound and an equimolar precursor mixture of the test compound with its (4-SiFA)Bz counterpart shown at the top of each of Systems A, B, and C, which divided the data into Lys, Asp, and Tyr systems, respectively. Quality control by HPLC showed the formation of two unidentifiable by-products (approximately 5 - 10%) for the Gal6N derivative, and these by-products were added to the integrated value of the test compound and are presumed to be caused by keto-enol tautomerism in the sugar moiety.

[0150] Thus, in this context, the novel (5-SiFA)Ip derivatives and X-(5-SiFA)Ip derivatives can be evaluated as exhibiting better labeling properties, particularly increased reactivity resulting in higher RCY.

[0151] 1.3 Determination of n-octanol-water partition coefficient (logD 7.4 ) In the development process of alternative SiFA analogs, the influence of the substitution pattern of the aromatic moiety on lipophilicity is particularly important. Since the 4-SiFA-Bz moiety used so far exhibits strong lipophilic characteristics, which is also a dominant factor in the properties of SiFA-ligand conjugates, the newly developed SiFA moiety has a more negative logD 7.4Whether it can bring about excellent hydrophilicity represented by a value was a major concern. Assuming better discrimination in the characteristics of various families of compensatory molecules, studies were conducted on small model peptides. The corresponding logD 7.4 values (n≥8) are shown in Figure 3.

[0152] Figures 3A - C are divided into Lys, Asp, and Tyr systems, and are shown as A, B, and C respectively 18 n - octanol - water partition coefficients (logD 7.4 , n≥8) of the F - labeled model peptides are shown.

[0153] The results in Figures 3A - C show only a moderately lipophilic change when the (4 - SiFA)Bz derivative is compared with the (3 - SiFA)Bz derivative. In contrast, the negative charge very close to the aromatic moiety introduced by the additional carboxylic acid itself within the (5 - Sifa)Ip motif, and the X - (5 - Sifa)Ip moiety (where X is - L - Lys - OH, - L - Glu - OH, - Gal6N, or - PEG8 - OH as a variable hydrophilic modifier that can be easily conjugated to this additional carboxylic acid via peptide chemistry) bring about dramatically improved hydrophilicity.

[0154] 1.4 Determination of human serum albumin (HSA) binding by high - performance affinity chromatography (HPAC) The binding ability of SiFA - MP to human serum albumin (HSA) was investigated using high - performance affinity chromatography (HPAC). The corresponding gold standard ((4 - SiFA)Bz - MP) shows very strong HSA binding as expected from published and internal data. This is associated with relatively slow and unfavorable blood clearance in vivo.

[0155] As shown in FIGS. 4A - C, when comparing the (3 - SiFA)Bz derivatives and (5 - SiFA)Ip derivatives with the (4 - SiFA)Bz derivative, only a very slight difference in HSA binding was observed. However, conjugation of additional modifiers to the (5 - SiFA)Ip moiety can dramatically reduce HSA binding, as shown in FIGS. 4A and 5. In the latter figure, in particular, the HO - L - Lys(4a) modifier, HOOC - PEG8(6a) modifier, and Gal6N(7a) modifier are clearly shown to be useful means for further optimizing two important parameters essential for the desired fast pharmacokinetics, namely, the reduction of HSA binding and the improvement of hydrophilicity.

[0156] FIGS. 4A - C show the HSA binding of SiFA - MPs by HPAC, which is divided into Lys, Asp, and Tyr series and shown as A, B, and C, respectively. FIG. 5 shows the comparison of logD 7.4 values and HSA binding for the Lys series a.

[0157] Therefore, the X - (5 - SiFA)Ip moiety can be summarized as not only being an extremely useful platform for F - labeling, but also functioning as an HSA - binding moiety for precisely adjusting the pharmacokinetic properties of ligands in vivo to the requirements in vivo, where the HSA binding can be easily adjusted over a wide range of binding forces by conjugating selected suitable modifiers to the additional carboxylic acids of the newly developed (5 - SiFA)Ip moiety. 18 As shown in FIGS. 4A - C, when comparing the (3 - SiFA)Bz derivatives and (5 - SiFA)Ip derivatives with the (4 - SiFA)Bz derivative, only a very slight difference in HSA binding was observed. However, conjugation of additional modifiers to the (5 - SiFA)Ip moiety can dramatically reduce HSA binding, as shown in FIGS. 4A and 5. In the latter figure, in particular, the HO - L - Lys(4a) modifier, HOOC - PEG8(6a) modifier, and Gal6N(7a) modifier are clearly shown to be useful means for further optimizing two important parameters essential for the desired fast pharmacokinetics, namely, the reduction of HSA binding and the improvement of hydrophilicity.

[0158] 1.5 Determination of the chemical stability of 18 F]F - Si bond under various conditions In various MPs 18 To determine the chemical stability of the 18 F]F - Si bond in various MPs, aliquots of the 177The stability under the conditions of the Lu labeling protocol (pH 5.5, 90 °C) and the reactivity towards reverse isotope exchange in an aqueous medium (1 mM NaF solution) were simulated. 18 For the quantification of F defluorination kinetics, samples were taken over 2 h (t = 0, 30, 60, 90 and 120 min), and the 18 proportion of the F-labeled peptide was monitored by radio TLC. The calculated corresponding half-lives (n = 3) of the fully 18 F-labeled MPs under three different conditions are shown in Figures 6A - C.

[0159] Figure 6 shows the half-lives (n = 3) of the fully F-labeled MPs partitioned into subset A: pH 7.4, 37 °C (simulated blood conditions), B: pH 5.5, 90 °C (SiFA radiolabeling protocol), and C: NaF (1 mM in H2O, pH 6.5, rt (reverse isotope exchange)), where * indicates that no half-life is shown due to a poor regression (R2 << 90%) with a stability of >95% of the fully MPs after 2 h. 177 Lu labeling protocol, and C: NaF (1 mM in H2O, pH 6.5, rt (reverse isotope exchange)). The calculated corresponding half-lives (n = 3) of the fully 18 F-labeled MPs are shown, where * indicates that no half-life is shown due to a poor regression (R2 << 90%) with a stability of >95% of the fully MPs after 2 h.

[0160] Notably, previous in vitro and in vivo experience has demonstrated the sufficient stability of the (4-SiFA)Bz derivatives. As reflected by the data shown below, the peptide sequences (Asp-MP vs Tyr-MP and Lys-MP), and even the position of the same amino acids ((5-SiFA)Ip-Gly-L-Lys-OH vs (5-SiFA)Ip-L-Lys-Gly-OH) are thought to have a dramatic impact on the observed half-lives of the fully MPs. Furthermore, with regard to the standard deviation, the corresponding (4-SiFA)-Bz-MP, (3-SiFA)-Bz-MP, and (5-SiFA)Ip-MP in one MP system generally show similar stability, while the X-(5-SiFA)Ip-MP (shown by the white bars) is determined to be less stable. These findings indicate that more reactive derivatives with higher (r)RCC and RCY also show faster 18 F defluorination in the stability assay. 18It is in good agreement with the results of the F-labeling. Nevertheless, it was shown that X-(5-SiFA)Ip-MP is less stable than the corresponding (4-SiFA)Bz-MP, but it can be concluded that the stability of the novel compound is within the range suitable for in vivo application.

[0161] 2. Comparative evaluation of the chemical properties of various SiFA moieties exemplified by vector-based ligands In the following, exemplary data of several vector-based ligands are shown to demonstrate the advantages of the novel (5-SiFA)Ip-based components.

[0162] 2.1. Gastrin-releasing peptide receptor (GRPR) ligands

[0163]

Table 3

[0164] As shown in Table 3, the modification change from the (4-SiFA)Bz compound to the (3-SiFA)Bz compound results in only a moderate improvement in HSA binding and a negligible change in hydrophilicity. In fact, the (5-SiFA)Ip derivative shows a desirable significant decrease in HSA binding and a significant increase in hydrophilicity.

[0165] Furthermore, the introduction of additional charged groups within the (5-SiFA)Ip moiety was expected to potentially affect receptor affinity. Whether this effect is beneficial or detrimental to affinity needs to be examined individually for each target and can be tailored by structure-activity correlations in subsequent development steps. Thus, the loss of affinity due to the initial use of a novel (5-SiFA)Ip moiety in a single compound is not necessarily an immutable limitation for the entire ligand group. However, the results indicate a promising step in efficiently correcting for high lipophilicity and strong HSA binding in the structural approximation with the t-Bu2FSi-Ar group by using a (5-SiFA)Ip moiety instead of the (4-SiFA)Bz moiety, or optionally an X-(5-SiFA)Ip moiety that can be further modified. 2.2. C-X-C chemokine receptor type 4 (CXCR4) ligands

[0166]

Chemical Structure

[0167] Structure of a radiolabeled hybrid CXCR4 ligand sharing pentixafor as a lead structure, modified with the gold standard (4-SiFA)Bz moiety or a novel (5-SiFA)Ip moiety attached to a chelator via an EDA linker.

[0168] Figures 7A, B show the HSA binding and n-octanol-water partition coefficient (logD 7.4 , n = 8, 18 F-labeled compound) of a radiolabeled hybrid CXCR4 ligand sharing pentixafor as a lead structure, modified with the gold standard (4-SiFA)Bz moiety or a novel (5-SiFA)Ip moiety attached to a chelator via an EDA linker.

[0169] Derivatives of the well-known CXCR4 ligand pentixafor, shown above, exhibit the same expected trend that, when combined with a (5-SiFA)Ip moiety instead of the standard (4-SiFA)Bz moiety, the lipophilicity significantly decreases. This effect is evident even in the presence of lipophilic amino acids added to the pharmacophore, namely Nal and Tyr, as well as the 4-Abz linker moiety, and is not dominated by them. At first glance, the HSA binding is not affected by the changes in the prosthetic molecular family, which probably indicates the dominant interaction of the aromatic amino acids of the pharmacophore with HSA. 2.3. Somatostatin receptor (SSTR) ligands Similar to the CXCR4 ligands shown above, octreotate (TATE), a cyclic octapeptide derived from pentixafor as shown in 2.2 above, constitutes a fairly lipophilic pharmacophore. Therefore, it is not surprising that high lipophilicity is similarly observed for the (4-SiFA)Bz conjugate, as both consist of a pharmacophore that is already lipophilic on its own and a prosthetic molecular family (Table 4, entries 1, 2).

[0170] In contrast, both (5-SiFA)Ip derivatives show an increase in hydrophilicity of 1.2 - 1.5 logarithmic units compared to the corresponding (4-SiFA)Bz conjugate (Table 4, entries 3, 4). Interestingly, the addition of a direct carboxylic acid in the SiFA moiety (Table 4, entry 4) results in a significantly better increase in hydrophilicity compared to the (4-SiFA)Bz derivative where the carboxylic acid has migrated to the linker (Table 4, entry 1). This finding clearly demonstrates the excellent efficiency and utility of the novel (5-SiFA)Ip moiety. Furthermore, additional modifications can be combined with the (5-SiFA) moiety to achieve an even greater increase in hydrophilicity (Table 4, entry 3).

[0171] Similar to the CXCR4 ligands described above, since the interaction with HSA is thought to be dominated by the strongly binding aromatic amino acids within the cyclic pharmacophore, the HSA binding is hardly affected by the modifications examined.

[0172]

Table 4

[0173] 2.4 Cholecystokinin B Receptor (CCK-2R) Ligands Further examples are constituted by ligands targeting the CCK-2 receptor. Also in this case, as for CXCR4 and SSTR ligands, the pharmacophore contains some lipophilic aromatic amino acids (Nal, Trp, and Tyr). Therefore, high HSA binding and high lipophilicity are expected. The conjugation of the hydrophilic DOTA chelator for Lu complex formation leading to the reference compound Lu-DOTA-MGS5 corrects this lipophilicity to a logD value of -2.25 (8D). Not surprisingly, the introduction of the (4-SiFA)Bz moiety or the (3-SiFA)Bz moiety via the trifunctional linker D-Dap results in a dramatic worsening of hydrophilicity with an increase in the logD value of about 2 - 2.5. In contrast, this change can be efficiently minimized by using the novel (5-SiFA)Ip moiety instead. As a conclusion, another example emphasizes the importance of the second carboxylic acid directly bonded to the aromatic unit within the (5-SiFA)Ip moiety to minimize the additional lipophilicity introduced by the introduction of the SiFA-based family of complementary molecules.

[0174]

Chemical Structure

[0175] CCK-2R ligand, i.e., the reference compound nat The structure of the radiolabeled hybrid derivatives of the reference compounds sharing the same pharmacophore modified with the gold standard (4-SiFA)Bz moiety, (3-SiFA)Bz moiety, and novel (5-SiFA)Ip moiety, and the reference compound Lu-DOTA-MGS5 for comparison.

[0176] Figures 8A - D show the CCK - 2R ligands, i.e., the reference compounds nat Lu - DOTA - MGS5, and the radioactive hybrid derivatives of the reference compounds sharing the same pharmacophore, modified with the (4 - SiFA)Bz moiety, (3 - SiFA)Bz moiety, and novel (5 - SiFA)Ip moiety of the gold standard, which are linked via the trifunctional linker - D - Dap - for comparison, for CCK - 2R affinity (IC 50 , n = 3), intracellular uptake (n = 3), expressed as % of the simultaneously evaluated reference F11N, HSA binding (HPAC), and n - octanol - water partition coefficient (logD 7.4 , n≥6, 177 Lu - labeled compounds).

[0177] 2.5. Prostate - specific membrane antigen (PSMA) ligands Further investigations were carried out using ligands targeting prostate - specific membrane antigen (PSMA). Table 5 summarizes the data of the purified ligands composed of the EuK binding motif linked to various SiFA moieties, i.e., (4 - SiFA)Bz - (first synthesized by Wirtz(1) and re - evaluated independently herein), (3 - SiFA)Bz -, and (5 - SiFA)Ip -. The values observed for HSA binding are approximately equal.

[0178] The determined IC 50 values show a good example of the structural - activity relationship, where the shift of the silyl group in the aromatic moiety is clearly beneficial for excellent affinity. The simple shift of the silyl group from the para - position (PSMA - 1) to the meta - position (PSMA - 2) causes an increase in affinity by more than 20 - fold, which can be further improved by 2 - fold by binding a carboxylic acid (PSMA - 3).

[0179] In addition, this dataset reveals a further example where the additional carboxylic acid directly linked to the SiFA moiety dramatically increases the hydrophilicity, as a difference of about one logarithmic unit is observed when comparing Entry 1 and 2 with Entry 3.

[0180]

Table 5

[0181] 18 Determined in vivo data for [¹⁸F]F-PSMA-3, 18 [¹⁸F]F, nat compared with the previously published data (2) of [⁶⁸Ga]Ga-rhPSMA-7.3 (Figure 9), this not only demonstrated the effect on pharmacokinetics, but also showed the stability of each [¹⁸F]F-Si bond, especially by comparison of bone accumulation. 18 [¹⁸F]F-Si bond stability was shown.

