Radiopharmaceuticals with enhanced tumor accumulation

Abstract

A theranostic compound, alone or as part of a radiopharmaceutical kit is hydrophilic and comprises a lipophilic membrane-inserting radical configured for radioactive labeling that is conjugated to a hydrophilic fibroblast activation protein cleavable radical.

Description

[0001] 1 / 126 pma25 10.02.2026

[0002] Radiopharmaceuticals with Enhanced Tumor Accumulation

[0003] The invention pertains to a pharmaceutical compound PC and a kit for nuclear imaging and radioligand therapy (RLT) with improved tumor-to-body dose ratio. The compound PC is configured for direct labeling with a radioisotope or for pretargeting. In the latter case the nuclear imaging and RLT kit comprises the compound PC and an additional compound PD for labeling with the radioisotope and delivery to diseased tissue.

[0004] The invention further pertains to a radioligand RT comprised of the compound PC and a radioisotope.

[0005] Since more than 80 years benign and malignant thyroid conditions are successfully treated with131I. In recent years, radioligands targeting the somatostatin receptor (SSTR) and the prostate-specific membrane antigen (PSMA) receptor have become new standards of care for treating neuroendocrine and prostate cancers. Although these treatments are highly effective and improve both survival and quality of life, they mainly offer palliative outcomes, unlike131I, which often cures thyroid cancer.

[0006] Tumor-to-body dose ratio or tumor-to-background ratio are synonymous to tumor-to-normal tissue dose ratio and hereafter abbreviated as " T / N" or " TBR". High expression of the sodium iodine symporter protein in thyroid tissue promotes accumulation of iodine isotopes in or near thyroid cancer cells with hitherto unparalleled T / N. Thyroid PET / CT with124l shows target-to-background (TBR) contrast that can surpass 1,000 and frequently reaches several 100s. Despite intensive worldwide development efforts, the T / N of newer radioligands targeting somatostatin (SSTR) and prostate-specific membrane antigen (PSMA) is significantly lower than that of131I.

[0007] The invention increases T / N by using a radiopharmaceutical compound PC that comprises a radical of a cell surface binder and enables radioisotope delivery and retention in tumor tissue over time periods of several days.

[0008] According to the invention, the term "cell surface binder" encompasses radicals which - after release from the radiopharmaceutical compound PC or radioligand RT - partition to the plasma membrane of cells and either

[0009] - are retained in the plasma membrane for extended time periods of ten hours up to several weeks, or

[0010] - after initial retention in the plasma membrane, are internalized to the cytosol via permeation or endocytosis.

[0011] In orderto prevent unwanted uptake and retention of the radiopharmaceutical compound PC or radioligand RT in blood and normal tissue, the cell surface binder radical is conjugated directly or via intermediate self-immolative spacer radicals to one or two substrate ligands of fibroblast activation protein (FAP) and thereto appended pharmacokinetic modulator groups. The one or two FAP substrate ligand radicals and thereto appended pharmacokinetic modulator groups act as capping groups and prevent attachment of the radiopharmaceutical2 / 126 pma25 10.02.2026

[0012] compound PC or radioligand RT on cell surfaces and intercalation in the lipid bilayer of plasma membranes.

[0013] FAP is highly expressed in the stroma of many solid tumors and rarely found in normal tissue. The one or two FAP substrate ligand radicals promote ligation of the radiopharmaceutical compound PC or radioligand RT to FAP. Upon binding (or homing) to FAP, the one or two FAP substrate ligands are enzymatically cleaved and the optional self-immolative spacers disintegrate. The thus released cell surface binder readily partitions to and inserts into the plasma membrane of proximal cells, regardless of their phenotype.

[0014] Known radioligands bind to specific transmembrane receptors, such as somatostatin (SSTR), prostate-specific membrane antigen (PSMA) or fibroblast activation protein (FAP) which are overexpressed in tumor tissue relative to healthy tissue. The number and concentration of cancer-associated transmembrane receptors is nonetheless limited and small compared to the total surface of cellular plasma membranes in the tumor. Contrary to known radioligands, the cell surface binder attaches to the plasma membrane of normal and oncogenic cells regardless of the presence or absence of specific receptors. Therefore, the cell surface binder significantly increases accumulation in tumor tissue.

[0015] The invention uses FAP substrate ligands which, contrary to FAP inhibitor ligands, rapidly dissociate from FAP after ligation and cleavage and do not measurably block its enzymatic pocket. The enzymatic activity of FAP is therefore largely unimpeded.

[0016] The concept of the invention is embodied by a compound PC that comprises one or two FAP substrate ligand radicals and a cell surface binder radical. The one or two FAP substrate ligand radicals are conjugated with the cell surface binder radical either directly or via self-immolative spacer radicals and prevent partition and attachment of the compound PC to cell surfaces. In the absence of FAP, the compound PC or a thereon based radioligand RT is physiologically inert and quickly cleared from the patient's body via the renal pathway.

[0017] PC can comprise polar or hydrophilic groups that prevent unwanted ligation to cell membranes and serum proteins, such as albumin. The hydrophilic groups can be linear or branched homo- or hetero-oligomers of ethylene glycol (–(CH2)2O–) and sarcosine (–N(C)CH2C(O)–). The polar or hydrophilic groups can comprise an oligopeptide. PC can be configured in such manner that, upon ligation to and cleavage by FAP, the polar or hydrophilic groups are separated from the cell surface binder radical. The lipophilic, respectively amphiphilic cell surface binder and the thereto appended radioisotope is released into the interstitial fluid and readily partitions to the plasma membrane of proximal cells.

[0018] The polar or hydrophilic groups can be configured to compensate and significantly outweigh the lipophilic, respectively amphiphilic character of the cell surface binder component. Notwithstanding, PC can also comprise radicals that bind to albumin with low affinity and moderately extend the residence time of PC in blood circulation and increase accumulation in tumor tissue.3 / 126 pma25 10.02.2026

[0019] According to the invention, the following considerations guide the structural design of PC: - PC can be hydrophilic to prevent off-target binding, mitigate extravasation from intact blood vessels in healthy tissue, reduce distribution volume, moderately prolong retention in blood circulation, promote renal excretion and mitigate uptake in liver and bone marrow,

[0020] - the cell surface binder component of PC can be configured as lipophilic, in particular amphiphilic radical which, in tumor tissue after FAP-mediated cleavage and release from PC and due to the hydrophobic effect, is displaced from the interstitial fluid and partitioned to the plasma membrane of cells,

[0021] - PC can comprise a radical that is adapted for radioisotope labeling or pretargeting and appended to the cell surface binder component,

[0022] - the cell surface binder component of PC can comprise one or more polar anchor radicals which form ionic bonds or intercalate with phosphatidylcholine radicals, respectively phosphorylcholine radicals of phospholipids in the outer leaflet of cell membranes and retain the cell surface binder there, either for an extended time period or transiently before being internalized to the cytosol by permeation or endocytosis,

[0023] - PC can contain a lipophilic radical as part of the FAP substrate ligand to promote its ligation to and cleavage by FAP,

[0024] - PC can be configured for efficient catalytic cleavage by FAP with a half-life of less than 1 minute to about 70 minutes,

[0025] - PC can comprise a self-immolative spacer that moderates the FAP-mediated enzymatic cleavage efficiency,

[0026] - PC can be configured for fast release of the cell surface binder component after FAP- mediated cleavage of the FAP substrate ligand,

[0027] - PC can comprise a self-immolative spacer that includes a radical of DMED (N, N'-d i methylethylenediamine) and slightly delays the release of the cell surface binder component after FAP-mediated cleavage of the FAP substrate ligand.