[0182] Figure 9 shows the biodistribution of the compounds 18 [¹⁸F]F, nat [⁶⁸Ga]Ga-rhPSMA-7.3 (n = 4) and 18 [¹⁸F]F-PSMA-3 (n = 5) in male tumor-bearing CB17-SCID mice at 1 hour post-injection (p.i.). The data are presented as percentage of injected dose per gram (%ID / g), mean ± standard deviation. 18 [¹⁸F]F, nat Data for [⁶⁸Ga]Ga-rhPSMA-7.3 were previously published by our group (2). <F

[0183] As shown in Figure 9, already at 1 hour p.i., 18 [¹⁸F]F-PSMA-3 shows a faster blood clearance with a blood level of 0.55 %ID / g, 18 [¹⁸F]F, nat compared to 0.96 %ID / g for [⁶⁸Ga]Ga-rhPSMA-7.3.

[0184] Apparently, 18 the derivative of [¹⁸F]F-PSMA-3 has the drawback of insufficient hydrophilicity in the absence of the hydrophilic DOTAGA chelate that leads to hepatobiliary excretion, as shown by the increased accumulation in the liver (7.2 ± 4.8 %ID / g) and intestine (17.7 ± 1.6 %ID / g). 18 ​The low renal value of [F]F-PSMA-3 (67.1 ± 13.9% ID / g) is not directly comparable.

[0185] The pharmacokinetics of these derivatives are not clearly identical, with unequal plasma half-lives, and thus different incubation conditions faced by the [F]F-Si bond within the derivatives, but the values of bone accumulation, presumably mainly caused by the cleaved [F] fluoride, reflect the tendency of reactivity found for the model peptides in the results of the in vitro studies described above (Figure 10). 18 The [F]F-Si bond gives rise to 18 The values of bone accumulation, presumably mainly caused by the cleaved [F] fluoride, reflect the tendency of reactivity found for the model peptides in the results of the in vitro studies described above (Figure 10). Figure 10 shows the comparison of the following in vitro data and in vivo data regarding the reactivity and stability of the [F]F-Si bond as part of different SiFA moieties [(4-SiFA)Bz-, (3-SiFA)Bz-, terminal (5-SiFA)Ip-, and cross-linked-(5-SiFA)Ip-]: A: Reactivity of the Lys-derived model peptide (MP) under [F]F-labeling conditions, represented as relative radiochemical conversion rate (rRCC), B: Half-life of the Lys-derived fully [F]F-labeled MP incubated in aqueous K2CO3 (pH 7.4, 37 °C; simulated blood conditions), C: Chemical shift [ppm] of the [F]{[Si]}NMR spectrum of the Lys-based, D: Ligand [F]F, [Ga]Ga-rhPSMA-7.3 and [F]F-PSMA-3 activity accumulation (% ID / g) at 1 hour post-injection (p.i.) in CB17-SCID mice (n ≥ 4). 18 The data of [F]F, [Ga]Ga-rhPSMA-7.3 were previously published by the inventors' group (2). 18 under [F]F-labeling conditions, represented as relative radiochemical conversion rate (rRCC), B: Half-life of the Lys-derived fully [F]F-labeled MP incubated in aqueous K2CO3 (pH 7.4, 37 °C; simulated blood conditions), C: Chemical shift [ppm] of the [F]{[Si]}NMR spectrum of the Lys-based 18 F-labeled MP, D: Ligand [F]F, 19 F{ 29 Si} NMR spectrum of the Lys-based 18 F]F, nat Ga-rhPSMA-7.3 and 18 F]F-PSMA-3 activity accumulation (% ID / g). 18 F]F, nat The data of [F]F, [Ga]Ga-rhPSMA-7.3 were previously published by the inventors' group (2).

[0186] The in vitro results of the Lys-MP system shown in Fig. 10A indicate that the relative radiochemical conversion rate (rRCC) of (3-SiFA)Bz-MP is equivalent to the normalized value of (4-SiFA)Bz-MP, the rRCC of the terminal (5-SiFA)Ip derivative is slightly higher at 1.3-fold, and the rRCC of the crosslinked (5-SiFA)Ip derivative is significantly higher at approximately 2.6-fold, showing a trend of reactivity.

[0187] The increased reactivity was also found to be associated with lower stability (Fig. 10B), and the 18 half-life of the [18F]F-Si bond in MP decreased by 15% when the (5-SiFA)Ip moiety was attached terminally and became one-fourth when the (5-SiFA)Ip moiety was attached in place of the classical (4-SiFA)Bz moiety in the crosslinked construct.

[0188] Furthermore, the enhanced reactivity and decreased stability are thought to correlate with a smaller negative 19 19F NMR shift representing a lower electron density at the fluorine atom (Fig. 10C). The in vitro data (Figs. 10A - C), although not determined for the PSMA ligand, still suggest that the data for the MPs found have values predictive of the in vivo stability trend of the [18F]F-Si bond within the PSMA ligand, as indicated by the accumulation of activity in bone (Fig. 10D) mainly due to dissociated 18 [18F]fluoride. Using the (5-SiFA)Ip moiety at the terminus of [18F]F-PSMA-3 resulted in bone accumulation of 1.16 ± 0.22%ID / g. In comparison, the (4-SiFA)Bz moiety utilized in [68Ga]Ga-rhPSMA-7.3 demonstrated higher stability with bone accumulation of 0.38 ± 0.32%ID / g (2). 18 [18F]F-Si bond 18 However, the clinical application of the (5-SiFA)Ip moiety, despite the bone accumulation found, 18 [18F]F, nat [68Ga]Ga-rhPSMA-7.3 demonstrated higher stability with bone accumulation of 0.38 ± 0.32%ID / g (2).

[0189] However, the clinical application of the (5-SiFA)Ip moiety, despite the bone accumulation found, 18Published results regarding F-SiFAlin-TATE (femur: 1.9 ± 0.6% ID / g at 60 minutes p.i. (estimated from figure); 1.31 ± 0.31% ID / g at 90 minutes p.i.) compared to, in mice 18 F]fluoride release is increased, yet considered suitable (3). In 13 patients, 68 Ga]Ga-DOTA-TOC was directly compared with 18 F]F-SiFAlin-TATE. The first clinical results led to the conclusion of favorable “characteristics” (4). In this study, 18 F]F-SiFAlin-TATE showed slightly higher bone accumulation compared to non-fluorinated 68 Ga]Ga-DOTA-TOC (SUV max : 1.2 ± 0.5 vs 0.7 ± 0.2; SUV mean : 0.6 ± 0.3 vs 0.4 ± 0.1). Thus, a certain instability of the SiFA compound is considered manageable in clinical applications.

[0190] 3. Conclusion The aim of this study was to provide an alternative by means of modifications that would result in a ligand maintaining the beneficial labeling properties and sufficient stability of the gold standard (4-SiFA)Bz moiety, while conversely having excellent pharmacokinetic properties. 18 This was the development and investigation of a new family of radiolabeling molecules for

[0191] The most prioritized requirement for such an alternative is a substantial reduction in the excessive lipophilicity as a limiting factor induced by the tBu2FSi-Ar group that has been used hitherto. Furthermore, the SiFA moiety exhibits structural elements also related to strong HSA binding, and the facile and effective modulation of the binding strength plays a decisive role in the optimization of the ligand's pharmacokinetics. Both can be successfully achieved by the development of the (5-SiFA)Ip moiety and its derivatives that are easily modified.

[0192] 4. Materials and Methods 4.1. Basic Information The protected amino acid analogs were purchased from Bachem (Bubendorf, Switzerland), Carbolution Chemicals (St. Ingbert, Germany), or Iris Biotech (Marktredwitz, Germany). The 2-chlorotrityl chloride (2-CTC) resin was obtained from Sigma-Aldrich (Steinheim, Germany). The chelators DOTA, DOTA-GA, and their derivatives were supplied from Chematech (Dijon, France). All necessary solvents and other organic reagents were purchased from either Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Steinheim, Germany), Fluorochem (Hadfield, United Kingdom), or VWR (Darmstadt, Germany). Solid-phase synthesis of peptides was carried out manually using an Intelli-Mixer syringe shaker (Neolab, Heidelberg, Germany). Analytical and preparative reversed-phase high-performance liquid chromatography (RP-HPLC) were performed using a Shimadzu gradient system (Shimadzu, Neufahrn, Germany) equipped with an SPD-20A UV / Vis detector (220 nm), respectively. A MultoKrom100 C18 (150×4.6 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany) was used at a flow rate of 1 mL / min for analytical measurements. The specific gradient and corresponding retention time t RBoth are shown in the text. Preparative RP-HPLC purification was carried out at a constant flow rate of 10 mL / min using a MultoKrom100 C18 (250×20 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany). Analytical and preparative radio RP-HPLC were performed using a MultoKrom100 C18 (150×4.6 mm, 5 μm particle size) column or a Multokrom100 C18 (125×4.6 mm, 5 μm particle size) column (CS Chromatographie Service, Langerwehe, Germany). Radioactivity was detected by connecting the outlet of the UV photometer to a HERM LB500 NaI detector (Berthold Technologies, Bad Wildbad, Germany) or Flowstar 2 LB514 (Berthold Technologies, Bad Wildbad, Germany). Reverse-phase high-performance flash chromatography (RP-HPFC) was carried out in a Biotage® SP HPFC system (Biotage, Charlottesville, VA USA) using a Biotage SNAP cartridge (KP-C18-HS, 12 g). The eluents for all HPLC operations were water (solvent A) and acetonitrile (solvent B), both containing 0.1% trifluoroacetic acid. Electrospray ionization mass spectra for the characterization of substances were obtained on an expression L CMS mass spectrometer (Advion, Harlow, United Kingdom). NMR spectra were recorded at 300 K on a Bruker (Billerica, United States) AVHD-300, AVHD-400, or AVHD-500 spectrometer. Chemical shifts are indicated in δ values [ppm], referenced to the residual proton signal of the deuterated solvent used or, in the case of no solvent signal, e.g., 19 F or 29In the case of Si NMR spectra, the chemical shifts are calibrated against the internal standards CFCl3 and tetramethylsilane, respectively. The pH values were measured using a SevenEasy pH meter (Mettler Toledo, Giessen, Germany). The quantification of activity was performed using a 2480WIZARD 2 automatic g-counter (PerkinElmer, Waltham, United States) or a CRCR-55tR dose calibrator (Mirion Technologies, Ramsey, NJ, USA). Radio thin layer chromatography (TLC) was performed using a Scan-RAM detector (LabLogic Systems, Sheffield, United Kingdom).

[0193] 4.2. Solid-phase peptide synthesis 4.2.1. Basic procedure (GP) Addition to standard 2-CTC resin (GP1a) The addition of an Fmoc-protected amino acid (AA) to 2-chlorotrityl chloride (2-CTC) resin was carried out by stirring a solution of 2-CTC resin (1.60 mmol / g) and Fmoc-AA-OH (1.5 equivalents) in DMF containing DIPEA (3.0 equivalents) at room temperature for 2 hours. Residual 2-chlorotrityl chloride was capped for 15 minutes by the addition of methanol (2 mL / g resin). The resin was then filtered, washed with DMF (8 × 5 mL / g resin) and DCM (3 × 5 mL / g resin), and dried under vacuum. The final addition amount l of Fmoc-AA-OH was determined by the following formula:

[0194]

Number

[0195] Addition to standard H-Rink amide ChemMatrix (registered trademark) resin (GP1b) The addition to H-Rink amide ChemMatrix® resin was achieved using the procedure for amide bond formation (GP2). The equivalents used were referenced to the initial addition amount to the resin indicated by the manufacturer (1.0 equivalent = 0.5 mmol / g resin). Note: For all GPs except the Dde deprotection step, when using H-Rink amide ChemMatrix® resin, NMP was applied instead of DMF.

[0196] Alternative addition to 2-CTC resin (GP1c) The addition to 2-chlorotrityl chloride (2-CTC) resin (GP1a) was carried out by stirring a solution of 2-CTC resin (1.60 mmol / g) and R-CO2H (1.5 equivalents) in DCM containing DIPEA (3.0 equivalents) at room temperature overnight (18 h). Residual 2-chlorotrityl chloride was capped for 15 min by the addition of methanol (2 mL / g resin). The resin was then filtered, washed with DCM (8 × 5 mL / g resin), and dried under vacuum. The final addition amount of the compound was determined as in GP1a.

[0197] Amide bond formation by coupling to resin-bound amine (GP2a) For the conjugation of components to the resin-bound peptide, a mixture of TBTU (1.5 equivalents) and HOAt (1.5 equivalents) was used for the pre-activation of carboxylic acid (1.5 equivalents) with DIPEA (4.5 equivalents) as the base in DMF (10 mL / g resin), or 2,4,6-trimethylpyridine (6.0 equivalents) when pre-activating diaminopropionic acid and its derivatives. After 10 min at rt, the solution was added to the swollen resin. Unless otherwise described in each synthetic protocol, the conjugation step was carried out for 2 h at rt. After the reaction, the resin was washed with DMF (6 × 5 mL / g resin).

[0198] Amide bond formation by coupling to resin-bound carboxylic acid (GP2b) For the conjugation of the component to the resin-bound peptide, a mixture of HATU (1.0 eq) and HOAt (1.0 eq) was used for the pre-activation of the resin-bound carboxylic acid (1.0 eq) with DIPEA (3.0 eq) in DMF (10 mL / g resin) for 30 min. Next, the free amine (3.0 eq) dissolved in DMF was added to the pre-activated resin. Unless otherwise stated in each synthetic protocol, the conjugation step was carried out for 2 h at rt. After the reaction, the resin was washed with DMF (6 × 5 mL / g resin).

[0199] Amide bond formation (GP2c) by coupling of succinic anhydride to the resin-bound amine For the conjugation of succinic anhydride to the resin-bound peptide with unprotected amine, a mixture of succinic anhydride (7.0 eq) and DIPEA (7.0 eq) in DMF (10 mL / g resin) was added to the resin. After 3 h at rt, the resin was washed with DMF (6 × 5 mL / g resin).

[0200] Urea bond formation (GP2d) by coupling to the resin-bound amine For the binding motif deviating from the Glu-urea-Glu compound, the synthesis of Glu-urea-X compounds, such as Glu-urea-Lys, was carried out in the same manner as the method on resin. A solution of (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamido)pentanedioate in 1,2-dichloroethane (DCE, 5 mL / g resin) was added to the resin-bound peptide. The suspension was cooled on ice for 30 min and TEA (3.0 eq) was added. The suspension was heated to 40 °C and stirred gently overnight. After the reaction, the resin was washed with DMF (6 × 5 mL / g resin).

[0201] Fmoc deprotection on resin (GP3) 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. Then, the resin was thoroughly washed with DMF (8 × 5 mL / g resin).

[0202] Dde Deprotection on Resin in the Absence of Fmoc Group (GP4a) The Dde-protected peptide was dissolved in a 2% hydrazine monohydrate solution in DMF (v / v, 5 mL / g resin) and shaken for 20 minutes. After deprotection, the resin was washed with DMF (8 × 5 mL / g resin).

[0203] Dde Deprotection on Resin in the Presence of Fmoc Group (GP4b) In the presence of the Fmoc group, Dde deprotection of the peptide conjugated to 2-CTC resin was carried out at room temperature for 3 hours (GP4b) by adding 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 Dde deprotection of the peptide conjugated to H-Rink amide ChemMatrix® resin, the same amount of DCM was used instead of DMF. After deprotection, the resin was washed with DMF (8 × 5 mL / g resin).