[0028] The cell surface binder component of PC can comprise a radical that is similar to one of the many known lipophilic fluorescent dyes, of which there are hundreds or thousands. The cell surface binder component can for example be a derivative of PKH2 (2-[(E,3Z)-3-(3-docosyl-l,3-benzoxazol-2-ylidene)prop-l-enyl]-3-propyl-l,3-benzoxazol-3-ium), Octadecyl Rhodamine B ([6-(diethylamino)-9-(2-octadecoxycarbonylphenyl)xanthen-3-ylidene]-diethylazanium), Di-8-ANEPPS (3-[4-[(E)-2-[6-(dioctylamino)naphthalen-2-yl]ethenyl] pyridin-l-ium-l-yl]pro-pane-l-sulfonate) or lopofosine 1-131 (18-(4-iodophenyl)octadecyl 2-(trimethylazaniumyl) ethyl phosphate), lopofosine 1-131 is also known as NM404 and structurally related to NM600, which includes DOTA-4-aminophenyl in lieu of 4-iodophenyl.

[0029] The cell surface binder component of PC can comprise radicals selected from

[0030] - mono- and polycyclic aromatic hydrocarbons (e.g. benzene, naphthalene, anthracene) or derivatives thereof,

[0031] – aliphatic chains (e.g. –(CH2)n–) with n being any number between 1 and 40, or4 / 126 pma25 10.02.2026

[0032] - conjugates of mono- or polycyclic aromatic hydrocarbons and aliphatic chains.

[0033] The cell surface binder component of PC can include one or more radicals of guanidine or cell penetrating peptides (CPPs) in order to promote insertion into the plasma membrane or permeation and internalization into the cytosol of cells.

[0034] PC can further be configured for direct or pretargeted delivery of radioisotopes to tumor tissue.

[0035] For direct delivery, PC can comprise one or two FAP substrate ligand radicals, a cell surface binder radical and a labeling radical for labeling with a radioisotope. The labeling radical can be a chelator for complexation of a radioisotope, such as68Ga,161Tb,177Lu,212Pb or225Ac, or a leaving group for substitution with a radioisotope, such as18F,131l or211At.

[0036] For pretargeted delivery, PC comprisesone or two FAP substrate ligand radicals, a cell surface binder radical that includes a radical of a first bioorthogonal click-reactant.

[0037] For pretargeted delivery the invention further uses a delivery compound PD which comprises a radical of a second bioorthogonal click-reactant and a labeling radical for labeling with a radioisotope. The first and second click-reactants are complementary in that they rapidly react with each other under physiological conditions and form a permanent covalent bond. Otherwise, the first and second bioorthogonal click-reactants are largely inert and are neither hydrolyzed nor bound by physiological enzymes, proteins and biomolecules such as albumin and glutathione.

[0038] Pretargeted delivery uses a compound PC that is not labeled with a radioisotope and can be administered at a high systemic dose to promote tumor uptake and accumulation. Systemic excretion of residual PC molecules, that are not cleaved by FAP and bound to the plasma membrane of a cell typically occurs within less than 2 hours. Therefore, after a time period of two or more hours, the delivery compound PD with a thereto appended radioisotope can be administered to the patient at a relatively low dose with minimal exposure to healthy tissue. High accumulation and long retention of the cell surface binder component of PC in tumor tissue ensure strong uptake and extended residence of the delivery compound PD with the thereto bound radioisotope.

[0039] In an expedient embodiment of the invention the first bioorthogonal click-reactant is a derivative of tetrazine and the second bioorthogonal click-reactant is a derivative of transcyclooctene, or vice versa.

[0040] For direct as well as pretargeted delivery it is beneficial to adapt the pharmacokinetic properties, particularly the hydrophilicity (logP, logD) or polarity of PC and PD for fast tissue clearance and predominantly renal excretion. This can be achieved through incorporation of suitable pharmacokinetic modulator radicals. In the compound PC the pharmacokinetic modulator radicals are advantageously conjugated to the part containing the FAP substrate ligands and the optional self-immolative spacers which, after cleavage by FAP, dissociate from the cell surface binder.5 / 126 pma25 10.02.2026

[0041] The compound PC of the invention can have a structure selected from the group comprising P1 — F1 — 11 — J1 — C1 — L1 — A1 — S1 -Ch

[0042] P1 — F1 —11 — J1 -C1 — L1 — A1 — S1 — LR

[0043] P1 -F1 — 11 — J1 — CR— L1 —AT

[0044] S5

[0045] I

[0046]

[0047] Ch

[0048] P1 -F1 — 11 -J1 — CR— L1 -AT

[0049] ss

[0050] LR CX-L1-A1^

[0051] si

[0052] P1 — F1 —11 -J1 — TE-S5-Ch

[0053] / S2

[0054] CY-L2-A2

[0055] CX-L1-A1^

[0056] s-i

[0057] P1 — F1 — 11 -J1 — TE-S5— LR

[0058] / S2

[0059] CY-L2-A2

[0060] CX-L1-A1^

[0061] s-i

[0062] P1 -F1 — 11 -J1 -C3-L3-A3-S3-TE-S5-Ch

[0063] / S2

[0064] CY-L2-A2

[0065] CX-L1-A1^

[0066] s-i

[0067] P1 -F1 — 11 -J1 -C3-L3-A3-S3-TE-S5— LR

[0068] / S2

[0069] CY-L2-A2

[0070] CX-L1

[0071] P1-F1-l1-J1-TZ-L4-S4-TE-S5-Ch

[0072] L3 S2

[0073] CZX

[0074]

[0075] CY-L2'6 / 126 pma25 10.02.2026

[0076] CX- LI ^A1

[0077] L3 S1 P1-F1-I1-J1-TZ-L4-S4-TE-S5-LR ±3 S2

[0078] ^A2

[0079]

[0080] CY-L2 P1-F1— I1-J1-C1-L1-A1-S1

[0081] / TL-S5-Ch P2-F2— I2-J2-C2-L2-A2-S2

[0082] P1 -F1 —11 — J1 — C1 — L1 — A1 -S1

[0083] / TL-S5-LR P2-F2— 12— J2— C2— L2— A2-S2

[0084] P1 -F1 — 11 — J1 — C1 — L1 — A1 — S1

[0085] ZTL-S5— Ch CY-L2— A2— S2

[0086] P1-F1— I1-J1-C1— L1— A1— S1

[0087] ZTL-S5— LR CY-L2— A2— S2

[0088] zC1— L1— A1— S1\ P3-F3-I3-J3— JT^ZTL— S5— Ch C2— L2— A2— S2 C1~ L1— A1— S1xP3-F3-I3-J3— JT^ZTL— S5— LR C2— L2— A2— S2

[0089] CX-L1-A1 C3— L3 S1 P3-F3-I3-J3-JT\: TL- L4- S4- TE- S5- Ch C3— L3

[0090] S2 CY-L2-A2 CX-L1-A1 C3— L3 S1 P3-F3-I3-J3-JT\: TL-L4-S4-TE-S5-LR C3— L3

[0091] S2

[0092] P1 — F1 — 11 — J1 -C1 — L1 — A1 — S1 — G P1 -F1 — 11 -J1 — CR— L1 -AT

[0093]

[0094] G7 / 126 pma25 10.02.2026

[0095] CX-L1-A1^

[0096] s-i

[0097] P1 — F1 —11 -J1 — TE-S5-G

[0098] / S2

[0099] CY-L2-A2

[0100] CX-L1 -Al^

[0101] si

[0102] P1 -F1 —11 -J1 -C3-L3-A3-S3-TE-S5-G

[0103] / S2

[0104] CY-L2-A2

[0105] CX-L1

[0106] P 1 - F 1 - 11 - J 1 — TZ— L4-S4-T E-S5-G

[0107] ±3 S2

[0108] ^A2

[0109]