[0204] Cleavage of Peptide from Resin with Concurrent Cleavage of Acid-Labile Protecting Groups (GP5a) To cleave the peptide from the resin while concurrently cleaving the acid-labile protecting groups (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 shaken for 30 minutes. This solution was filtered and the resin was treated similarly for an additional 30 minutes. The two filtrates were combined and stirred at rt for an additional 1 - 24 hours. Product formation was monitored by HPLC. After removing TFA under a nitrogen stream, the residue was dissolved in a mixture of tert-butanol and water and freeze-dried.

[0205] Cleavage of Peptide from Resin with Preservation of Acid-Labile Protecting Groups (GP5b) To cleave the peptide from the resin under preservation of the acid-labile protecting group (GP5b), 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. This solution was filtered and the resin was treated similarly for an additional 1 hour. Both filtrates were combined and concentrated under a nitrogen stream. The residue was dissolved in a mixture of tert-butanol and water and freeze-dried.

[0206] Allyl / Alloc deprotection on resin (GP6) The allyl / Alloc-protected resin-bound peptide was dissolved in a mixture of phenylsilane (24 equivalents) and Pd(PPh3)4 (0.1 equivalent) in DCM (5 mL / g resin) and placed in the dark during a 20-minute reaction. This solution was filtered and the resin was treated similarly for an additional 20 minutes. To remove residual black palladium, the resin was washed alternately with sodium diethyldithiocarbamate in DMF (0.5 wt%, 5 mL / g resin) and 0.5% DIPEA in DMF (5 mL / g resin) for 3 × 5 minutes for each solution. Thereafter, the resin was washed further with DMF (8 × 5 mL / g resin).

[0207] p-Nosyl protection (GP7) The resin-bound peptide was dissolved in a solution of p-nosyl chloride (5.0 equivalents) and 2,4,6-collidine (10.0 equivalents) in NMP (10 mL / g resin) and shaken at rt for 30 minutes. After deprotection, the resin was washed with NMP (6 × 10 mL / g resin).

[0208] p-Nosyl deprotection (GP8) A solution of DBU (5.0 equivalents) in NMP (10 mL / g resin) was added to the p-nosyl-protected resin-bound peptide. After a 5-minute incubation, β-mercaptoethanol (10 equivalents) was added and shaken at rt for 15 minutes. This procedure was repeated once. Thereafter, the resin was washed with NMP (6 × 10 mL / g resin).

[0209] N-Methylation (GP9) The resin was suspended in a solution of PPh3 (0.3 M in anhydrous THF, 5.0 equiv) and MeOH (10 equiv), and the resin was shaken at RT for 1 minute. Then, DIAD (5.0 equiv) was added, and the reaction mixture was shaken at rt for 30 minutes. After repeating the previous procedure, the resin was washed with NMP (6×10 mL / g resin).

[0210] Amide bond formation in solution (GP10) For conjugation of the components to the unbound peptide, a mixture of HATU (1.1 equiv) and HOAt (1.1 equiv) was used for pre-activation of the carboxylic acid (1.1 equiv) using DIPEA (3.0 equiv) as the base in DMF (10 mL / g resin). After 5 minutes at rt, the mixture was added to the free amine peptide dissolved in DMF. Unless otherwise stated in each synthetic protocol, the conjugation step was carried out for 2 hours at rt. After the reaction, the solvent was removed under reduced pressure.

[0211] Fmoc deprotection in solution (GP11) The unbound Fmoc peptide was treated with 20% piperidine (v / v) in DMF for 20 minutes, and then the solvent was removed under reduced pressure.

[0212] Cyclization of the side-chain protected peptide in solution (GP12) To a solution of HATU (0.1 equiv) and DIPEA (6.0 equiv) in DMF (100 μL / μmol Pep), Pep. (1.0 equiv) in DMF (100 μL / μmol) and HATU (3.0 equiv) in DMF (100 μL / μmol Pep) were added dropwise with vigorous stirring, respectively. When the addition was complete, the reaction was stirred for an additional 15 minutes, and then the solvent was removed under reduced pressure.

[0213] Removal of acid-labile side-chain protecting groups in solution (GP13) The peptide was dissolved in a solution of TFA and water (95:5) (v:v), stirred for 1 - 2 hours, and then the solvent was removed under a nitrogen stream. When the Trt protecting group was present, a solution of TFA / H2O / TIPS (v / v / v = 95:2.5:2.5) was used.

[0214] Allyl Deprotection in Solution (GP14) 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 placed in the dark during a 1 h reaction at rt. The solvent was removed under reduced pressure. Unless otherwise stated, residual Pd was quenched by the addition of TFA / H2O (v / v = 95 / 5) which induces further side-chain deprotection.

[0215] Acm Deprotection with Concurrent Disulfide Cross-Bridge Formation (GP15) The resin-bound Cys(Acm)-containing peptide was incubated with Tl(TFA)3 (4.0 eq) in DMF (8 mL / g resin). After 45 min at rt, the solution was discarded and the procedure was repeated once with a fresh solution. The resin was then washed with DMF (6 × 5 mL / g resin).

[0216] 4.2.2. Synthesis of SiFA-Based Components 4-(Di-tert-butylfluorosilyl)benzoic acid ((4-SiFA)Bz-OH) (Prepared according to Wurzer et al. (5) with minor modifications)

[0217]

Chemical Structure

[0218] ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane (i) To a stirred solution of 4-bromobenzyl alcohol (4.68 g, 25.0 mmol, 1.0 equiv) in anhydrous DMF (70 mL) were added imidazole (2.04 g, 30.0 mmol, 1.2 equiv) and TBDMSCl (4.52 g, 30.0 mmol, 1.2 equiv), 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 fractions were washed with sat. aq. 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) to give i as a colorless oil (7.18 g, 95%). RP-HPLC (50 - 100% B in 15 min): t R = 15 min. K’ = 7.43.

[0219] Di-tert-butyl[4-((tert-butyldimethylsilyloxy)methyl)phenyl]fluorosilane (ii) Under magnetic stirring at -78 °C, a solution of tBuLi in pentane (7.29 mL, 1.7 mol / L, 12.4 mmol 2.4 equiv) was added to a solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (i) (1.56 g, 5.18 mmol, 1.0 equiv) in dry THF (15 mL). After the reaction mixture was stirred at -78 °C for 30 min, the resulting suspension was added dropwise over 30 min to a cooled (-78 °C) solution of di-tert-butyldifluorosilane (1.12 g, 6.23 mmol, 1.2 equiv) in dry THF (10 mL). The reaction mixture was warmed to room temperature over 12 h and then hydrolyzed with saturated aqueous NaCl solution (100 mL). The organic layer was separated and the aqueous layer was extracted with diethyl ether (3 × 50 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give ii as a yellowish oil (1.88 g, 95%). It was used for the subsequent reaction without further purification. RP-HPLC (50 - 100% B in 20 min): t R = 19 min. K’ = 9.67.

[0220] 4-(Di-tert-butylfluorosilyl)benzyl alcohol (iii) 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 h and then the solvent and volatiles were removed under reduced pressure. The residue was redissolved in diethyl ether (40 mL) and the solution was washed with saturated aqueous NaHCO3. The aqueous layer was extracted with diethyl ether (3 × 50 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give iii as a yellowish oil (1.29 g, 98%), which solidified. The product was used without further purification. RP-HPLC (50 - 100% B in 15 min): t R = 8.2 min. K’ = 3.61.

[0221] 4-(Di-tert-butylfluorosilyl)benzoic acid ((4-SiFA)Bz-OH, iv) At rt, 5.8 g of KMnO4 (36.7 mmol, 1.5 equiv) was dissolved in H2O and added to a solution of iii (6.61 g, 24.6 mmol, 1.0 equiv), tert-butanol (65 mL), dichloromethane (9 mL), and 1.25 M NaH2PO4·H2O buffer (36 mL) at pH 4.0 - 4.5. After the mixture was stirred for 25 min, it was cooled on ice for 10 min and then excess KMnO4 (7.8 g, 49.2 mmol, 2.0 equiv) was added. The reaction mixture was stirred on ice for 2 h and then warmed to rt for 30 min. The reaction was then quenched by the addition of saturated aqueous Na2SO3 (50 mL). The addition of 2 M aqueous HCl dissolved all of the MnO2. The resulting solution was extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure to give a white solid, which was purified by recrystallization from Et2O / n-hexane (1:3, 12 h) to give iv (2.57 g, 37%). 11H NMR (300 MHz, CDCl3): δ [ppm] = 8.10 (d, 2H 3 J( 1 H, 1 H) = 8.1 Hz; H m ), 7.74 (d, 2H, 3 J( 1 H, 1 H) = 8.1 Hz; H o ), 1.07 (s, 18H; CCH3); 13 13C{ 1 1H} NMR (101 MHz, DMSO-D6): δ [ppm] = 167.2 (s; COOH), 138.3 (d, 2 J( 13 C, 19 F) = 14 Hz; C p ), 133.8 (d, 3 J( 13 C, 19 F) = 4 Hz; 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 19F{ 29 29Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -187.2; 29 29Si{ 1 1H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.1 (d, 1 J( 19 F, 29 29Si) = 299 Hz). RP-HPLC (50 - 100% B in 15 minutes): t R = 8.5 minutes. K’ = 3.78. ESI-MS (positive): Calculated monoisotopic mass for (C 15 H 23 F1O2Si): 282.15; Observed: m / z = 283.2 [M + H] + 、265.2 [M - H2O + H] + 。

[0222] [Chemical formula]

[0223] 3-(Di-tert-butylfluorosilyl)benzoic acid ((3-SiFA)Bz-OH)

[0224] [Chemical formula]

[0225] Di-tert-butylfluoro(3-tolyl)silane (i) A solution of 342 mg of 3-bromo-toluene (2.0 mmol, 1.0 equiv) in 6 mL of dry THF was cooled to -78 °C, 2.59 mL of tBuLi (4.40 mmol, 1.6 M in pentane, 2.2 equiv) was added dropwise, and the mixture was stirred at -78 °C for 30 minutes. The reaction mixture was then added at -78 °C to a solution of 397 mg of di-tert-butyldifluorosilane (2.20 mmol, 1.1 equiv) in 4.0 mL of THF, and the mixture was stirred overnight while warming to rt under pressure control. The reaction was stopped by the addition of 40 mL of brine. The aqueous layer was extracted with Et2O (3 × 20 mL), the combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure to give the crude product as a yellow oil. The mixture was used in the next step without further purification.

[0226] 3-(Di-tert-butylfluorosilyl)benzoic acid ((3-SiFA)Bz-OH, ii) To a solution of the complete crude product (i) (estimated: 2.0 mmol, 1.0 equivalent) in 6.4 mL of tBuOH / DCM (v / v = 7 / 1), 8.1 mL of a NaH2PO4·H2O solution (20.0 mmol, 1.25 M in H2O, 10.0 equivalents) was added. To this solution, 1.89 g of KMnO4 (12.0 mmol, 6.0 equivalents) was added at rt, and the reaction was carefully heated stepwise to 75 °C and stirred for 24 h. The reaction was quenched by the addition of saturated aqueous NaSO3 (15 mL). Concentrated aqueous HCl (5 mL) was added to completely dissolve the MnO2. This solution was extracted with Et2O (3 × 40 mL), and 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 of 3-(di-tert-butylfluorosilyl)benzoic acid (0.5 mmol, 25% in two steps) as a colorless solid. 1 H NMR (400 MHz, CDCl3): δ [ppm] = 8.36 (s, 1H; H Ar-2 ), 8.16 (dt, 1H, 3 J( 1 H, 1 H) = 7.8 Hz, 4 J( 1 H, 1 H) = 1.6 Hz; H Ar-6 ), 7.86 (dt, 1H, 3 J( 1 H, 1 H) = 7.4 Hz, 4 J( 1 H, 1 H) = 1.3 Hz; H Ar-4 ), 7.51 (t, 1H, 3 J( 1 H, 1 H) = 7.6 Hz; H Ar-5 ), 1.08 (s, 18H; CCH3); 13 C{ 1 H} NMR (101 MHz, DMSO-D6): δ [ppm] = 167.3 (s; COOH), 137.8 (d, 3 J( 13 C, 19 F) = 4 Hz; CAr-4 ), 134.1 (d, 3 J( 13 C, 19 F) = 4 Hz; C Ar-2 ), 133.1 (d, 2 J( 13 C, 19 F) = 14 Hz; 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 (376 MHz, DMSO-D6): δ [ppm] = -187.3; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (50 - 100% B in 15 min): t R = 9.2 min. K’ = 4.17. ESI-MS (positive): Calculated monoisotopic mass for (C 15 H 23 FO2Si): 282.15; Found: m / z = 283.3 [M + H][[ID=]50] + , 266.3 [M - H2O + H] + .

[0227]

Chem.

[0228] 3-(Di-tert-butylfluorosilyl)-5-((allyloxy)carbonyl)benzoic acid (AllO-(5-SiFA)Ip-OH)

[0229]

Chem.

[0230] Di-tert-butyl(3,5-dimethylphenyl)fluorosilane (i) A solution of 4.54 g of 1-bromo-3,5-dimethylbenzene (25.1 mmol, 1.0 equiv) in 73.1 mL of dry THF was cooled to -78 °C, 34.7 mL of tBuLi (55.5 mmol, 1.6 M in pentane, 2.2 equiv) was added dropwise, and the mixture was stirred at -78 °C for 30 minutes. Then, the reaction mixture was added to a solution of 5.0 g of di-tert-butyldifluorosilane (27.7 mmol, 1.1 equiv) in 49.1 mL of THF at -78 °C and stirred overnight while warming to rt under pressure control. The reaction was stopped by the addition of 100 mL of brine. The aqueous layer 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 6.6 g of di-tert-butyl(3,5-dimethylphenyl)fluorosilane (24.8 mmol, 99%) as a colorless solid. 1 H NMR (500 MHz, CDCl3): δ [ppm] = 7.19 (s, 2H; H o ), 7.04 (s, 1H; H p ), 2.33 (s, 6 H; CH3), 1.06 (s, 18 H; CCH3). RP-HPLC (50 - 100% B in 15 min, 100% B for 10 min): t R = 16.4 min. K’ = 8.21.

[0231] 5-(Di-tert-butylfluorosilyl)isophthalic acid ((5-SiFA)Ip-OH, ii) 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·HO solution (40.0 mmol, 2.5 M in HO, 10.0 equiv.). To this solution was added 7.6 g of KMnO4 (48.0 mmol, 12.0 equiv.) at rt, and the reaction was carefully heated stepwise to 75 °C and stirred for 24 h. The reaction was quenched by the addition of saturated aqueous NaSO3 (50 mL). Concentrated aqueous HCl (10 mL) was added to completely dissolve the MnO2. The solution was extracted with Et2O (3 x 100 mL), the combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure to give ii (1.3 g, 4.0 mmol, 100%) as a colorless solid. 1 H NMR (400 MHz, DMSO-D6): δ ppm = 8.53 (t, 1 H, 4 J( 1 H, 1 H) = 1.7 Hz; H Ar-2 ), 8.32 (d, 2 H, 4 J( 1 H, 1 H) = 1.6 Hz; H Ar-4,-6 ), 1.03 (s, 18 H; CH3); 13 C{ 1 H} NMR (101 MHz, DMSO-D6): δ [ppm] = 166.5 (s; COOH), 137.9 (d, 3 J( 13 C, 19 F) = 4 Hz; C Ar-4,-6 ), 134.0 (d, 2 J( 13 C, 19 F) = 14 Hz; 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 (376 MHz, DMSO-D6): δ [ppm] = -187.1; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (50 - 100% B in 15 min): t R = 5.7 min. K’ = 2.20. ESI-MS (positive): Calculated monoisotopic mass for (C 16 H 23 FO4Si): 326.13; Found: m / z = 327.2 [M + H] + , 309.2 [M - H2O + H] + .