[0110] CY-L2

[0111] P1-F1— I1-J1-C1-L1-A1-S1

[0112] / TL-S5-G

[0113] P2-F2— I2-J2-C2-L2-A2-S2

[0114] P1-F1— I1-J1-C1— L1— A1— S1

[0115] / TL-S5— G

[0116] CY-L2— A2— S2

[0117] C1 — L1 — A1 — S1\

[0118] P3-F3-I3— J3— JT^ZTL— S5— G and

[0119] C2— L2— A2— S2

[0120] CX-L1-A1

[0121] ZC3— L3 S1

[0122] P3-F3-I3-J3-JT TL-L4-S4-TE-S5-G

[0123] XC3— L3Z

[0124] / S2

[0125]

[0126] CY-L2-A2

[0127] The delivery compound PD of the invention can have a structure selected from the group comprising

[0128] Gc— S6— Ch and Gc— S6— LR

[0129] In the above structure formulas

[0130] – P1, P2, P3 independently of one another can be radicals of hydrogen (H–) or radicals of pharmacokinetic modulator groups,8 / 126 pma25 10.02.2026

[0131] - Pl, P2, P3 independently of one another can comprise a radical of a linear or branched ethylene glycol (–(CH2)2O–) or sarcosine (-N(C)CH2C(O)-) oligomer,

[0132] - Pl, P2, P3 independently of one another can comprise a radical of a linear or branched hetero-oligomer of ethylene glycol (–(CH2)2O–) and sarcosine (-N(C)CH2C(O)-),

[0133] – P1, P2, P3 independently of one another can comprise one, two, three or more amino acid radicals,

[0134] – P1, P2, P3 independently of one another can comprise one, two, three or more aspartic acid radicals,

[0135] – P1, P2, P3 independently of one another can comprise a radical selected from the group comprising

[0136]

[0137] - Fl, F2, F3 are radicals of FAP substrate ligands and independently of one another can comprise

[0138] - a radical having the structure

[0139]

[0140] wherein X = H or CH3, Y1= H or F , Y2= H or F ,

[0141] or

[0142] - a radical selected from the group comprising peptide radicals -Gly-Pro-Ser-, -Ala-Pro-Ser and -Gly-Pro-Val-,

[0143] - 11, 12 independently of one another can be absent, radicals of bivalent self-immolative spacers or radicals of bivalent self-immolative spacer subunits,

[0144] - 11, 12 independently of one another can comprise a pharmacokinetic modulator radical P4, – J1, J2 independently of one another can be absent, radicals of bivalent self-immolative spacers or radicals of bivalent self-immolative spacer subunits,

[0145] – J1, J2 independently of one another can comprise a pharmacokinetic modulator radical P4,9 / 126 pma25 10.02.2026

[0146] - -I1-J1-, -I2-J2- independently of one another can be absent or radicals of bivalent self- immolative spacers,

[0147] - 13 can be absent or a radical of a trivalent self-immolative linker subunit,

[0148] - 13 can comprise a pharmacokinetic modulator radical P4,

[0149] - J3 can be absent or a radical of a trivalent self-immolative linker subunit,

[0150] - J3 can comprise a pharmacokinetic modulator radical P4,

[0151] - the radical

[0152] ' F13- JT\^ ' ^“J3— JT'y>orFl3-J3-JTy

[0153]

[0154] can be a radical of a trivalent self-immolative linker,

[0155] - P4 can be a hydrogen radical (H-) or a pharmacokinetic modulator radical,

[0156] – P4 can comprise a radical of a linear or branched ethylene glycol (–(CH2)2O–) or sarcosine (–N(C)CH2C(=O)–) oligomer,

[0157] – P4 can comprise a radical of a linear or branched hetero-oligomer of ethylene glycol (–(CH2)2O–) and sarcosine (–N(C)CH2C(=O)–),

[0158] - P4 can comprise one, two, three or more amino acid radicals,

[0159] - P4 can comprise one, two, three or more aspartic acid radicals,

[0160] - P4 can comprise a radical selected from the group comprising

[0161]

[0162] 10 / 126 pma25 10.02.2026

[0163] and

[0164]

[0165] radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol,

[0166] 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP) with the proviso that Cl, C2, C3 independently of one another comprise a terminal radical selected from the group comprising

[0167]

[0168] CX, CY, CZ independently of one another can be selected from the group comprising

[0169]

[0170] radicals of hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-11 / 126 pma25 10.02.2026

[0171] hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP),

[0172] - CX, CY, CZ independently of one another can comprise a radical selected from the group comprising

[0173]

[0174] - CR can be selected from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol, 27-hydroxycholesterol,

[0175] 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP) with the proviso that CR comprises a terminal radical selected from the group comprising

[0176]

[0177] - LI, L2, L3, L4 independently of one another can be absent or lipophilic radicals,

[0178] - Al, A2, A3, AT independently of one another can be absent, polar or hydrophilic radicals, - Al, A2, A3, AT independently of one another can comprise a radical of

[0179] 3-(trimethylazaniumyl)propane-l-sulfonate,

[0180] - Al, A2, A3, AT independently of one another can comprise a radical of phosphorylcholine,

[0181] - Al, A2, A3, AT independently of one another can comprise a covalent linker radical CW selected from the group comprising -S7-U-V-(W1=)S(=W2)-F, -S7-C(=O)-BT, -S7-C(=O)-NA,-S7-C(=O)-ML and -S7-C(=O)-NP, wherein

[0182] - S7 is a bivalent spacer radical,

[0183] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,

[0184] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0185] - W1 is =0 or =NH,

[0186] - W2 is =0 or =NH,12 / 126 pma25 10.02.2026

[0187] - BT is a substituted or unsubstituted benzotriazole radical,

[0188] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0189] - NP is

[0190]

[0191] - SI, S2, S3, S4, S5, S6, S7 independently of one another can be absent or bivalent spacer radicals,

[0192] - TL can be a radical of a trivalent linker,

[0193] - TL can comprise a covalent linker radical CW selected from the group comprising -S7-U-V-(W1=)S(=W2)-F, -S7-C(=O)-BT, -S7-C(=O)-NA, -S7-C(=O)-ML and

[0194] -S7-C(=O)-NP, wherein

[0195] - S7 is a bivalent spacer radical,

[0196] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,

[0197] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0198] - W1 is =0 or =NH,

[0199] - W2 is =0 or =NH,

[0200] - BT is a substituted or unsubstituted benzotriazole radical,

[0201] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0202]

[0203] - TE can be a radical of a tetravalent linker,

[0204] - TE can comprise a covalent linker radical CW selected from the group comprising -S7-U-V-(W1=)S(=W2)-F, -S7-C(=0)-BT, -S7-C(=O)-NA, -S7-C(=O)-ML and

[0205] -S7-C(=0)-NP, wherein

[0206] - S7 is a bivalent spacer radical,

[0207] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,13 / 126 pma25 10.02.2026

[0208] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0209] - W1 is =0 or =NH,

[0210] - W2 is =0 or =NH,

[0211] - BT is a substituted or unsubstituted benzotriazole radical,

[0212] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0213] O

[0214] - NP is ’

[0215]

[0216] O

[0217] - TZ can be a radical of a tetravalent linker,

[0218] - Ch can be a radical of a chelator for complexation of a radioisotope,

[0219] - LR can be a radical configured

[0220] - as a leaving group for substitution with a radioisotope, or

[0221] - as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope,

[0222] - G can be a radical of a first bioorthogonal reactant and Gc can be a radical of a second bioorthogonal reactant, wherein G and Gc are configured to react with each other and form a covalent bond under physiological conditions,

[0223] - G can comprise a tetrazine radical and Gc can comprise a trans-cyclooctene radical, or vice versa, G can comprise a trans-cyclooctene radical and Gc can comprise a tetrazine radical. For therapeutic use, the compound PC is either labeled with a radioisotope or equipped with a first bioorthogonal click-reactant G. After cleavage by FAP a cell surface binder is released which can have the structure