[0232] 3-(Di-tert-butylfluorosilyl)-5-((allyloxy)carbonyl)benzoic acid (AllO-(5-SiFA)Ip-OH, iii) A suspension of 1.0 g of 5-(di-tert-butylfluorosilyl)isophthalic acid (ii) (3.1 mmol, 1.0 equiv) and 1.3 g of K2CO3 (9.2 mmol, 3.0 equiv) in 300 mL of DMF was cooled to 0 °C, and a solution of 185.0 mg of allyl bromide (132.0 μL, 1.5 mmol, 0.5 equiv) in 10.0 mL of DMF was slowly added dropwise over 20 min. The mixture was stirred overnight at rt. Then, the mixture was filtered, and all volatile substances in the filtrate were removed under reduced pressure. The residue was dissolved in 100 mL of HCl (1 M), and the aqueous layer was extracted with Et2O (3 × 200 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 iii as a colorless solid (250.9 mg, 684.6 mmol, 19%). 1 H NMR (400 MHz, DMSO-D6): δ [ppm] = 8.57 (t, 1H, 4 J( 1 H, 1 H) = 1.5 Hz; H Ar-6 ), 8.36 (t, 1H,4 J( 1 H, 1 H) = 1.5 Hz; H Ar-2 ), 8.34 (t, 1H, 4 J( 1 H, 1 H) = 1.5 Hz; H Ar-4 ), 6.07 (ddt, 1H, 3 J( 1 H, 1 H) = 17.3, 10.7, 5.5 Hz; CH2-CH=CH2), 5.41 (dd, 1H, 3 J( 1 H, 1 H) = 17.2 Hz, 2 J( 1 H, 1 H) = 1.7 Hz; CH2-CH=CH2(E)), 5.30 (dd, 1H, 3 J( 1 H, 1 H) = 10.3 Hz, 2 J( 1 H, 1 H) = 1.6 Hz; CH2-CH=CH2(Z)), 4.85 (d, 2H, 3 J( 1 H, 1 H) = 5.6 Hz; CH2-CH=CH2), 1.03 (s, 18H; CCH3); 13 C{ 1 H} NMR (101 MHz, DMSO-D6): δ [ppm] = 166.3 (COOH), 164.6 (CO-OAll), 138.3 (d, 3 J( 13 C, 19 F) = 4 Hz; C Ar-4 ), 137.6 (d, 3 J( 13 C, 19 F) = 4 Hz; C Ar-6 ), 134.3 (d, 2 J( 13 C, 19 F) = 14 Hz; C Ar-5 ), 132.4 (CH2-CH=CH2), 131.2 (CAr-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 (376 MHz, DMSO-D6): δ [ppm] = -187.0; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.8 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (50 - 100% B in 15 min): t R = 10.4 min. K’ = 4.84.

[0233]

Chem.

[0234] 4.2.3. Synthesis of Model Peptide (MP) (4-SiFA)Bz-Gly-L-Lys-OH (1a)

[0235]

Chem.

[0236] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 under simultaneous deprotection (GP5a) and isolated as a colorless solid after lyophilization (77%). 19 F{ 29Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -187.17; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.08 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (30 - 90% B in 15 min): t R = 7.4 min. K’ = 3.16. ESI-MS (positive): Calculated monoisotopic mass for (C 23 H 38 FN3O4Si): 467.26; Found: m / z = 468.4 [M + H] + 。

[0237] (4-SiFA)Bz-Gly-L-Asp-OH (1b)

[0238]

Chem.

[0239] Fmoc-L-Asp(tBu)-OH was added to 2-CTC resin (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 under simultaneous deprotection (GP5a) and isolated as a colorless solid after lyophilization (86%). 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -187.17; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.08 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (30 - 90% B in 15 min): t R= 9.1 points. K’ = 4.11. ESI-MS (positive): Calculated monoisotopic mass (C 21 H 31 FN2O6Si): 454.19; Observed: m / z = 455.3 [M+H] + 。

[0240] (4-SiFA)Bz-Gly-L-Tyr-OH (1c)

[0241]

Chem.

[0242] Fmoc-L-Tyr(OtBu)-OH was added to 2-CTC resin (GP1a). After Fmoc deprotection (GP3), Fmoc-Gly-OH was coupled to the resin-bound amino acid (GP2a). After Fmoc deprotection (GP3) was performed once again, (4-SiFA)Bz-OH was conjugated to the free amine (GP2a). The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after lyophilization (90%). 19 F{ 29 Si} NMR (37,6 MHz, DMSO-D6): δ [ppm] = -187.12; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (30 - 90% B in 15 min): t R = 10.2 min. K’ = 4.73. ESI-MS (positive): Calculated monoisotopic mass (C 26 H 35 FN2O5Si): 502.23; Observed: m / z = 503.3 [M+H] + 。

[0243] (3-SiFA)Bz-Gly-L-Lys-OH (2a)

[0244] [Chemistry]

[0245] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 under simultaneous deprotection (GP5a) and isolated as a colorless solid (95%) after lyophilization. 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.90; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.98 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 11.3 min. K’ = 5.35. ESI-MS (positive): calculated monoisotopic mass for C 23 H 38 FN3O4Si): 467.26; found: m / z = 468.5 [M + H] + .

[0246] (3-SiFA)Bz-Gly-L-Asp-OH (2b)

[0247] [Chemistry]

[0248] Fmoc-L-Asp(OtBu)-OH was added to 2-CTC resin (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 under simultaneous deprotection (GP5a) and isolated as a colorless solid after lyophilization (79%). 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.90; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.98 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 10.3 min. K’ = 4.79. ESI-MS (positive): calculated monoisotopic mass for (C 21 H 31 FN2O6Si): 454.19; found: m / z = 455.4 [M + H] + .

[0249] (3-SiFA)Bz-Gly-L-Tyr-OH (2c)

[0250]

Chem.

[0251] Fmoc-L-Tyr(OtBu)-OH was added to 2-CTC resin (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 under simultaneous deprotection (GP5a) and isolated as a colorless solid after lyophilization (77%). 19 F{ 29Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.86; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.99 (d, 1 J( 19 F, 29 Si) = 298 Hz). RP-HPLC (gradient from 20% to 90% B in 15 min): t R = 8.8 min. K’ = 3.94. ESI-MS (positive): calculated monoisotopic mass for (C 26 H 35 FN2O5Si): 502.23; found: m / z = 503.8 [M+H] + 。

[0252] (5-SiFA)Ip-Gly-L-Lys-OH (3a)

[0253]

Chem.

[0254] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 carried out (GP6), and the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (25%) after HPFC-based purification and lyophilization. 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.66; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.96 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (gradient from 20% to 90% B in 15 min): tR = 9.6. K' = 4.39. ESI-MS (positive): calculated monoisotopic mass (C 24 H 38 FN3O6Si): 511.25; found: m / z = 512.1 [M+H] + .

[0255] (5-SiFA)Ip-Gly-L-Asp-OH (3b)

[0256] [Chemical formula]

[0257] Fmoc-L-Asp(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (38%) after purification based on HPFC and lyophilization. 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.65; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.94 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 8.6 min. K' = 3.83. ESI-MS (positive): calculated monoisotopic mass (C 22 H 31 FN2O8Si): 498.18; found: m / z = 499.1 [M+H] + .

[0258] (5-SiFA)Ip-Gly-L-Tyr-OH (3c)

[0259] [Chemical formula]

[0260] Fmoc-L-Tyr(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (18%) after purification based on HPFC and lyophilization. 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.62; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 13.96 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20 - 90% B in 15 minutes): t R = 9.6 minutes. K’ = 4.39. ESI-MS (positive): Calculated monoisotopic mass for (C 27 H 35 FN2O7Si): 546.22; Observed: m / z = 547.0 [M + H] + .

[0261] HO-L-Lys-(5-SiFA)Ip-Gly-L-Lys-OH (4a)

[0262] [Chemical formula]

[0263] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 minutes under incubation with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (6.0 eq) in DMF, followed by addition of the amino acid (1.5 eq) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after HPFC-based purification and lyophilization (16%). 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.19; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 5.7 min. K’ = 2.20. ESI-MS (positive): calculated monoisotopic mass for (C 30 H 50 FN5O7Si): 639.35; found: m / z = 640.6 [M + H] + .

[0264] HO-L-Lys-(5-SiFA)Ip-Gly-L-Asp-OH (4b)

[0265]

Chemical Structure

[0266] Fmoc-L-Asp(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 min under incubation with HOAt (1.5 equiv), TBTU (1.5 equiv) and DIPEA (6.0 equiv) in DMF, followed by addition of the amino acid (1.5 equiv) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (21%) after purification based on HPFC and lyophilization. 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.22; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.09 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 6.6 min. K’ = 2.71. ESI-MS (positive): calculated monoisotopic mass for (C 28 H 43 FN4O9Si): 626.28; found: m / z = 627.5 [M + H] + .

[0267] HO-L-Lys-(5-SiFA)Ip-Gly-L-Tyr-OH (4c)

[0268]

Chemical Structure

[0269] Fmoc-L-Tyr(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Lys(Boc)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 min under incubation with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (6.0 eq) in DMF, followed by addition of the amino acid (1.5 eq) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after purification based on HPFC and lyophilization (9%). 19 F{ 29 Si} NMR (376 MHz, DMSO-D6): δ [ppm] = -186.28; 29 Si{ 1 H}INEPT NMR (79 MHz, DMSO-D6): δ [ppm] = 14.06 (d, 1 J( 19 F, 29 Si) = 299 Hz). RP-HPLC (20 - 90% B in 15 min): t R = 7.3 min. K’ = 3.10. ESI-MS (positive): calculated monoisotopic mass for (C 33 H 47 FN4O8Si): 674.31; found: m / z = 675.5 [M + H] + .

[0270] HO-L-Glu-(5-SiFA)Ip-Gly-L-Lys-OH (5a)

[0271]

Chemical Structure

[0272] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 minutes under incubation with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (6.0 eq) in DMF, followed by addition of the amino acid (1.5 eq) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after purification based on HPFC and lyophilization (12%). RP-HPLC (20 - 90% B in 15 min): t R = 6.7 min. K’ = 2.76. ESI-MS (positive): calculated monoisotopic mass (C 29 H 45 FN4O9Si): 640.29; found: m / z = 640.7 [M + H] + 。

[0273] HO-L-Glu-(5-SiFA)Ip-Gly-L-Asp-OH (5b)

[0274]

Chemical Structure

[0275] Fmoc-L-Asp(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 minutes under incubation with HOAt (1.5 equiv), TBTU (1.5 equiv) and DIPEA (6.0 equiv) in DMF, followed by addition of the amino acid (1.5 equiv) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (23%) after purification based on HPFC and lyophilization. RP-HPLC (20 - 90% B in 15 min): t R = 7.5 min. K’ = 3.21. ESI-MS (positive): calculated monoisotopic mass (C 27 H 38 FN3O 11 Si): 627.23; found: m / z = 627.7 [M+H] + 。

[0276] HO-L-Glu-(5-SiFA)Ip-Gly-L-Tyr-OH (5c)

[0277]

Chemical Structure

[0278] Fmoc-L-Tyr(OtBu)-OH was added to 2-CTC resin (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 carried out (GP6), and H-L-Glu(OtBu)-OtBu·HCl was coupled to the deprotected carboxylic acid by modified GP2. The resin-coupled peptide was pre-activated for 20 min under incubation with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (6.0 eq) in DMF, followed by addition of the amino acid (1.5 eq) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (15%) after purification by HPFC and lyophilization. RP-HPLC (20–90% B in 15 min): t R = 8.3 min. K’ = 3.66. ESI-MS (positive): calculated monoisotopic mass (C 32 H 42 FN3O 10 Si): 675.26; found: m / z = 675.7 [M+H] + .

[0279] (5-SiFA)Ip-L-Lys-Gly-OH (3a*)

[0280] [Chemical Structure]

[0281] Fmoc-Gly-OH was added to 2-CTC resin (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 carried out (GP6), and the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (26%) after purification based on RP-HPLC and lyophilization. RP-HPLC (20 - 90% B in 15 min): t R = 7.6 min. K’ = 3.27. ESI-MS (positive): Calculated monoisotopic mass for (C 24 H 38 FN3O6Si): 511.25; Found: m / z = 511.6 [M + H] + .

[0282] HOOC-PEG8-(5-SiFA)Ip-Gly-L-Lys-OH (6a)

[0283] [Chemical Structure]

[0284] For the preparation of model peptide 6a, a strategy combining liquid-phase peptide synthesis and solid-phase peptide synthesis was used. First, the dipeptide H-Gly-L-Lys(Boc)-OtBu·TFA was synthesized by pre-activating 178 mg of Fmoc-Gly-OH (0.6 mmol, 1.2 eq) using 82 mg of HOAt (0.6 mmol, 1.2 eq) and 228 mg of HATU (0.6 mmol, 1.2 eq) in 5 mL of DMF, and adding 510 μL of DIPEA (3.0 mmol, 5.0 eq). After 15 min at rt, 1 mL of a solution of 169 mg of H-L-Lys(Boc)-OtBu (0.5 mmol, 1.0 eq) in DMF was added and stirred at rt for 4 h. Subsequently, 2.5 mL of piperidine was added to the solution for Fmoc deprotection using 30 vol% piperidine in DMF. After 30 min, the solvent was removed at 60 °C under reduced pressure. Purification of the dipeptide by HPFC and subsequent lyophilization gave 184 mg of a colorless solid (78%). RP-HPLC (10 - 90% B in 15 min): t R = 8.9 min. K’ = 4.00. ESI-MS (positive): calculated monoisotopic mass (C 17 H 33 N3O5): 359.24; found: m / z = 359.8 [M + H] + .

[0285] Fmoc-NH-PEG8-CH2-CH2-COOH was added to 2-CTC resin (GP1a). After Fmoc deprotection (GP3), AllO-(5-SiFA)Ip-OH was conjugated to the free amine (GP2a). Allyl deprotection was carried out (GP6), and H-Gly-L-Lys(Boc)-OtBu·TFA was coupled to the deprotected carboxylic acid with modified GP2. The resin-coupled peptide was pre-activated for 20 min under incubation with HOAt (1.5 eq), TBTU (1.5 eq) and DIPEA (6.0 eq) in DMF, followed by addition of the amino acid (1.5 eq) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after purification based on RP-HPLC and lyophilization (25%). RP-HPLC (20 - 90% B in 15 min): t R= 7.5 points. K’ = 3.21. ESI-MS (positive): Calculated monoisotopic mass (C 43 H 75 FN4O 15 Si): 934.50; Observed: m / z = 934.4 [M+H] + 。

[0286] Gal6N-(5-SiFA)Ip-Gly-L-Lys-OH (7a)

[0287]

Chem.