[0224] H-C1 — L1 — A1 — S1 -Ch* H-C1 — L1 — A1 — S1 — LR*, H-C1— L1— A1-S1-G H— CR— L1 —AT H— CR— L1— AT H— CR— L1— AT ss ss, S5 I

[0225] Ch* LR* G CX-L1-A1^ CX-L1-A1^ CX-L1-A1^ si s-i s-i H-TE-S5-Ch* H-TE-S5— LR* H-TE-S5-G, I

[0226] / S2 / S2 / S2C

[0227]

[0228] Y-L2-A2 CY-L2-A2 CY-L2-A214 / 126 pma25 10.02.2026

[0229] CX-L1-A1^ CX-L1-A1^

[0230] s-i si H-C3-L3-A3-S3-TE-S5-Ch* H-C3-L3-A3-S3-TE-S5-LR*

[0231] / S2 / S2CY-L2-A2 CY-L2-A2

[0232] CX-L1 CX-L1 — Al^

[0233] S1 H-C3-L3-A3-S3- -S5-G H— TZ— L4— S4— TE— S5— Ch*

[0234] / S2CY-L2— A2 ^A2

[0235] CY-L2 CX-L1 CX-L1 > A1 L3 S1 H— TZ-L4-S4-TE-S5-LR* H— TZ-L4-S4-TE-S5-G L3 S2CZ^A2 ^A2 CY-L2 CY-L2 H-C1— L1— A1— S1 H-C1— L1— A1— S1

[0236] / TL— S5- Ch*ZTL- S5- LR* H-C2— L2— A2— S2 H-C2— L2— A2— S2 H-C1— L1— A1— S1 H-C1 — L1— A1 — S1

[0237] ZTL-S5-G yri_-S5-Ch* H-C2— L2— A2— S2 CY-L2— A2— S2 H-C1— L1— A1— S1 H-C1— L1 — A1— S1

[0238] / TL— S5- LR*ZTL-S5-G CY-L2— A2— S2 CY-L2— A2— S2 CX-L1-A1 CX-L1 -A1 H-C3— L3 S1

[0239] : TL- L4- S4- TE- S5- Ch: TL-L4-S4-TE-S5-LR’ H-C3— L3

[0240] S2 S2 CY-L2-A2 CY-L2-A2 CX-L1 — A1^

[0241] q-1 H-C3— L3 |

[0242] / TL-L4-S4-TE-S5-G H-C3— L3 I

[0243]

[0244] CY-L2— A2 wherein H is a hydrogen radical (H-) and Ch* and LR* represent a chelator complexed with a radioisotope and a radioisotope substituent, respectively, and G denotes a first bioorthogonal click-reactant.15 / 126 pma25 10.02.2026

[0245] The compound PC embodies the central concept of the invention, either when being implemented as radioligand precursor or as pretargeting compound of a radiopharmaceutical kit.

[0246] The above recited radicals

[0247] - Pl, P2, P3,

[0248] - Fl, F2, F3,

[0249] - 11, 12, 13, JI, J2, J3, P4, JT,

[0250] - Cl, C2, C3, CX, CY, CZ, CR,

[0251] - LI, L2, L3, L4,

[0252] - Al, A2, A3, AT,

[0253] - SI, S2, S3, S4,

[0254] - TL, TE, S5,

[0255] - Ch, LR, G, Gc, S6,

[0256] have different pharmacological functions and can belong to a chemical genus of limited size or be formed in countless different ways.

[0257] Prior to cleavage of PC by FAP in diseased tissue, either of the FAP substrate ligands Fl, F2, F3, particularly in conjunction with either of the pharmacokinetic modulator radicals Pl, P2, P3, P4 prevents attachment of PC to the plasma membrane of cells.

[0258] In an expedient embodiment of the compound PC, the FAP substrate ligand radicals Fl, F2, F3 can be selected independently of one another from the group comprising

[0259] and

[0260]

[0261] o16 / 126 pma25 10.02.2026

[0262]

[0263] wherein X = H or CH3, Y1= H or F , Y2= H or F .

[0264] After FAP-mediated cleavage of PC and release of the cell surface binder, the lipophilic radicals Cl, C2, C3, CX, CY, CZ, CR, LI, L2, L3, L4 intercalate the aliphatic chains of membrane phospholipids and the polar anchor radicals Al, A2, A3, AT especially when implemented as radicals of 3-(trimethylazaniumyl)propane-l-sulfonate or phosphorylcholine, form ionic bonds or intercalate with phosphatidylcholine radicals, respectively phosphorylcholine radicals of phospholipids. Therefore, either of Cl, C2, C3, CX, CY, CZ, CR, LI, L2, L3, L4 in conjunction with either of Al, A2, A3, AT can be essential for attachment and retention of the cell surface binder on plasma membranes after FAP-mediated cleavage and release from PC. Cl, C2, C3, CX, CY, CZ, CR can be radicals of cell-penetrating moieties, such as guanidine, cell penetrating peptides (CPPs) and cholesterol derivatives, which promote insertion of the cell surface binder in plasma membranes after FAP-mediated cleavage and release from PC. Cl, C2, C3, CX, CY, CZ independently of one another can also comprise a radical of 4-(l,3-benzothiazol-2-yl)aniline or a derivative thereof, such as depicted beneath,

[0265]

[0266] which prolongs the retention of PC in the plasma membrane of cells.

[0267] CX, CY, CZ independently of one another can also comprise a terminal (2-methylpropyl) benzene, iodobenzene, benzoxazole or (trifluoromethyl) benzene radical which promotes weak binding to serum albumin and moderately prolongs plasma retention.

[0268] Al, A2, A3, AT and the linkers TL and TE can comprise a covalent linker CW that can form a covalent bond with a membrane protein, such as carbonic anhydrase IX or XII (CA IX / XII) and thereby attach the cell surface binder component to the plasma membrane in an irreversible and substantially prolonged manner. The covalent linker radical CW is largely inert under physiological conditions and only forms a covalent bond with a nucleophile, such as the side chain of serine, tyrosine, lysine or histidine, when positioned in close proximity thereto. Proximity conditions for covalent bond formation are met, when the cell surface binder17 / 126 pma25 10.02.2026

[0269] component, respectively its lipophilic portion attaches to the plasma membrane. The sequence of

[0270] - ligation of the lipophilic portion of the cell surface binder to the outer leaflet of the plasma membrane, followed by

[0271] - proximity-mediated covalent bond formation between the covalent linker CW and a nucleophilic residue of a membrane protein,

[0272] is analogous to the mechanism of action of covalent drugs or targeted covalent inhibitors. In an expedient embodiment of the invention the covalent linker CW can comprise a sulfonyl fluoride (-SO2F) radical.

[0273] The molar ratio of phospholipids to membrane proteins is estimated at about 40:1. Accordingly, covalent binding to membrane proteins contributes to irreversible attachment of the cell surface binder component to the plasma membrane.

[0274] If the cell surface binder permeates into the cytosol or is internalized via endocytosis the covalent linker CW can bind to intracellular proteins and thus prolong the residence time. Phosphatidylserine in the outer leaflet of the plasma membrane plays a vital role in the growth and proliferation of cancer cells and has been identified as a potential target for cancer treatment. In healthy cells phosphatidylserine is almost exclusively present in the inner membrane leaflet. In this context, it is noteworthy that lopofosine 1-131 selectively binds to the plasma membrane of cancer cells and subsequently appears to be internalized. This phenomenon, while not fully elucidated has been associated with lipid rafts.

[0275] The pharmacokinetic modulator radicals Pl, P2, P3, P4, especially when formed as hydrophilic radicals, promote systemic clearance of PC and extravasation into tumor tissue. Therefore, at least one of Pl, P2, P3, P4 can have an important pharmacological function.

[0276] The pharmacokinetic modulator radicals Pl, P2, P3, P4 independently of one another can also comprise a terminal (2-methylpropyl)benzene, iodobenzene, benzoxazole or (trifluoromethyl) benzene radical to cause weak binding to serum albumin and moderately prolong blood retention.

[0277] The bivalent spacers SI, S2, S3, S4, S5, S7 are facultative. SI, S2, S3, S4, S5, S7, the trivalent linker TL and the tetravalent linkers TE and TZ can be formed in countless different ways many of which do not significantly change the pharmacological properties of PC. Therefore, SI, S2, S3, S4, S5, S7, TL, TE and TZ are specified initially as linking elements rather than by a chemical genus, as the latter would unduly limit the scope of the invention and allow easy circumvention.

[0278] The bivalent spacer radical S6, especially when formed as polar or hydrophilic radical, can be used to adapt the pharmacokinetics of the delivery compound PD. Accordingly, S6 can have an important pharmacological function.18 / 126 pma25 10.02.2026

[0279] PC can comprise one, two, three or four aliphatic radicals LI, L2, L3, L4 of the type -(CH2)n-where n is a number between 1 and 30, similar to the commercial membrane-inserting fluorescent dyes PKH26 and PKH2 depicted below in Scheme la and lb.

[0280]

[0281] Scheme la: Fluorescent dye PKH26 (2-((E)-3-((E)-3,3-dimethyl-l-tetradecylindolin-2- ylidene)prop-l-en-l-yl)-l-docosyl-3,3-dimethyl-3H-indol-l-ium iodide)

[0282]

[0283] Scheme lb: Fluorescent dye PKH2 (2-[(E,3Z)-3-(3-docosyl-l,3-benzoxazol-2- ylidene)prop-l-enyl]-3-propyl-l,3-benzoxazol-3-ium iodide)

[0284] Various authors report the use of membrane-inserting fluorescent and radioactive dyes PKH2, PKH3, PKH26,125I-PKH95 for cell labeling and in vivo tracking over extended time periods of 7 to 80 days:

[0285] - Horan PK, Melnicoff MJ, Jensen BD, Slezak SE. Fluorescent cell labeling for in vivo and in vitro cell tracking. Methods Cell Biol. 1990;33:469-90. doi: 10.1016 / s0091- 679x(08)60547-6. https: / / www.sciencedirect.com / science / article / abs / pii / S0091679X08605476

[0286] - Audran R, Collet B, Moisan A, Toujas L. Fate of mouse macrophages radiolabelled with PKH-95 and injected intravenously. Nucl Med Biol. 1995 Aug;22(6):817-21. doi:

[0287] 10.1016 / 0969-8051(95)00013-n. PMID: 8535344. https: / / www.sciencedirect.com / science / article / abs / pii / 096980519500013N

[0288] - Ford JW, Welling TH 3rd, Stanley JC, Messina LM. PKH26 and125I-PKH95: characterization and efficacy as labels for in vitro and in vivo endothelial cell localization and tracking. J Surg Res. 1996 Apr;62(l):23-8. doi: 10.1006 / jsre.1996.0167. https: / / www.sciencedirect.com / science / article / abs / pii / S0022480496901675

[0289] - Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, Brisken C, Minucci S, Di Fiore PP, Pelicci PG. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009 Sep 18;138(6):1083-95. doi:

[0290] 10.1016 / j.celL2009.06.048. https: / / www.cell.com / fulltext / S0092-8674(09)00840-X19 / 126 pma25 10.02.2026

[0291] - Regan JL, Schumacher D, Staudte S, Steffen A, Lesche R, Toedling J, Jourdan T, Haybaeck J, Mumberg D, Henderson D, Gyorffy B, Regenbrecht CRA, Keilholz U, Schafer R, Lange M. RNA sequencing of long-term label-retaining colon cancer stem cells identifies novel regulators of quiescence. iScience. 2021 May 24;24(6):102618. doi:

[0292] 10.1016 / j.isci.2021.102618. https: / / www.cell.com / iscience / fulltext / S2589- 0042(21)00586-1

[0293] - Regan JL. Protocol for isolation and functional validation of label-retaining quiescent colorectal cancer stem cells from patient-derived organoids for RNA-seq. STAR Protoc. 2022 Mar 10;3(l):101225. doi: 10.1016 / j.xpro.2022.101225. https: / / www.sciencedirect.com / science / article / pii / S2666166722001058

[0294] - Pinchuk AN, Rampy MA, Longino MA, Skinner RW, Gross MD, Weichert JP, Counsell RE.

[0295] Synthesis and structure-activity relationship effects on the tumor avidity of radioiodinated phospholipid ether analogues. J Med Chem. 2006 Apr 6;49(7):2155-65. https: / / pubs.acs.org / doi / 10.1021 / jm050252g

[0296] - US 2002 / 0065429 Al

[0297] - Hernandez R, Grudzinski JJ, Aluicio-Sarduy E, Massey CF, Pinchuk AN, Bitton AN, Patel R, Zhang R, Rao AV, Iyer G, Engle JW, Weichert JP.177Lu-NM600 Targeted Radionuclide Therapy Extends Survival in Syngeneic Murine Models of Triple-Negative Breast Cancer. J Nucl Med. 2020 Aug; 61(8):1187-1194. doi: 10.2967 / jnumed.119.236265. https: / / jnm.snmjournals. Org / content / 61 / 8 / 1187.long

[0298] - WO 2018 / 022125 Al

[0299] According to Ford et al., PKH26 and125I-PKH95 efficiently label endothelial cells and are retained in vivo for up to 60 days without notably affecting cell proliferation.

[0300] Cicalese and Regan et al. use PKH26 to label stem cells and observe undiminished dye retention in vivo over 7 and 12 days. This suggests that the invention could enable labeling and eradication of rare cancer stem cells in tumor tissue in vivo with therapeutic radioisotopes Terbium-161, Lutetium-177, Lead-212 and Actinium-225.

[0301] Hernandez et al. report dosimetry results for the membrane inserting radioligand177Lu-NM600 in a mouse model with triple-negative breast cancer xenograft. The unlabeled precursor NM600 has the structure DOTA-NH-Phe-(CH2)i8PO4“(CH2)2N+(CH3)3 and comprises a Cis-chain conjugated to a polar phosphocholine radical, similar to phosphatidylcholine lipids which are the most abundant phospholipids in the outer membrane leaflet, followed by sphingomyelin lipids (https: / / www.ncbi.nlm.nih.gov / books / NBK9898 / ; https: / / www2.hu-berlin.de / biologie / molbp / lipid / myoblast.htm).

[0302] Recently developed membrane-inserting fluorescent dyes and theranostic compounds with improved water solubility and reduced agglomeration are described in the beneath cited publications:20 / 126 pma25 10.02.2026

[0303] - Zhang S, Lilienkampf A, Bradley M. Solid-Phase Synthesis of Fluorescent Probes for Plasma Membrane Labelling. Molecules. 2021 Jan 12;26(2):354. doi:10.3390 / molecules26020354. https: / / www.mdpi.eom / 1420-3049 / 26 / 2 / 354

[0304] - Niwa M, Hirayama T, Oomoto I, Wang DO, Nagasawa H. Fe(ll) Ion Release during Endocytotic Uptake of Iron Visualized by a Membrane-Anchoring Fe(ll) Fluorescent Probe. ACS Chem Biol. 2018 Jul 20;13(7):1853-1861. doi: 10.1021 / acschembio.7b00939. https: / / pubs.acs.org / doi / 10.1021 / acschembio.7b00939

[0305] - Collot M, Ashokkumar P, Anton H, Boutant E, Faklaris O, Galli T, Mely Y, Danglot L, Klymchenko AS. MemBright: A Family of Fluorescent Membrane Probes for Advanced Cellular Imaging and Neuroscience. Cell Chem Biol. 2019 Apr 18;26(4):600-614.e7. doi: 10.1016 / j.chembioL2019.01.009. https: / / www.sciencedirect.com / science / article / pii / S2451945619300315