[0288] Fmoc-L-Lys(Boc)-OH was added to 2-CTC resin (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 carried out (GP6), and a modified version of GP2 was used for the next coupling step. The resin-coupled peptide was pre-activated for 20 min under incubation with HOAt (1.5 equiv), TBTU (1.5 equiv) and DIPEA (6.0 equiv) in DMF, followed by addition of 6-amino-6-deoxy-1,2;3,4-di-O-isopropylidene-D-galactopyranoside (1.5 equiv) dissolved in DMF at rt. The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid after purification based on RP-HPLC and lyophilization (17%). RP-HPLC (20 - 90% B in 15 min): t R = 5.8 min. K’ = 2.26. ESI-MS (positive): Calculated monoisotopic mass (C 30 H 49 FN4O 10 Si): 672.32; Observed: m / z = 672.8 [M+H] + 。

[0289] 4.2.4. Synthesis of Vector-Based Ligands Synthesis of GRPR Ligand Fmoc-D-Dap(NH2)-EDA-DOTA(tBu)2-[α-Me-Trp 8 MJ9(PG)(1)

[0290]

Chem.

[0291] All GRPR targeting compounds were synthesized by standard Fmoc-based SPPS (GP1b, GP2a, GP3) using H-Rink amide ChemMatrix® resin (particle size 35 - 100 mesh, loading 0.4 - 0.6 mmol / g). According to GP1b, Fmoc-L-Leu-OH was added to the resin. Subsequently, the amino acids Fmoc-Sta-OH, Fmoc-L-His(Trt)-OH, Fmoc-Gly-OH, Fmoc-L-Val-OH, Fmoc-L-Ala-OH, Fmoc-α-Me-L-Trp(Boc)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-D-Phe-OH, and Fmoc-4-APipAc-OH were alternatively coupled (GP2a) and Fmoc deprotected (GP3). DOTA-di(tBu)-OH was coupled to the resin according to GP2a. Fmoc-EDA-NH2 was coupled as in GP2b and Fmoc deprotection was carried out according to GP3. The coupling of Fmoc-D-Dap(Dde)-OH on resin was carried out using 2,4,6-trimethylpyridine (6.0 equiv) as the base for its pre-activation (GP2a). The side chain was Dde deprotected under Fmoc preservation (GP4b) to complete the resin-bound precursor for the synthesis of the following GRPR ligands.

[0292] DOTAGA-D-Dap[(4-SiFA)Bz]-EDA-DOTA-[α-Me-Trp 8 MJ9(2)

[0293]

Chem.

[0294] (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 for a long time of 6 h at rt (modified GP2a). The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (8%) after HPLC-based purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 11.6 min. K’ = 6.25. ESI-MS (positive): calculated 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+ 。

[0295] DOTAGA-D-Dap[(3-SiFA)Bz]-EDA-DOTA-[α-Me-Trp 8 MJ9(3)

[0296]

Chemical Structure

[0297] (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 a long time of 6 h at rt (modified GP2a). The peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (7%) after HPLC-based purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 11.3 min. 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+ .

[0298] DOTAGA-D-Dap[(5-SiFA)Ip]-EDA-DOTA-[α-Me-Trp 8 MJ9(4)

[0299]

Chem.

[0300] 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 for 6 hours at rt (modified GP2a). The peptide was allyl deprotected (GP6), cleaved from the resin under simultaneous deprotection (GP5a), and isolated as a colorless solid (5%) after HPLC-based purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 10.6 min. K’ = 5.63. ESI-MS (positive): calculated 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+ .

[0301] Synthesis of CXCR4 Ligand CPCR4 (cyclo[Gly-L-2Nal-L-Arg-N(Me)-D-Orn-D-Tyr])(1)

[0302]

Chem.

[0303] 1 was synthesized according to the general procedure (GP) using solid-phase peptide synthesis. Briefly, Fmoc-Gly-OH was added to the resin (GP1a) and Fmoc was deprotected (GP3). Subsequently, Fmoc-L-2Nal-OH, Fmoc-L-Arg(Pbf)-OH, and Fmoc-D-Orn(Boc)-OH were alternatively coupled according to GP2a for the coupling step and GP3 for Fmoc deprotection. p-Nosyl protection followed by N-methylation and p-nosyl deprotection were carried out according to GP7 - 9. Fmoc-D-Tyr(tBu)-OH was coupled and Fmoc was deprotected according to GP2a and GP3. Cleavage of the resin under retention of the protecting groups was carried out as in GP5b. The peptide was cyclized (GP12) and side-chain deprotection was carried out in the final step (GP13). 1 was obtained as a colorless solid (68.3%) and used without further purification. RP-HPLC (10 - 90% B in 15 min): t R = 6.2 min, K’ = 1.48. ESI-MS (positive): calculated monoisotopic mass (C 36 H 47 N9O6): 701.36; found: m / z = 702.6 [M + H] + .

[0304] H2N-Amba-CPCR4(2)

[0305]

Chemical Structure

[0306] Fmoc-Amba-OH was coupled to 1 according to GP10. After completion of the reaction, the solvent was removed under reduced pressure and Fmoc was deprotected according to GP11. 2 was obtained as a colorless solid (38%) after HPFC purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 6.3 min, K’ = 1.86. ESI-MS (positive): calculated monoisotopic mass (C 44 H 54 N 10 O7): 834.42; found: m / z = 835.4 [M + H] +。

[0307] (4-SiFA)Bz-EDA-DOTA(tBu)2-OH(3)

[0308]

Chem.

[0309] DOTA-di(tBu)-OH was coupled to the resin according to GP1c. Fmoc-EDA-NH2 was coupled in the same manner as GP2b and deprotected according to GP3. (4-SiFA)Bz-OH was coupled according to GP2a and cleaved from the resin while retaining the protecting groups (GP5b). 3 was obtained as a colorless solid (36%) after HPFC purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 11.8 min, K’ = 4.13. ESI-MS (positive): calculated monoisotopic mass for C 41 H 71 FN6O8Si): 822.51; found: m / z = 823.7 [M + H] + 。

[0310] AllO-(5-SiFA)Ip-EDA-DOTA(tBu)2-OH(4)

[0311]

Chem.

[0312] DOTA-di(tBu)-OH was coupled to the resin according to GP1c. Fmoc-EDA-NH2 was coupled in the same manner as GP2b and deprotected according to GP3. AllO-(5-SiFA)Ip-OH was coupled according to GP2a and cleaved from the resin while retaining the protecting groups (GP5b). After HPFC purification and lyophilization, 4 was obtained as a colorless solid (23%). RP-HPLC (10 - 90% B in 15 min): t R = 12.5 min, K’ = 4.00. ESI-MS (positive): calculated monoisotopic mass for C 45H 75 FN6O 10 Si): 906.53; Measured value: m / z = 907.6 [M+H] + 。

[0313] (4-SiFA)Bz-EDA-DOTA-Amba-CPCR4(5)

[0314]

Chem.

[0315] Coupled 2 to 3 according to GP10 and deprotected the side chain according to GP13. 5 was obtained as a colorless solid (40%) after purification via RP-HPLC and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 9.80 min, k’ = 3.08. ESI-MS (positive): Calculated value of monoisotopic mass (C 77 H 107 FN 16 O 14 Si): 1526.79; Measured value: m / z = 1528.7 [M+H] + , 764.8 [M+2H] 2+ 。

[0316] (5-SiFA)Ip-EDA-DOTA-Amba-CPCR4(6)

[0317]

Chem.

[0318] Coupled 2 to 4 according to GP10 and then deprotected allyl and side chain according to GP14 and GP13 respectively. 6 was obtained as a colorless solid (19%) after purification via RP-HPLC and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 9.00 min, K’ = 3.09. ESI-MS (positive): Calculated value of monoisotopic mass (C 78 H 107 FN 16 O 16Si): 1570.78; Measured value: m / z = 1572.2 [M+H] + , 786.9 [M+2H] 2+ .

[0319] Synthesis of SSTR Ligands 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 (Fmoc-TATE(PG)-2-CTC resin)(1)

[0320]

Chem.

[0321] The synthesis of all SSTR ligands described in this specification was initiated using the same resin-bound precursor H-TATE(PG)-2-CTC resin. In the first step, Fmoc-L-Thr(tBu)-OH was added to the 2-CTC resin (GP1a). Subsequently, the peptide backbone was constructed by alternately coupling the corresponding Fmoc-protected amino acids, 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 (GP2a), followed by Fmoc deprotection (GP3). The previously fully protected linear peptide sequence was deprotected from Acm and cyclized (GP15). To confirm the identity of the precursor, a small resin sample was processed according to GP5a. RP-HPLC (10 - 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 14Calculated monoisotopic mass of (S2): 1270.5; Measured value: m / z = 1273.4 [M+H] + .

[0322] (4-SiFA)Bz-EDA-DOTATATE(2)

[0323]

Chem.

[0324] The Fmoc-TATE(PG)-loaded resin (1) was treated according to GP3 for Fmoc deprotection. DOTA(tBu)2 was coupled to the resin according to GP2a. Fmoc-EDA-NH2 was coupled in the same manner as 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 under simultaneous cleavage of the acid-labile protecting groups (GP5a). The product was obtained as a colorless solid (5%) after RP-HPLC purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 9.8 min, K’ = 3.00. ESI-MS (positive): Calculated monoisotopic mass (C 82 H 117 FN 16 O 19 S2Si): 1740.8; Measured value: m / z = 1741.9 [M+H] + , 871.2 [M+2H] 2+ , 581.2 [M+3H] 3+ .

[0325] (4-SiFA)Bz-D-Dap(DOTATATE)(3)

[0326]

Chem.

[0327] The Fmoc-TATE(PG)-loaded resin (1) was treated according to GP3 for Fmoc deprotection. DOTA(tBu)2 was coupled to the resin according to GP2a. Fmoc-D-Dap-OtBu·HCl was coupled in the same manner as 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 under simultaneous cleavage of the acid-labile protecting groups (GP5a). The product was obtained as a colorless solid (8%) after RP-HPLC purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 9.7 min, K’ = 2.96. ESI-MS (positive): calculated 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+ .

[0328] (5-SiFA)Ip-EDA-DOTATATE(4)

[0329]

Chem.

[0330] The Fmoc-TATE(PG)-loaded resin (1) was treated according to GP3 for Fmoc deprotection. DOTA(tBu)2 was coupled to the resin according to GP2a. Fmoc-EDA-NH2 was coupled in the same manner as 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 under simultaneous cleavage of the acid-labile protecting groups (GP5a). The product was obtained as a colorless solid (4%) after RP-HPLC purification and lyophilization. RP-HPLC (10 - 90% B in 15 min): t R = 9.1 min, K’ = 2.71. ESI-MS (positive): calculated monoisotopic mass (C 83 H 117 FN16 O 21 S2Si): 1784.8; Measured value: m / z = 1787.4 [M+H] + , 894.1 [M+2H] 2+ 。

[0331] (5-SiFA)Ip-D-Dap(DOTATATE)(5)

[0332]

Chemical formula

[0333] The Fmoc-TATE(PG)-attached resin (1) was treated according to GP3 for Fmoc deprotection. DOTA(tBu)2 was coupled to the resin according to GP2a. Fmoc-D-Dap-OtBu·HCl was coupled in the same manner as 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 under simultaneous cleavage of the acid-labile protecting groups (GP5a). The product was obtained as a colorless solid (9%) after RP-HPLC purification and lyophilization. RP-HPLC (10 - 90% B in 15 minutes): t R = 9.0 minutes, K’ = 2.67. ESI-MS (positive): Calculated value of the monoisotopic mass (C 84 H 117 FN 16 O 23 S2Si): 1828.8; Measured value: m / z = 1832.0 [M+H] + , 915.9 [M+2H] 2+ , 611.0 [M+3H] 3+ 。

[0334] Synthesis of CCK-2R ligand 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)

[0335]

Chemical formula

[0336] 1 was synthesized using solid-phase peptide synthesis according to the basic procedure (GP). Briefly, Fmoc-L-1-Nal-OH was coupled to pre-loaded H-Rink amide resin (GP1b), followed by Fmoc deprotection (GP3). Subsequently, Fmoc-L-Asp(tBu)-OH and Fmoc-L-Nle-OH were coupled according to (GP2a), and the Fmoc protecting group was cleaved after each coupling step (GP3). The free N-terminus of Nle was p-nosyl protected (GP7), N-methylated (GP9), and p-nosyl deprotected (GP8). Then, 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 according to GP2a, and then Fmoc deprotected respectively (GP3). 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 preservation (GP4b). The resin-bound peptide was used for synthesis without further purification and analysis.

[0337] 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)

[0338]

Chemical Structure

[0339] (4-SiFA)Bz-OH was coupled to 1 (GP2a), the Fmoc protecting group was cleaved (GP3), and DOTA(tBu)3 was coupled (GP2a). Subsequently, the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (6%) after purification based on RP-HPLC and lyophilization. RP-HPLC (10 - 70% B in 15 minutes): tR = 14.5 min, K’ = 6.25. ESI-MS (positive): calculated 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+ .

[0340] 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)

[0341] [Chemistry]

[0342] (3-SiFA)Bz-OH was coupled to 1 (GP2a), the Fmoc protecting group was cleaved (GP3), and DOTA(tBu)3 was coupled (GP2a). Subsequently, the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (9%) after purification based on RP-HPLC and lyophilization. RP-HPLC (10 - 70% B in 15 min): t R = 14.3 min, K’ = 6.15. ESI-MS (positive): calculated 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+ .

[0343] DOTA-rhCCK-54 (DOTA-D-Dap[(5-SiFA)Ip]-D-glu-L-Ala-L-Tyr-Gly-L-Trp-L-Nle-L-Asp-L-1-Nal)(4)

[0344] [Chemistry]

[0345] 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). Subsequently, the peptide was cleaved from the resin under simultaneous deprotection (GP5a) and isolated as a colorless solid (5%) after purification based on RP-HPLC and lyophilization. RP-HPLC (10 - 70% B in 15 min): t R = 13.6 min, K’ = 5.80. ESI-MS (positive): calculated 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+ 。

[0346] Synthesis of PSMA ligand (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))

[0347]

Chemical formula

[0348] Di-tert-butyl (1H-imidazole-1-carbonyl)-L-glutamate (i) A solution of 2.0 g (7.71 mmol, 1.0 equiv) of di-tert-butyl-L-glutamate·HCl in 20 mL of DCM was cooled on ice for 30 minutes and then treated with 2.69 mL of TEA (19.28 mmol, 2.5 equiv) and 3.3 mg (0.3 mmol, 0.04 equiv) of DMAP. After an additional 5 minutes of stirring, 1.38 g (8.84 mmol, 1.1 equiv) of 1,1'-carbonyldiimidazole (CDI) dissolved in DCM was slowly added over 30 minutes. The reaction mixture was stirred overnight and warmed to rt. The reaction was quenched using 8 mL of saturated NaHCO3 and subjected to simultaneous washing steps with water (2×30 mL) and brine (2×30 mL) and dried over Na2SO4. The remaining solvent was removed under vacuum and the crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamido)pentanedioate (i) was used without further purification.