[0306] - Danylchuk DI, Sezgin E, Chabert P, Klymchenko AS. Redesigning Solvatochromic Probe Laurdan for Imaging Lipid Order Selectively in Cell Plasma Membranes. Anal Chem. 2020 Nov 3;92(21):14798-14805. https: / / pubs.acs.org / doi / 10.1021 / acs.analchem.0c03559 - Shimomura T, Seino R, Umezaki K, Shimoda A, Ezoe T, Ishiyama M, Akiyoshi K. New Lipophilic Fluorescent Dyes for Labeling Extracellular Vesicles: Characterization and Monitoring of Cellular Uptake. Bioconjug Chem. 2021 Apr 21;32(4):680-684. doi:

[0307] 10.1021 / acs.bioconjchem.lc00068. https: / / pubs.acs.org / doi / 10.1021 / acs.bioconjchem.lc00068

[0308] - Ling J, Liu Y, Dumoulin A, Sheng D, Fu Y, Liu S, Ding L, Huang L, Xi P, Tang H, Stoeckli ET, Chen Z. A gentle palette of plasma membrane dyes. Proc Natl Acad Sci U S A. 2025 Jul 22;122(29):e2504879122. https: / / www.pnas.org / doi / 10.1073 / pnas.2504879122

[0309] - Carney CE, MacRenaris KW, Mastarone DJ, Kasjanski DR, Hung AH, Meade TJ. Cell labeling via membrane-anchored lipophilic MR contrast agents. Bioconjug Chem. 2014 May 21;25(5):945-54. https: / / pubs.acs.org / doi / 10.1021 / bc500083t

[0310] The following references pertain to FAP-activatable theranostic compounds and the prodrug Faridoxorubicin (AVA6000) which has entered regulatory trial NCT04969835 (https: / / www.clinicaltrials.gov / study / NCT04969835).

[0311] - De Decker A, Vliegen G, Van Rompaey D, Peeraer A, Bracke A, Verckist L, Jansen K, Geiss- Friedlander R, Augustyns K, De Winter H, De Meester I, Lambeir AM, Van der Veken P. Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP). ACS Med Chem Lett. 2019 Jul 9; 10(8):1173-1179. https: / / pubs.acs.org / doi / 10.1021 / acsmedchemlett.9b00191

[0312] Luo Y, Zeng Z, Shan T, Xu X, Chen J, He Y, Zhang T, Huang Z, Chai G, Huang Y, Zhao Y, Zhao C. Fibroblast activation protein a activatable theranostic pro-photosensitizer for accurate21 / 126 pma25 10.02.2026

[0313] tumor imaging and highly-specific photodynamic therapy. Theranostics. 2022 May l;12(8):3610-3627. https: / / www.thno.org / vl2p3610.htm

[0314] US 10,245,248 B2

[0315] FAP is expressed on the surface of cancer-associated fibroblasts (CAF) and is involved in remodeling the extracellular matrix (ECM) of the tumor microenvironment (TME).

[0316] Apparently, FAP has evolved to retain its enzymatic activity in the harsh conditions in inflamed tissue and - incidentally - also the TME. For a serine protease, like FAP it is generally expected that the catalytic triad Ser624-Asp702-His734, particularly His734, is adversely affected by the lowered pH ≈ 6.0–7.0 in the TME. However, FAP retains its endopeptidase activity and ability to cleave collagen.

[0317] The compound PC or radioligand RT of the invention are hydrophilic and readily extravasate from deleterious ("leaky") arterial microvessels of a tumor or metastasis and perfuse through the TME by diffusion and convective flow. In case that PC or RT are cleaved by FAP prior to intravasation into venous or lymphatic vasculature, a lipophilic or amphiphilic cell surface binder with a thereto appended radioisotope or biorthogonal click-reactant are released into the TME.

[0318] The TME is densely packed, so that the membrane surface density amounts to approximately 1500 to 3000 cm2per cm3of tissue. Assuming that the cell surface binder occupies a membrane surface area of about 0.5 nm2, the concentration of "membrane receptors Rm" corresponds to [Rm] = 0.5 - 1.0 mM. Further assuming that the affinity of the cell surface binder for plasma membranes corresponds to a dissociation constant KD= 50 μM yields the retardation factor R = 1 + [Rm] / KD = 11 - 21, which essentially equates to immobilization. It is noted that probe 2 of the above cited article by Zhang et al.

[0319] (doi:10.3390 / molecules26020354) is retained in plasma membranes for at least 2 hours, which is consistent with a dissociation constant KD in the micromolar range.

[0320] Similar applies, if the retardation factor is estimated based on membrane partitioning of the lipophilic cell surface binder. Assuming volume portions Vm= 2 - 5% and Vw= 20% for plasma membrane and interstitial (extracellular) water, a cell surface binder with logP = 2 yields the retardation factor R = 1 + (Vm / Vw)·10logP= 11 - 26.

[0321] The compound PC or radioligand RT of the invention can comprise a membrane anchor radical, such as 3-(trimethylazaniumyl)propane-l-sulfonate, which in conjunction with a polar radioisotope-chelator complex (e.g.177Lu[Lu]-DOTA) promotes retention in the plasma membrane and mitigates internalization into the cytosol and subsequent metabolization. The pharmacological concept of the invention is briefly explained with reference to Schemes 2a and 2b. Scheme 2a shows an exemplary compound PC, which contains some optional radicals for illustrative purposes.22 / 126 pma25 10.02.2026

[0322] O

[0323]

[0324] F F Scheme 2b: Exemplary compound PC Scheme 2a: Exemplary compound PC

[0325] after FAP-mediated cleavage23 / 126 pma25 10.02.2026

[0326] The exemplary compound PC of Scheme 2a comprises, starting from the top and proceeding to the bottom, a DOTA-chelator radical for complexation with a radioisotope, a 3-(trimethyl-azaniumyl)propane-l-sulfonate radical for anchoring on the surface of plasma membranes, an aliphatic (CH2)18–amine radical for insertion and intercalation in the lipophilic portion of plasma membranes, a thereto conjugated self-immolative spacer comprising a branched and a linear p-aminobenzylcarbamate (PABC) spacer radical, wherein the branched PABC spacer carries an oligo(ethylene glycol) and dendritic oligosarcosine radical, and a quinoline-based FAP substrate ligand radical with a thereto tethered oligosarcosine radical. The oligo(ethylene glycol) and oligosarcosine radicals render PC hydrophilic which reduces distribution volume and promotes renal excretion of PC. Scheme 2b shows the exemplary compound PC after FAP-mediated cleavage, disintegration of the self-immolative PABC spacers and release of the lipophilic, respectively amphiphilic membrane inserting cell surface binder with the thereto appended chelator.

[0327] As depicted in Scheme 2b, FAP-mediated cleavage causes the compound PC to disintegrate into five main fragments, of which the cell surface binder with the DOTA-chelator corresponds to a radioligand precursor and represents the pharmacologically active compound. The aliphatic (CH2)18radical of the cell surface binder is terminated by an amine radical. In addition to an amine radical, the present invention encompasses alternatives such as a thiol (— SH) or guanidine (–N=C(NH2)2) radical, which can promote membrane insertion.

[0328] Schemes 3a and 3b show an example of a radioligand according to the invention before and after FAP-mediated cleavage. The radioligand depicted in Scheme 3a is a linear conjugate comprising a hydrophilic oligomer composed of four ethylene glycol and twenty sarcosine units (PEG4-PSAR20), a quinoline based FAP substrate ligand, a self-immolative PABC and a cell surface binder composed of a lipophilic membrane-inserting 4-octadecylaniline radical, a 3-(trimethylazaniumyl)propane-l-sulfonate membrane anchor and a radioactive177Lu-DOTA complex. The dotted lines in Scheme 3a indicate bonds that are cleaved during disintegration of the PABC spacer.

[0329] In the radioligand according to Scheme 3a the PABC spacer is optional and can be omitted, such that the C-terminus of the proline radical of the FAP substrate ligand is directly conjugated to the 4-octadecylaniline radical of the cell surface binder.

[0330] The synthesis of a precursor compound for the radioligand of Scheme 3a is described in the Examples section of this patent application.24 / 126 pma25 10.02.2026

[0331]

[0332] Scheme 3a: Radioligand according to the invention25 / 126 pma25 10.02.2026

[0333]

[0334] Scheme 3b: The radioligand of Scheme 3a after FAP-mediated cleavage26 / 126 pma25 10.02.2026

[0335] PC can include a macrocycle comprising a first and second arm joined by a trivalent self-immolative linker JT and a trivalent linker TL. The trivalent self-immolative linker JT is conjugated via optional self-immolative spacers I3, J3 with the FAP substrate ligand F3.

[0336] Cleavage of F3 by FAP causes the trivalent self-immolative linker JT to dissociate from the first and second arm as depicted in Scheme 4.

[0337] / 1st arm^ FAP Ist arm.

[0338] ?JT\ / TL“? - / TL—s

[0339]

[0340] ^2nd arrrr 2nd arrrr

[0341] Scheme 4: Macrocyclic cell surface binder radical with trivalent self-immolative linker JT and trivalent linker TL before and after cleavage by FAP

[0342] Haberkorn et al. emphasize the need to improve the efficacy of FAP-targeting radioligands. - Haberkorn U, Altmann A, Giesel FL, Kratochwil C. 1,090 Publications and 5 Years Later: Is FAP-Targeted Theranostics Really Happening? J Nucl Med. 2024 Oct l;65(10):1518-1520. https: / / jnm.snmjournals.org / content / 65 / 10 / 1518

[0343] The invention has the object to improve the efficacy of FAP-targeting radioligand therapy and diagnostics.

[0344] The object of the invention is achieved through a compound PC or a salt thereof, alone or as part of a radiopharmaceutical kit, characterized in that PC comprises a cell surface binder radical CSB conjugated to either an activator radical ARI, two activator radicals ARI and AR2, or an activator radical AR3, wherein

[0345] - CSB comprises a lipophilic membrane-inserting radical,

[0346] - CSB comprises one of

[0347] - a chelator radical Ch for complexation of a radioisotope,

[0348] - a radical LR configured

[0349] - as a leaving group for substitution with a radioisotope, or

[0350] - as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope,

[0351] or

[0352] - a radical G of a first bioorthogonal click-reactant that includes a radical of triazine or trans-cyclooctene,

[0353] - CSB comprises one or two terminal radicals selected independently of one another from amine, oxy or sulfide radicals,

[0354] - AR1 comprises a fibroblast activation protein (FAP) substrate ligand radical F1 and a hydrophilic pharmacokinetic modulator radical P1,27 / 126 pma25 10.02.2026

[0355] - AR2 comprises a FAP substrate ligand radical F2 and a hydrophilic pharmacokinetic modulator radical P2,

[0356] - AR3 comprises a FAP substrate ligand radical F3, a hydrophilic pharmacokinetic modulator radical P3 and a trivalent self-immolative spacer radical SI3 conjugated to a first radical of F3 via an amine radical and to terminal amine, oxy or sulfide radicals of CSB, wherein SI3 is configured to disintegrate and release CSB upon FAP-mediated cleavage of F3 from SI3, - Fl, F2, F3 independently of one another comprise

[0357] - a radical having the structure

[0358]

[0359] X

[0360] wherein X = H or CH3, Y1= H or F, Y2= H or F,

[0361] or

[0362] - a radical selected from the group comprising peptide radicals -Gly-Pro-Ser-, -Ala-Pro-Ser- and -Gly-Pro-Val-.

[0363] The object of the invention is further achieved through a compound PC ora salt thereof, alone or as part of a radiopharmaceutical kit, characterized in that

[0364] - PC has a structure selected from the group comprising

[0365] P1— F1— 11— J1-C1— L1— A1— S1-Ch

[0366] P1— F1— 11— J1-C1— L1— A1— S1— LR

[0367] P1 -F1 — 11 — J1 — CR— L1 —AT

[0368] S5

[0369] I

[0370] Ch

[0371] P1 -F1 — 11 — J1 — CR— L1 —AT

[0372] S5

[0373] I LR CX-L1 -Al^

[0374] si

[0375] P1 -F1 — 11 -J1 — TE-S5-Ch

[0376] I

[0377] / S2

[0378]

[0379] CY-L2-A228 / 126 pma25 10.02.2026

[0380] CX-L1-A1

[0381] S1

[0382] P1-F1- I1-J1— ' E-S5-LR

[0383] / S2

[0384] CY-L2-A2

[0385] CX-L1-A1^

[0386] si

[0387] P1 -F1 — 11 -J1 -C3-L3-A3-S3-TE-S5-Ch / S2

[0388] CY-L2-A2

[0389] CX-L1-A1^

[0390] s-i

[0391] P1 -F1 — 11 -J1 -C3-L3-A3-S3-TE-S5— LR / S2

[0392] CY-L2-A2

[0393] CX-L1 CZ

[0394] L3 S1 P1— F1— 11— J1— TZ— L4— S4— TE— S5— Ch ±3 S2

[0395] ^A2 CY-L2 CX-L1^

[0396] P 1 - F 1 - 11 - J 1 -TZ- L4-S4-T E-S5- LR ±3 S2

[0397] ^A2

[0398]

[0399] CY-L2 P1-F1 — I1-J1-C1-L1-A1-S1

[0400] / TL-S5-Ch P2-F2— I2-J2-C2-L2-A2-S2

[0401] P1 -F1 — 11 — J1 — 01 — L1 — A1 -S1

[0402] / TL-S5-LR P2-F2—I2—J2—C2—L2—A2-S2

[0403] P1 -F1 — 11 — J1 -01 — L1 — A1 — S1

[0404] ZTL-S5— Ch CY-L2— A2— S229 / 126 pma25 10.02.2026

[0405] P1 -F1 —11 -J1 -C1 — L1 — A1 — S1

[0406] / TL-S5— LR CY-L2— A2— S2

[0407] ZC1— L1— A1— S1xP3-F3-I3-J3— JT^ / TL— S5— Ch C2— L2— A2— S2ZC1— L1— A1— S1xP3-F3-I3-J3— JT^ / TL— S5— LR C2— L2— A2— S2

[0408] CX-L1-A1

[0409] S1 C3— L3 P3- F3- 13- J3- JT^,: TL- L4- S4- TE- S5- Ch C3— L3

[0410] S2 CY-L2-A2 CX-L1-A1 C3— L3 S1 P3-F3-I3-J3-JT\ ^TL-L4-S4-TE-S5-LR C3— L3

[0411] S2

[0412]

[0413] CY-L2-A2

[0414] P1— F1— 11— J1-C1— L1— A1— S1— G

[0415] P1 -F1 — 11 — J1 — CR— L1 —AT

[0416] ss

[0417] G CX-L1 -Al^

[0418] si

[0419] P1 -F1 — 11 -J1 — TE-S5-G

[0420] / S2

[0421] CY-L2-A2

[0422] CX-L1-A1^

[0423] s-i

[0424] P1 — F1 — 11 -J1 -C3-L3-A3-S3-TE-S5-G / S2

[0425] CY-L2-A230 / 126 pma25 10.02.2026

[0426] CX-L1

[0427] P 1 - F 1 - 11 - J 1 — TZ— L4-S4-T E-S5-G

[0428] L3 S2

[0429] CZ_^A2

[0430]