[0349] 5-Benzyl 1-(tert-butyl)(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-glutamate (ii) 2.72 g (7.71 mmol, 1.0 equiv) of the crude product (S)-di-tert-butyl-2-(1H-imidazole-1-carboxamido)pentanedioate (i) was dissolved in 20 mL of 1,2-dichloroethane (DCE) and cooled on ice for 30 minutes. To this solution, 2.15 mL (15.42 mmol, 2.0 equiv) of TEA and 2.54 g (7.71 mmol, 1.0 equiv) of H-L-Glu(OBzl)-OtBu·HCl were added and the solution was stirred at 40 °C overnight. The remaining solvent was evaporated and the crude product was purified using silica gel flash chromatography 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.

[0350] (tBuO)EuE(OtBu)2(iii) 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 EtOH, and 0.34 g (0.57 mmol, 0.1 eq) of palladium on activated carbon (10%) was added to this solution. First, the flask containing the reaction mixture was purged with H2, and the solution was stirred at rt overnight under a slight H2 pressure (balloon). The crude product was filtered through celite, and the solvent was evaporated under vacuum. The product (iii) was obtained as a hygroscopic solid (84%). RP-HPLC (10 - 90% B in 15 min): t R = 11.3 min. ESI-MS (positive): calculated monoisotopic mass for (C 23 H 40 N2O9): 488.3; found: m / z = 489.4 [M + H] + , 516.4 [M + Na] + .

[0351]

Chemical formula

[0352] (tBuO)KuE(OtBu)2 (prepared according to Weineisen et al. (6))

[0353]

Chemical formula

[0354] 6-(Benzyloxy)carbonyl-1-(tert-butyl)(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-L-lysinate (i) Dissolve 2.72 g (7.71 mmol, 1.0 eq) of the crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamido)pentanedioate (see the synthesis of (tBuO)EuE(OtBu)2) in 20 mL of 1,2-dichloroethane (DCE), and cool it on ice for 30 minutes. To this solution, add 2.15 mL (15.42 mmol, 2.0 eq) of TEA and 2.87 g (7.71 mmol, 1.0 eq) of H-L-Lys(Z)-OtBu·HCl, and stir the solution at 40 °C overnight. Evaporate the remaining solvent, and purify the crude product by silica gel flash chromatography using an eluent mixture containing ethyl acetate / hexane / TEA (v / v / v = 500:500:0.8). After removal of the solvent, (i) was obtained as a colorless oil.

[0355] (tBuO)KuE(OtBu)2 (ii) To synthesize (tBuO)KuE(OtBu)2, dissolve 3.40 g (5.47 mmol, 1.0 eq) of (i) in 75 mL of EtOH, and add 0.34 g (0.57 mmol, 0.1 eq) of palladium on activated carbon (10%) to this solution. First, purge the flask containing the reaction mixture with H2, and stir the solution at rt overnight under a light H2 pressure (balloon). Filter the crude product through celite, and evaporate the solvent under vacuum. The product (ii) was obtained as a hygroscopic solid (92%). RP-HPLC (10 - 90% B in 15 minutes): t R = 12.6 minutes. K’ = 6.41. ESI-MS (positive): calculated monoisotopic mass for C 24 H 45 N3O7): 487.6; found: m / z = 488.3 [M + H] + , 510.3 [M + Na] + .

[0356]

Chemical Structure

[0357] PSMA-1(1)

[0358] [Chemistry]

[0359] (4-SiFA)Bz-OH (4.2 mg, 14.9 μmol, 1.0 equivalent) was pre-activated in 1 mL of DMF with HOAt (2.0 mg, 14.9 μmol, 1.0 equivalent), TBTU (4.8 mg, 14.9 μmol, 1.0 equivalent) and DIPEA (4.5 equivalents) at rt for 15 minutes. For coupling, 500 μL of a solution of (tBuO)KuE(OtBu)2 (1.0 equivalent) in DMF was added to the pre-activated SiFA component and stirred at rt for 2 hours. Next, the solvent was evaporated at 60 °C under reduced pressure. The residue was dissolved in 1 mL of TFA / TIPS / DCM (v / v / v = 95:2.5:2.5) and reacted at rt for 1 hour. Then, the volatile substances were removed under a nitrogen stream, and the dried crude product was purified by RP-HPLC and lyophilized to obtain a colorless solid (3.24 mg, 5.55 mmol, 37%). RP-HPLC (10 - 70% B in 15 minutes): t R = 11.7 minutes. K’ = 5.57. ESI-MS (positive): Calculated monoisotopic mass (C 27 H 42 FN3O8Si): 583.3; Found: m / z = 583.8 [M+H] + .

[0360] PSMA-2

[0361] [Chemistry]

[0362] (3-SiFA)Bz-OH (4.2 mg, 14.9 μmol, 1.0 equiv) was pre-activated in 1 mL of DMF 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) at rt for 15 min. For coupling, 500 μL of a solution of (tBuO)KuE(OtBu)2 (1.0 equiv) in DMF was added to the pre-activated SiFA component and stirred at rt for 2 h. Next, the solvent was evaporated at 60 °C under reduced pressure. The residue was dissolved in 1 mL of TFA / TIPS / DCM (v / v / v = 95:2.5:2.5) and reacted at rt for 1 h. Then, the volatile substances were removed under a nitrogen stream and the dry crude product was purified by RP-HPLC and lyophilized to give a colorless solid (7.92 mg, 13.57 μmol, 91%). RP-HPLC (10 - 70% B in 15 min): t R = 11.5 min. K’ = 5.46. ESI-MS (positive): calculated monoisotopic mass for (C 27 H 42 FN3O8Si): 583.3; found: m / z = 584.4 [M + H] + .

[0363] PSMA-3

[0364]

Chemical Structure

[0365] Fmoc-L-Lys(Dde)-OH was added to 2-CTC resin (GP1). The resin-bound amino acid was Fmoc-deprotected (GP3). Urea bond formation on the resin was carried out according to GP7 using (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamido)pentanedioate. The Lys side chain was Dde-deprotected (GP4a), and AllO-(5-SiFA)Ip-OH was coupled (GP2a). The peptide was allyl-deprotected (GP6), followed by cleavage from the resin while simultaneously deprotecting the acid-labile protecting groups (GP5a). The cleaved dry crude product was purified by RP-HPLC and lyophilized to obtain a colorless solid (41%). RP-HPLC (10 - 70% B in 15 min): t R = 10.0 min. K’ = 4.62. ESI-MS (positive): calculated monoisotopic mass (C 28 H 42 FN3O 10 Si): 627.3; found: m / z = 627.8 [M + H] + 。

[0366] rhPSMA-7.3

[0367]

Chemical Structure

[0368] The reference ligand rhPSMA-7.3 was prepared according to the published protocol (5). RP-HPLC (10 - 70% B in 15 min): t R = 10.0 min. K’ = 4.67. ESI-MS (positive): calculated 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+ 。

[0369] 4.3. Synthesis of Cold Metal Complexes 4.3.1. nat Ga Complex nat Ga-SSTR ligand of SSTR ligand nat Ga complex formation: Purified chelator-containing SSTR ligand (2 mM, 1.0 equivalent in DMSO) and nat Ga(NO3)3 (20 mM, 3.0 equivalents in Tracepur® H2O) were diluted to a final concentration of 1 mM using Tracepur® H2O and heated at 70 °C for 1 hour. After cooling, nat Ga chelate formation was confirmed by RP-HPLC / ESI-MS.

[0370] nat Ga-(4-SiFA)Bz-EDA-DOTATATE: RP-HPLC (10 - 90% B in 15 min): t R = 12.8 min, K’ = 4.22. ESI-MS (positive): Calculated 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+ .

[0371] nat Ga-(4-SiFA)Bz-D-Dap(DOTATATE): RP-HPLC (10 - 90% B in 15 min): t R = 10.1 min, K’ = 3.12. ESI-MS (positive): Calculated 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+ .

[0372] nat Ga-(5-SiFA)Ip-EDA-DOTATATE: RP-HPLC (10 - 90% B in 15 min): t R= 9.6 min, K’ = 3.00. ESI-MS (positive): calculated 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+ 。

[0373] nat Ga-(5-SiFA)Ip-D-Dap (DOTATATE): RP-HPLC (10 - 90% B in 15 min): t R = 9.5 min, K’ = 2.96. ESI-MS (positive): calculated 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+ 。

[0374] nat Ga-CXCR4 ligand nat Ga-(4-SiFA)Bz-EDA-DOTA-Amba-CPCR4: RP-HPLC (10 - 60% B in 15 min): t R = 14.4 min, K’ = 5.26. ESI-MS (positive): calculated monoisotopic mass (C 77 H 107 FGaN 16 O 14 Si): 1595.7; found: m / z = 798.6 [M+2H] 2+ 。

[0375] nat Ga-(4-SiFA)Bz-EDA-DOTA-Amba-CPCR4: RP-HPLC (10 - 60% B in 15 min): t R = 13.8 min, K’ = 5.00. ESI-MS (positive): calculated monoisotopic mass (C 78 H 105 FGaN16 O 16 Si): 1637.7; Measured value: m / z = 820.3 [M+2H] 2+ 。

[0376] 4.3.2. nat Lu complex nat Lu-GRPR ligand Of the GRPR ligand nat Lu complex formation: The purified chelator-containing GRPR ligand (10 in Tracepur® H2O) -3 M, 1.0 equivalent) and nat LuCl3 (20 mM in Tracepur® H2O, 2.5 equivalents) were diluted to a final concentration of 10 -4 M using Tracepur® H2O and heated at 95 °C for 30 minutes. After cooling, nat The formation of the Lu chelate was confirmed by RP-HPLC / ESI-MS.

[0377] nat Lu-DOTAGA-D-Dap((4-SiFA)Bz)EDA-transDOTA-[α-Me-Trp 8 MJ9: RP-HPLC (10 - 90% B in 15 minutes): t R = 11.4 minutes, K’ = 6.13. ESI-MS (positive): Calculated monoisotopic mass (C 118 H 180 FLuN 28 O 29 Si): 2677.0; Measured value: m / z = 951.0 [M+Lu+3H] 3+ 。

[0378] nat Lu-DOTAGA-D-Dap((3-SiFA)Bz)EDA-transDOTA-[α-Me-Trp 8 MJ9: RP-HPLC (10 - 90% B in 15 minutes): t R = 11.2 minutes, K’ = 6.00; ESI-MS (positive): Calculated monoisotopic mass (C 118 H 180 FLuN 28 O 29Si): 2677.0; Measured value: m / z = 951.0 [M+Lu+3H] 3+ .

[0379] nat Lu-DOTAGA-D-Dap((5-SiFA)Ip)EDA-transDOTA-[α-Me-Trp 8 MJ9: RP-HPLC (10 - 90% B in 15 minutes): t R = 10.5 minutes, K’ = 5.56; ESI-MS (positive): Calculated value of monoisotopic mass (C 119 H 180 FLuN 28 O 31 Si): 2721.0; Measured value: m / z = 965.5 [M+Lu+3H] 3+ .

[0380] nat Lu-CCK-2R ligand of CCK-2R ligand nat Lu complex formation: The corresponding nat Lu complex of CCK-2R ligand was prepared from a 2 mM solution of the ligand (1.0 equivalent) in DMSO and nat a 20 mM aqueous solution of LuCl3 (2.5 equivalents), and heated at 95 °C for 30 minutes. After cooling, nat Lu chelate formation was confirmed by RP-HPLC / ESI-MS.

[0381] nat Lu-DOTA-rhCCK-52: RP-HPLC (10 - 90% B in 15 minutes): t R = 12.7 minutes, K’ = 7.88. ESI-MS (positive): Calculated value of monoisotopic mass (C 88 H 116 FLuN 16 O 22 Si): 1972.0; Measured value: m / z = 1972.6 [M+H] + , 986.8 [M+2H] 2+ .

[0382] nat Lu-DOTA-rhCCK-53: RP-HPLC (10 - 90% B in 15 minutes): t R= 12.5 min, K’ = 7.74; ESI-MS (positive): calculated monoisotopic mass (C 88 H 116 FLuN 16 O 22 Si): 1972.0; found: m / z = 1973.2 [M + H] + 、986.9 [M + 2H] 2+ 。

[0383] nat Lu-DOTA-rhCCK-54: RP-HPLC (10 - 90% B in 15 min): t R = 14.1 min, K’ = 8.86; ESI-MS (positive): calculated monoisotopic mass (C 89 H 116 FLuN 16 O 24 Si): 2016.1; found: m / z = 1008.8 [M + 2H] 2+ 。

[0384] 4.4. Radioactive Labeling 4.4.1. 18 18F Labeling 18 Two given steps regarding the 18F labeling procedure have been previously optimized in the inventors' group by Daniel Di Carlo (unpublished data).

[0385] 18 Drying of the 18F fluoride aqueous solution 18 The 18F fluoride aqueous solution (in vitro studies: 100 - 300 MBq, biodistribution studies: up to 1.7 GBq; approximately 0.6 - 2.0 GBq / mL at the time of use; obtained from Klinikum Rechts der Isar, Munich, Germany) was passed through a preconditioned SAX cartridge (Sep-Pak Accell Plus QMA Carbonate Plus Light, 46 mg, 40 μm, Waters) using 10 mL of ultrapure water. 18 ​​​The fluoride-added cartridge was rinsed with 8 mL of anhydrous DMSO and subsequently dried with 10 mL of air. 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 and then 5 mL of air.

[0386] Drying 18 Labeling of SiFA-modified peptides with fluoride solution For labeling, 125 - 500 μL of eluate 18 The fluoride solution was added to a proportional amount of the precursor solution (7.5 - 30 nmol, 1 mM in anhydrous DMSO). After 5 minutes at rt, samples were taken and the radiochemical conversion rate (RCC) was determined by thin-layer chromatography (TLC). The labeling mixture was diluted with 10 mL of PBS* (pH 3, adjusted with 1 M aq. HCl) and passed through an Oasis HLB Plus Light cartridge (30 mg, 30 μm, freshly preconditioned with 10 mL of EtOH and 10 mL of ultrapure H2O, Waters), followed by 10 mL of PBS* and 10 mL of air. 18 A mixture of the 18F-labeled peptide and its chemically identical cold precursor was eluted with 300 μL of EtOH / PBS* (v / v = 7:3). 18 The radiochemical purity of the 18F-labeled compound was determined by radio RP-HPLC and radio TLC (silica gel 60 F 254 , mobile phase: MeCN / PBS (v / v = 3:2), +10% NaOAc solution (2 M in H2O), +1% TFA). The radiochemical yield (RCY) was determined using a dose calibrator and calculated taking into account attenuation correction. *Note: For subsequent stability studies, the PBS used for purification was replaced with ultrapure H2O. TLC analysis after cartridge-based purification showed less than 1% free 18F for all labeled compounds, so only the PBS used for TLC was not replaced. 18 The fluoride-added cartridge was rinsed with 8 mL of anhydrous DMSO and subsequently dried with 10 mL of air. 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 and then 5 mL of air.

[0387] 4.4.2. 125 125I Labeling Reference compound for GRPR-based assay [3- 125I]I-tyr 6 MJ9's 125 I-label IC 50 Reference ligand for research ([3- 125 I]I-tyr 6 MJ9) was prepared according to the previously published procedure with minor modifications by the group of the present inventors (7). Briefly, 0.2 mg of the precursor ([tyr 6 MJ9) was dissolved in 20 μL of Tracepur® H2O and 280 μL of TRIS buffer (25 mM TRIS HCl, 0.4 M NaCl, pH = 7.9). This solution was added to a vial containing 150 μg of Iodo-Gen® (1,3,4,6-tetrachloro-3α,6α-diphenylglycouril, surface-bound, Merck KGaA, Darmstadt, Germany), and then 5.0 μL (16 MBq) of [125I]NaI (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany) was added. The reaction solution was incubated at rt for 15 minutes and purified by RP-HPLC. Immediately after purification, sodium ascorbate (0.1 M in Tracepur® H2O, 10 vol%) was added to prevent radiolysis. RP-HPLC (20 - 35% B in 20 minutes): t R = 18.9 minutes, K’ = 10.46 ([3- 125 I]I-tyr 6 MJ9).

[0388] Reference compound for SSTR-based assays 125 I]I-TOC's 125 I-label The iodine labeling was performed in the same manner as the previously published procedure (8). For TOC 125For I-labeling, 50 - 150 μg of TOC was dissolved in 20 μL of DMSO in a 1.5 mL Eppendorf reaction tube (Protein LowBind), and 280 μL of TRIS buffer (25 mM TRIS-HCl, 0.4 mM NaCl, pH 7.5) was added. This solution was transferred to a reaction tube (1.5 mL, Protein LowBind) coated with Iodogen® (150 μg), and 5.00 μL (10 - 20 MBq) of 125 125I]NaI solution (74 TBq / mmol, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany) was added. After 15 minutes at rt, the reaction was stopped by separation from the oxidant (Iodogen®). The crude product 125 125I]I-TOC was purified by analytical RP-HPLC. To prevent radiolysis, 10 vol% sodium ascorbate solution (100 mM in H2O) was added to the resulting product solution. RP-HPLC (20 - 50% B in 15 minutes): t R = 8.2 minutes. K’ = 3.97 ( 125 125I]I-TOC).

[0389] Reference compound for assays based on CXCR4 125 125I]I-FC131's 125 125I-labeling The iodine labeling was carried out according to the procedures published hitherto (9). Before the iodine labeling step, 1.5 mg of Iodogen (1,3,4,6-tetrachloro-3R,6R-diphenylglycoluril, Pierce, Rockford, IL) was dissolved in 1.0 mL of dry DCM and distributed into 10 Eppendorf caps (100 μL of iodogen solution in each cap) to coat the reaction vials. The DCM was evaporated under a nitrogen stream, and the Iodogen-coated Eppendorf caps were stored at -20 °C under nitrogen until further application. Approximately 0.5 mg (0.5 μmol) of FC131 was added to the reaction vials prepared as such and dissolved in 20 μL of DMSO and 200 μL of Tris buffer (25 mM in H2O). To this solution, 5 μL (23.1 MBq) of 125 125I]NaI (74 TBq / mmol, 3.1 GBq / mL 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany) was added and incubated at rt for 15 minutes. The crude product was isolated from unlabeled FC131 via analytical RP-HPLC to obtain the desired product. RP-HPLC (20 - 40% B in 20 minutes); tR = 18.0 minutes, K’ = 9.0 ( 125 125I]I-FC131).

[0390] Reference compound for PSMA-based assays 125 125I]I-BA-KuE's 125 125I]I labeling Reference ligand for in vitro studies ( 125 125I]I-BA)KuE was prepared according to the procedures published hitherto (6, 10). For the iodine labeling, the peracetic acid solution used was freshly prepared by incubating 50 μL of acetic acid in 130 μL of 30 vol% H2O2 in H2O at rt for 2 hours. Approximately 0.1 mg of the stannylated precursor Sn(n-Bu)3-BA-(tBuO)KuE(OtBu)2 was mixed with 20 μL of peracetic acid and 5.0 μL of 125I] NaI (20 ± 5 MBq, 74 TBq / mmol, 40 mM in NaOH, Hartmann Analytic, Braunschweig, Germany) was dissolved in a mixture of 20 μL of MeCN and 10 μL of acetic acid. The reaction solution was incubated at rt for 15 min, diluted with 10 mL of H2O, and loaded onto a Sep-Pak C18-Plus Short cartridge (360 mg, 55 - 105 μm, Waters, preconditioned with 10 mL of MeOH followed by 10 mL of H2O). After purging the cartridge with 10 mL of H2O followed by 10 mL of air, the peptide was eluted with 1.5 mL of EtOH / MeCN (v / v = 1:1). The eluate was evaporated to dryness at 70 °C under a gentle nitrogen stream and treated with 500 μL of TFA for 45 min. After removing the TFA in a nitrogen stream, the crude product was purified by radio RP-HPLC to obtain 125 I] I-BA) KuE (10 ± 2 MBq). HPLC (20 - 40% B in 20 min): t R = 13.0 min.

[0391] 4.4.3. 177 Lu Labeling 177 For Lu labeling, the previously published procedure was applied with minor modifications (11). The labeling precursor (1.0 nmol, 5 μL, 0.2 mM in DMSO) was added to 10 μL of AcOH / NaOAc buffer (1.0 M in H2O, pH 5.5, 1.0 M). Then, 10 - 110 MBq of 177 LuCl3 (specific activity (S A ) > 3000 GBq / mg, 740 MBq / mL, 0.04 M HCl, ITM, Garching, Germany) was added and the mixture was made up to 100 μL with 0.04 M aq. HCl. The reaction mixture was heated at 90 °C for 20 min, 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)).

[0392] 4.5. in vitro Experiments 4.5.1. Cell Culture GRPR + Culture of PC-3 Cells GRPR + PC-3 cells (Merck KGaA, Darmstadt, Germany) were cultured in Dulbecco's Modified Eagle Medium / Ham's F-12 (DMEM / F-12, v / v = 1 / 1, containing stable glutamine, Biochrom GmbH, Berlin, Germany) supplemented with fetal bovine serum (10%, FBS Superior, Biochrom GmbH, Berlin, Germany) at 37 °C in a humidified 5% CO2 atmosphere. Cells were harvested using a mixture of trypsin and ethylenediaminetetraacetic acid (0.05%, 0.02%) in PBS (Biochrom GmbH, Berlin, Germany). Cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Lauda-Koenigshofen, Germany).

[0393] Culture of Jurkat Cells hCXCR4-positive Jurkat human T-cell leukemia (Merck Millipore, Darmstadt, Germany) was cultured in RPMI 1640 medium (2.0 g / L NaHCO3, without L-glutamine, low endotoxin, Biochrom, Berlin, Germany) containing 10% (v:v) FBS Superior (Biochrom GmBH, Berlin, Germany) and maintained at 37 °C in a humidified CO2 atmosphere (5%). For subculture, Jurkat suspension cells were harvested by centrifugation (1300 rpm, 3 minutes) and resuspended in the culture medium. Individual cell cultures were subcultured approximately twice a week depending on the cell growth rate. Cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Lauda-Koenigshofen, Germany). All procedures were performed under sterile conditions using an MSC-Advantage safety workbench manufactured by Thermo Fisher Scientific Inc.

[0394] Culture of CHO / Sst2(a) cells Stably Sst2(a)-transfected Chinese hamster ovary (CHO / Sst2(a)) cells were monolayer-cultured at 37 °C in a humidified atmosphere (5% CO2) in CELLSTAR® cell culture flasks obtained from Greiner Bio-One GmbH (Frickenhausen, Germany) using a HERAcell 150i-Incubator manufactured by Thermo Fisher Scientific Inc. (Waltham, United States). As the nutrient medium, DMEM / F12 GlutaMax medium supplemented with 10% FBS Superior (Biochrom GmbH, Berlin, Germany) was used. Furthermore, Dulbecco's PBS solution containing 0.05% trypsin and 0.1% EDTA (v / v) was applied to detach the cells for cell passage. The detached cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Lauda-Koenigshofen, Germany). For optimal growth, the cells were harvested at approximately 80% confluence. In addition, all operations under sterile conditions were performed using an MSC-Advantage safety workbench manufactured by Thermo Fisher Scientific Inc.

[0395] Culture of AR42J cells CCK-2R-expressing rat pancreatic cancer cells AR42J (CLS GmbH, Eppelheim, Germany) were cultured in a monolayer at 37°C in a humidified atmosphere (5% CO2) in CELLSTAR® cell culture flasks obtained from Greiner Bio-One GmbH (Frickenhausen, Germany) using a HERAcell 150i-Incubator manufactured by Thermo Fisher Scientific Inc. (Waltham, United States). As the nutrient medium, RPMI 1640 medium supplemented with 5 mM L-Glu, 5 mL non-essential amino acids (100×), and 10% FBS Superior (Biochrom GmbH, Berlin, Germany) was used. Furthermore, Dulbecco's PBS solution containing 0.05% trypsin and 0.1% EDTA (v / v) was applied to detach the cells for cell passage. The detached cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Lauda-Koenigshofen, Germany). For optimal growth, the cells were harvested at approximately 80% confluence. In addition, all operations under sterile conditions were performed using an MSC-Advantage safety workbench manufactured by Thermo Fisher Scientific Inc.

[0396] Culture of LNCaP cells PSMA-positive LNCaP cells (ACC256; DSMZ - German Collection of Microorganisms and Cell Cultures GmbH, Braunschweig, Germany) were cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (1:1) containing Glutamax (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%). Cells were harvested using a mixture of trypsin and EDTA (0.05%, 0.02%) in PBS (Biochrom GmbH, Berlin, Germany). Cells were counted using a Neubauer hemocytometer (Paul Marienfeld, Lauda-Koenigshofen, Germany).

[0397] 4.5.2. Affinity determination (IC 50 ) GRPR affinity study For the determination of GRPR affinity (IC 50 ) in PC-3 cells, cells were harvested 24 ± 2 hours before the experiment and seeded in 24-well plates (1.5 × 10 5 cells in 1 mL / well).

[0398] After removal of the culture medium, cells were washed once with 500 μL of HBSS (Hanks' Balanced Salt Solution, Biochrom GmbH, Berlin, Germany, supplemented with 1% bovine serum albumin (BSA, v / v)) and left for 9 minutes at room temperature in 200 μL of HBSS (1% BSA, v / v) for equilibration. Then, a 25 μL / well solution containing either HBSS (1% BSA, v / v) as a control or each compound at increasing concentrations (10 -10 ~10 -4 M) in HBSS (1% BSA, v / v) was added, followed by [3- 125 I]I-D-Tyr 625 μL of MJ9 (2.0 nM) was added. All experiments were performed in triplicate for each concentration. After a 2-hour incubation at rt, the experiment was terminated by removing the medium and subsequently rinsing with 300 μL of HBSS (1% BSA, v / v). The media from both steps were combined into one fraction, which represents the amount of free 125 I]I-tyr 6 MJ9. The cells were then lysed with 300 μL of 1 M NaOH for at least 15 minutes and combined with the 300 μL of NaOH in the subsequent wash step. The quantification of bound and free 3- 125 I]I-D-Tyr 6 -MJ9 was performed on a gamma counter. The IC 50 determination of each conjugate was repeated twice.

[0399] hCXCR4 affinity study For the receptor binding assay, Jurkat cells were counted, separated from the culture medium, and resuspended in HBSS (Hank's balanced salt solution, +1% BSA). 200 μL of the suspension (400,000 cells) was incubated with 25 μL each of the reference radioligand 125 I]I-FC131 (400,000 cpm / 25 μL) and different concentrations of 25 μL of the competitor (10 -4 to 10 -10 M), and 25 μL of HBSS (1% BSA) for the control experiment. After 2 hours at a temperature of 4 - 9 °C, the incubation was terminated by centrifugation (1300 rpm, 3 minutes). The cell pellet was washed with HBSS (containing 0.35 g / L NaHCO3, Ca 2+ containing, Mg 2+ containing, phenol red-free) and centrifuged, and these were each performed twice. The radioactivity of both the supernatant / wash fraction and the cell-bound fraction was determined by using a gamma counter. The experiment was performed in triplicate at n = 3 per concentration. The IC 50 values were calculated using GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States).

[0400] SSTR Affinity Study To determine SSTR affinity, CHO / Sst2(a) cells (1.0×10 5 ) were seeded into 24-well plates 24 ± 2 hours before the test, and 1 mL of nutrient medium (DMEM / F12 GlutaMax medium supplemented with 10% FBS Superior) was used for cell incubation at 37 °C in a humid atmosphere (5% CO2).

[0401] After removing the medium, each well was washed with 300 μL of HBSS (1% BSA, v / v). For the cell assay, triplicate 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) as a radiolabeled reference, and 25 μL of increasing concentrations of the peptide of interest (10 -10 ~10 -4 M) were added to the cells. Then, the assay was incubated at rt for 1 hour and the supernatant was collected. The cells were washed with 300 μL of ice-cold PBS and the collected fractions were combined. The cells were lysed with NaOH (300 μL, 1 N) for 20 minutes, then each well was washed with NaOH (300 μL, 1 N) and both fractions were combined. The radioactivity of both, i.e., the supernatant fraction and the lysate fraction, was quantified using a gamma counter. The obtained data were evaluated by GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States) for calculating the half-maximal inhibitory concentration (IC 50 ) of the peptide.

[0402] CCK-2R Affinity Study To determine the receptor affinity of a number of peptides, AR4-2J cells (2.0×10 5 ) were seeded into 24-well plates 24 ± 2 hours before the test, and 1 mL of nutrient medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS) was used for cell incubation at 37 °C in a humid atmosphere (5% CO2).

[0403] After removing the medium, each well was washed with 500 μL of PBS. For the cell assay, triplicates of 200 μL of nutrient medium (RPMI 1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS, 5% BSA), 177 Lu]Lu-DOTA-PP-F11N (25 μL, 0.3 pmol) as a radioactive-labeled reference, and 25 μL of the peptide of interest at increasing concentrations (10 -10 ~10 -4 M) were added to the cells. Then, the assay was incubated at 37 °C for 3 h and the supernatant was collected. The cells were washed with 300 μL of PBS and the collected fractions were combined. The cells were lysed with NaOH (300 μL, 1 N) for 15 min, each well was washed with NaOH (300 μL, 1 N), and both fractions were combined. The radioactivity of both, i.e., the supernatant fraction and the lysate fraction, was quantified using a gamma counter. The obtained data were evaluated by GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States) to calculate the half-maximal inhibitory concentration (IC 50 ).

[0404] PSMA Affinity Study For the determination of PSMA affinity (IC 50 ), each ligand was diluted in Hank's balanced salt solution (HBSS, Biochrom GmbH, Berlin, Germany) supplemented with 1% bovine serum albumin (BSA, Biowest, Nuaille, France) (serial dilution of 10 -4 ~10 -10 M). In the case of the metal complex ligand, the crude reaction mixture was diluted similarly without further purification. The cells were harvested 24 ± 2 h before the experiment and seeded in 24-well plates (1.5 × 10 5cells). After removing the culture medium, the cells were carefully washed with 500 μL of HBSS (1% BSA) and left on ice for 15 minutes in 200 μL of HBSS (1% BSA) for equilibration. Next, a 25 μL / well solution containing either HBSS (1% BSA, control) or each test ligand at increasing concentrations (10 -10 ~10 -4 M) was added, and then 25 μL of 125 I]I-BA-KuE (2.0 nM) was added in HBSS (1% BSA) as a radiolabeled competitor. For each concentration, the experiment was performed in triplicate. After a 60-minute incubation on ice, the experiment was terminated by removing the medium and subsequently rinsing with 200 μL of HBSS (1% BSA). The media from both steps were combined into one fraction, which represents the amount of free radioligand. Then, the cells were lysed with 250 μL of NaOH (1 M in H2O) for at least 15 minutes. After a washing step with NaOH (250 μL, 1 M in H2O), both fractions representing the amount of bound ligand were combined. Quantification of all recovered fractions was performed in a gamma counter. IC 50 values were calculated using GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States). All PSMA affinity determinations were performed at least three times per ligand.

[0405] 4.5.3. Intracellular Uptake Studies CCK-2R Intracellular Uptake Studies To determine the intracellular uptake kinetics of various peptides, AR42J cells (3.0×10 5 ) were seeded into poly-L-lysine-coated 24-well plates and 1 mL of nutrient medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS) was added. Then, the cells were incubated at 37 °C for 24 ± 2 hours in a humidified atmosphere (5% CO2).

[0406] On the day of the experiment, the medium was removed, and each well was washed with incubation medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×)) (300 μL). Then, 200 μL of nutrient medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS), 25 μL of 177 Lu]Lu-labeled peptide (0.3 pmol, n = 6), and in the case of intracellular uptake studies (n = 3), 25 μL of nutrient medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×), 10% FCS), and in the case of blocking studies (n = 3), 25 μL of DOTA-PP-F11N (10 μmol) were added respectively. Then, the assay was incubated at 37 °C for 6 hours in a humid atmosphere (5% CO2). After incubation, the cells were placed on ice and the supernatant was collected. Next, the cells were washed with ice-cold incubation medium (RPMI1640, 5 mM L-Glu, 5 mL of non-essential amino acids (100×)) (300 μL), and both fractions were combined. To remove the peptide from the cell membrane, 300 μL of ice-cold glycine buffer (1 M, 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 (1 M, pH 2.2). Both fractions were combined. After lysing the cells with NaOH (300 μL, 1 N) for 15 minutes, each well was washed with NaOH (300 μL, 1 N), and both fractions were combined. The radioactivity of the supernatant fraction, acid wash fraction, and lysate fraction was quantified using a γ counter.

[0407] 4.5.4. Determination of relative radiochemical conversion rate (rRCC) In the first step, the 18 F]aqueous fluoride solution provided by the Klinikum Rechts der Isar was dried according to the above procedure (4.4.1 18 F]F labeling). For the competitive labeling reaction, the dry 18A fluoride solution (30 - 50 MBq) was added to 10 μL of an equimolar mixture (5 nmol each in DMSO) of the test compound and the corresponding (4-SiFA)Bz reference compound. After 5 minutes at rt, samples were taken and immediately analyzed by radio RP-HPLC. If necessary, the standard solvent gradient (10 - 90% B in 15 minutes) was changed to achieve baseline separation ((3-SiFA)Bz-Gly-L-X vs (4-SiFA)Bz-Gly-L-X, where X = Tyr: 45 - 65% B in 15 minutes; X = Asp: 40 - 60% B in 15 minutes; X = Lys: 35 - 55% B in 15 minutes). In these cases, mixtures of the cold precursor and approximately 3-fold excess of the (3-SiFA)Bz compound were analyzed using the corresponding gradient for clear peak assignment. The relative radiochemical conversion rate (rRCC) was calculated by peak integration and expressed as the ratio [%] of the test compound to the reference compound. This experiment was repeated (n = 3).

[0408] 4.5.5. Determination of the n-octanol-water partition coefficient (logD 7.4 ) Approximately 1 MBq of 177 Lu-labeled tracer or 0.5 MBq of 18 F-labeled tracer was dissolved in 1 mL of n-octanol / PBS (v / v = 1:1) in a reaction vial (1.5 mL). The suspension was mixed vigorously for 3 minutes at rt, then 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. This experiment was repeated (n ≥ 6).

[0409] 4.5.6. Determination of human serum albumin (HSA) binding by high performance affinity chromatography (HPAC) The HSA binding of PSMA-targeting ligands by HPAC was determined by HPLC according to the procedures published hitherto (12). A Chiralpak HSA column (50 × 3 mm, 5 μm, H13H-2433, Daicel Corporation, Tokyo, Japan) was used at a constant flow rate of 0. mL / min at rt. Mobile phase A was a freshly prepared 50 mM aqueous solution of NH4OAc (pH 6.9), and mobile phase B was isopropanol (HPLC grade, VWR). The gradient applied to all experiments was 100% A (0 - 3 minutes), followed by 80% A (3 - 40 minutes). Prior to the experiment, the column was calibrated using nine reference substances known from the literature to have HSA binding in the range of 13 - 99% (12, 13). All substances were dissolved in a 1:1 mixture (v / v) of isopropanol and a 50 mM aqueous solution of NH4OAc (pH 6.9) to a final concentration of 0.5 mg / mL. Nonlinear regression was established using OriginPro 2016G software (Northampton, United States).

[0410] Figure 11 shows an exemplary sigmoid plot showing the correlation between the human serum albumin (HSA) binding of selected reference substances and the retention time (t R ). The values of HSA binding shown in the following table were obtained from the literature (lit. HSA [%]) (12, 13).

[0411]

Table 6

[0412] 4.5.7. 18 F]F - Si bond stability ( 18 half-life of F defluorination) determination Under in vivo conditions (pH 7.4, 37 °C) chemically mimicking blood 18 F defluorination Starting from 200 - 300 MBq of 18 F]fluoride aqueous solution, the test compound was labeled according to the above procedure (4.4.1 18 F labeling). 18The [ [ F ] ] F-labeled compound (10 μL per vial, approximately 0.8 - 1.0 nmol, 2.5 - 5.0 MBq) was added to 90 μL of K2CO3 solution (3 mM in ultrapure H2O, adjusted to pH 7.4 using formic acid) per vial. The pH value of the incubation solution was controlled using test paper (resolution: 0.5). After incubation at 37 °C for 0, 30, 60, 90 and 120 minutes in separate reaction vials, the samples were analyzed by radio-TLC (silica gel 60 F 254 , mobile phase: MeCN / PBS (v / v = 3:2), + 10% NaOAc solution (2 M in H2O), + 1% TFA), and the released 18 F] fluoride immobilized at the baseline was distinguished from the labeled test compound. This experiment was repeated (n = 3). Using the proportion of the fully 18 F-labeled peptide at different time points, 18 the half-life of [[ [ F ] ] ] F defluorination was calculated. GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States) was used for evaluation.

[0413] For radioactive hybrids 177 under the [[ [ Lu ] ] ] Lu-labeling conditions (pH 5.5, 90 °C), 18 F defluorination Starting from 200 - 300 MBq of 18 aqueous [[ [ F ] ] ] F fluoride solution, the test compound was labeled according to the above procedure (4.4.1 18 F labeling). 18 The [ [ F ] ] F-labeled compound (10 μL per vial, approximately 0.8 - 1.0 nmol, 2.5 - 5.0 MBq) was added to 80 μL of aqueous HCl solution (40 mM) and 10 μL of AcOH / NaOAc buffer (1.0 M in H2O, pH 5.5, 1.0 M) per vial. The pH value of the incubation solution was controlled using test paper (resolution: 0.5). After incubation at 37 °C for 0, 30, 60, 90 and 120 minutes in separate reaction vials, the samples were analyzed by radio-TLC (silica gel 60 F 254, analyzed by mobile phase: MeCN / PBS (v / v = 3:2), +10% NaOAc solution (2 M in H2O), +1% TFA), and the released 18 F] fluoride was distinguished from the labeled test compound. This experiment was repeated (n = 3). The complete 18 F-labeled peptide ratio at different time points was used to 18 calculate the half-life of

[0414] F defluorination. For evaluation, GraphPad PRISM software (GraphPad Software Inc., La Jolla, United States) was used. 18 Isotope exchange from F to natF in aqueous solution (1 mM NaF, pH 6.5, rt) 18 started from a 200 - 300 MBq 18 F] fluoride aqueous solution, and the test compound was labeled according to the above procedure (4.4.1 18 F labeling). 254 The 18 F] fluoride released and immobilized at the baseline was distinguished from the labeled test compound by radio TLC (silica gel 60 F 18 using the mobile phase: MeCN / PBS (v / v = 3:2), +10% NaOAc solution (2 M in H2O), +1% TFA). This experiment was repeated (n = 3). The complete 18 F-labeled peptide ratio at different time points was used to

[0415] 4.6. In Vivo Distribution Studies All animal experiments were conducted in accordance with the general animal welfare regulations in Germany (German Animal Protection Law, as amended on May 18, 2018, Law of March 29, 2017, I 626, Section 141, Approval Number 55.2-1-54-2532-71-13) and the guidelines of the facility regarding animal housing and use. 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 subcutaneously inoculated into the right shoulder of 6- to 8-week-old CB17-SCID mice (Charles River, Sulzfeld, Germany). When the tumors grew to a diameter of 2-6 mm (4-20 weeks after inoculation), the mice were used for the experiment.

[0416] Approximately 2-5 MBq (50-120 pmol) of 177 Lu-labeled ligand or approximately 1-2 MBq (50-120 pmol) of 18 F-labeled ligand was administered by injection into the tail vein of male LNCaP tumor-bearing CB-17 SCID mice, and the mice were sacrificed 1 hour or 24 hours post injection (p.i.). The selected organs were excised, weighed, and measured in a gamma counter. All results were attenuation-corrected and expressed as % of the injected dose per gram of tissue (%ID / g).

[0417] 5. References 1. Wirtz M. Development of biomarkers for molecular imaging and endoradiotherapy of prostate cancer. PhD thesis, Technical University Munich. 2015. 2. Wurzer A, Parzinger M, Konrad M, et al. Preclinical comparison of four 18 F,nat Ga]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics. EJNMMI Research. 2020;10:149. 3. Niedermoser S, Chin J, Wangler C, et al. In Vivo Evaluation of 18 F-SiFAlin-Modified TATE: A Potential Challenge for 68 Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET. J Nucl Med. 2015;56:1100. 4. Ilhan H, Lindner S, Todica A, et al. Biodistribution and first clinical results of 18 F-SiFAlin-TATE PET: a novel 18 F-labeled somatostatin analog for imaging of neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2020;47:870-880. 5. Wurzer A, DiCarlo D, Schmidt A, et al. Radiohybrid ligands: a novel tracer concept exemplified by 18 F- or 68 Ga-labeled rhPSMA-inhibitors. J Nucl Med. 2019:jnumed.119.234922. 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. 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. 8. Schottelius M, Simecek J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ. Twins in spirit - episode I: comparative preclinical evaluation of 68 Ga]DOTATATE and 68 Ga]HA-DOTATATE. EJNMMI Res. 2015;5:22. 9. Osl T. Development of cyclic pentapeptide ligands for chemokine receptor targeting, PhD thesis, Technical University Munich. 2017. 10. Vaidyanathan G, Zalutsky MR. Preparation of N-succinimidyl 3-[*I]iodobenzoate: an agent for the indirect radioiodination of proteins. Nat Protoc. 2006;1:707-713. 11. Sosabowski JK, Mather SJ. Conjugation of DOTA-like chelating agents to peptides and radiolabeling with trivalent metallic isotopes. Nat Protoc. 2006;1:972-976. 12. Valko K, Nunhuck S, Bevan C, Abraham MH, Reynolds DP. Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol / water and immobilized artificial membrane lipophilicity. J Pharm Sci. 2003;92:2236-2248. 13. Yamazaki K, Kanaoka M. Computational prediction of the plasma protein-binding percent of diverse pharmaceutical compounds. J Pharm Sci. 2004;93:1480-1494.

Claims

1. Compounds containing a group selected from the groups of formulas (Ia), (Ib), and (Ic), or salts thereof: 【Chemistry 1】 During the ceremony, R １ These are linear or branched C3-C10 alkyl groups; R ２ These are linear or branched C3-C10 alkyl groups; R ３ teeth, (i) -OH or -O － , (ii) Sugar portion or amino sugar portion, (iii) Amino acid portion or oligopeptide portion, (iv) PEG moiety, and any two or more combinations of (ii), (iii), and (iv) Selected from; The wavy lines indicate a bond that connects the group to the remainder of the compound.

2. The compound according to claim 1, which is a compound of formula (IIa), (IIb), or (IIc), or a salt of said compound: 【Chemistry 2】 In the formula, R １ , R ２ , and R ３ is defined similarly to the same claim, R Ｅ This is a group that contains the targeting portion.

3. R ３ where the amino acid moiety as R is derived from a hydrophilic amino acid containing an additional basic or acidic functional group in addition to an amino group and a carboxyl group, or R ３ where the oligopeptide moiety as R is derived from an oligopeptide having at least one hydrophilic amino acid containing an additional basic or acidic functional group in addition to an amino group and a carboxyl group, the compound or salt according to claim 1.

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

5. R ３ The compound or salt according to claim 1, wherein the oligopeptide portion is a linear or branched portion comprising 2 to 10, preferably 2 to 5, more preferably 2 or 3 amino acid portions.

6. R ３ The PEG portion as is in the formula -NH-(CH ２ -CH ２ -O) Ｘ -R Ｐ１ (In the formula, the nitrogen atom that provides the open bond is R ３ It forms an amide bond –NH–C(O)– with the carbon atom to which it is bonded, and X is an integer from 2 to 10, R Ｐ１ is, -CH ２ -COOH and -CH ２ -CH ２ (Selected from COOH) The compound or salt according to claim 1, which is the part of the compound or salt.

7. R ３ The compound or salt according to claim 1, wherein the sugar portion or amino sugar portion is a residue derived from 6-amino-6-deoxy-D-galactopyranose and its corresponding tautomer.

8. R Ｅ The compound or salt according to claim 2, comprising 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. The compound or salt according to claim 2, wherein the targeting portion is a peptide portion.

10. The compound or salt according to claim 2, wherein the targeting portion is a receptor-binding portion, and the receptor-binding portion enables the compound or salt of formula (IIa), (IIb), or (IIc) including the targeting portion to function as a ligand for a receptor selected from gastrin-releasing peptide receptor (GRPR), C-X-C chemokine receptor 4 (CXCR4), somatostatin receptor (SSTR), and cholecystokinin B receptor (CCK-2R).

11. R Ｅ The compound or salt according to claim 2, further comprising a chelate-forming portion, or a chelate portion formed by a chelate-forming portion and a chelated radioactive or non-radioactive metal cation.

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

13. Fluorine that is directly bonded to the Si atom via a covalent bond [ １８ F] The compound or salt according to any one of claims 1 to 12, wherein F is fluorine.

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

15. A targeted radiopharmaceutical based on formula (Ia), (Ib), or (Ic) as defined in any of claims 1 or 3 to 7 １８ Use as a silicon-based fluoride acceptor group for labeling.

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