[0431] CY-L2

[0432] P1-F1— I1-J1-C1-L1-A1-S1

[0433] / TL-S5-G

[0434] P2-F2— I2-J2-C2-L2-A2-S2

[0435] P1-F1 — I1-J1-C1— L1— A1— S1

[0436] / TL-S5— G

[0437] CY-L2— A2— S2

[0438] C1~ L1— A1— S1x

[0439] P3-F3-I3— J3— JT^ / TL— S5— G and

[0440] C2— L2— A2— S2

[0441] CX-L1-A1

[0442] S1

[0443] C3— U3

[0444] P3-F3-I3-J3-JT\,: TL-L4-S4-TE-S5-G

[0445] C3— L3

[0446] S2

[0447]

[0448] CY-L2-A2

[0449] wherein

[0450] - Pl, P2, P3 independently of one another are radicals of hydrogen (H-) or radicals of pharmacokinetic modulator groups,

[0451] - Fl, F2, F3 independently of one another comprise

[0452]

[0453] wherein X = H or CH3, Y1= H or F, Y2= H or F,

[0454] or

[0455] - a radical selected from the group comprising peptide radicals -Gly-Pro-Ser-, -Ala-Pro-Ser- and -Gly-Pro-Val-.31 / 126 pma25 10.02.2026

[0456] - 11, 12 independently of one another are absent, radicals of bivalent self-immolative spacers or radicals of bivalent self-immolative spacer subunits,

[0457] - JI, J2 independently of one another are absent, radicals of bivalent self-immolative spacers or radicals of bivalent self-immolative spacer subunits,

[0458] - -I1-J1-, -I2-J2- independently of one another are absent or radicals of bivalent self- immolative spacers,

[0459] - 13 is absent or a radical of a trivalent self-immolative linker subunit,

[0460] - J3 is absent or a radical of a trivalent self-immolative linker subunit,

[0461] - the radical

[0462] or I3— J3— JT

[0463]

[0464] is a radical of a trivalent self-immolative linker,

[0465] - Cl, C2, C3 independently of one another are selected from the group comprising

[0466]

[0467] radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine,32 / 126 pma25 10.02.2026

[0468] cell penetrating peptides (CPP) with the proviso that Cl, C2, C3 independently of one another comprise a terminal radical selected from the group comprising

[0469]

[0470] - CX, CY, CZ independently of one another are selected from the group comprising

[0471] O

[0472]

[0473] radicals of hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP),

[0474] - CR is selected from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, polycyclic aromatic hydrocarbons, substituted polycyclic aromatic hydrocarbons, naphthalene, substituted naphthalene, anthracene, substituted anthracene, pyrene, substituted pyrene, perylene, substituted perylene, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol,

[0475] 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP) with the proviso that CR comprises a terminal radical selected from the group comprising

[0476]

[0477] LI, L2, L3, L4 independently of one another are absent or lipophilic radicals,33 / 126 pma25 10.02.2026

[0478] - Al, A2, A3, AT independently of one another are absent, polar or hydrophilic radicals, - SI, S2, S3, S4, S5 independently of one another are absent or bivalent spacer radicals, - TL is a radical of a trivalent linker,

[0479] - TE is a radical of a tetravalent linker,

[0480] - TZ is a radical of a tetravalent linker,

[0481] - Ch is a radical of a chelator for complexation of a radioisotope,

[0482] - LR is a radical configured

[0483] as a leaving group for substitution with a radioisotope, or

[0484] as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope,

[0485] and

[0486] - G is a radical of a first bioorthogonal click-reactant.

[0487] Expedient embodiments of the invention are characterized by one of the following features or a combination of two or more of the following features insofar the combined features are not mutually exclusive or contradictory and according to which:

[0488] - PC comprises one radical having the structure

[0489]

[0490] wherein Y1= H or F, Y2= H or F.

[0491] - Fl, F2, F3 comprise a terminal carbonyl radical (— C(=O)— ) which is bound to an amine radical.

[0492] - PC comprises one radical having the structure

[0493]

[0494] wherein X = H or CH3, Y1= H or F , Y2= H or F .34 / 126 pma25 10.02.2026

[0495] PC comprises two radicals which independently of one another have the structure

[0496]

[0497] wherein Y1= H or F, Y2= H or F.

[0498] PC comprises two radicals which independently of one another have the structure

[0499]

[0500] wherein X = H or CH3, Y1= H or F , Y2= H or F .

[0501] PC has a structure selected from the group comprising

[0502] P1— F1— 11— J1-C1— L1— A1— S1-Ch

[0503] P1— F1— 11— J1-C1— L1— A1— S1— LR

[0504] P1 -F1 —11 — J1 — CR— L1 —AT

[0505] S5

[0506] Ch

[0507] P1 -F1 — 11 — J1 — CR— L1 —AT

[0508] ss

[0509] LR CX-L1 -Al^

[0510] si

[0511] P1 — F1 — 11 -J1 — TE-S5-Ch

[0512] / S2

[0513] CY-L2-A2

[0514] CX-L1-A1^

[0515] S1

[0516] P1 — F1 —11 -J1 — TE-S5-LR

[0517] / S2

[0518] CY-L2-A235 / 126 pma25 10.02.2026

[0519] CX-L1-A1

[0520] P1 -F1 — 11 -J1 -C3-L3-A3-S3-TE-S5-Ch / S2CY-L2-A2 CX-L1-A1^ si P1 — F1 — 11 -J1 -C3-L3-A3-S3-TE-S5— LR / S2CY-L2-A2 CX-L1

[0521] P1-F1-l1-J1-TZ-L4-S4-TE-S5-Ch S2 ^A2 CY-L2' CX-L1

[0522] P 1 - F 1 - 11 - J 1 — TZ— L4-S4-T E-S5- LR L3 S2cz_A2

[0523] CY-L2 P1-F1— I1-J1-C1-L1-A1-S1

[0524] / TL-S5-Ch P2-F2— I2-J2-C2-L2-A2-S2 P1 -F1 — 11 — J1 — C1 — L1 — A1 -S1

[0525] / TL-S5-LR P2-F2— 12— J2— C2— L2— A2-S2 P1 -F1 — 11 — J1 -C1 — L1 — A1 — S1 yri_-s5— Ch CY-L2— A2— S2 P1 -F1 —11 -J1 -C1 — L1 — A1 — S1

[0526] / TL-S5— LR CY-L2— A2— S2 C1~ L1— A1— S1xP3-F3-I3-J3— JT^ / TL— S5— Ch

[0527]

[0528] C2— L2— A2— S236 / 126 pma25 10.02.2026

[0529] C1~ L1— A1— S1\

[0530] P3-F3-I3-J3— JT^ ^TL— S5— LR

[0531] C2— L2— A2— S2

[0532] CX-L1-A1

[0533] C3— L3

[0534] P3- F3- 13- J3- JT^ ^TL-L4-S4-TE-S5-Ch and

[0535] / S2

[0536] CX-L1-A1

[0537] C3— L3 S1

[0538] P3-F3-I3-J3-JT\ ^TL-L4-S4-TE-S5-LR

[0539] C3— L3

[0540] S2

[0541]

[0542] CY-L2-A2

[0543] wherein

[0544] - Ch is a radical of a chelator for complexation of a radioisotope,

[0545] and

[0546] - LR is a radical configured

[0547] - as a leaving group for substitution with a radioisotope, or

[0548] - as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope.

[0549] - PC is part of radiopharmaceutical kit that further comprises a delivery compound PD, - PC has a structure selected from the group comprising

[0550] P1— F1— I1— J1-C1— L1— A1— S1— G

[0551] P1 -F1 — 11 — J1 — CR— L1 —AT

[0552] I

[0553] S5

[0554] I G CX-L1-A1^

[0555] si

[0556] P1 — F1 — 11 -J1 — TE-S5-G

[0557] I

[0558] / S2

[0559]

[0560] CY-L2-A237 / 126 pma25 10.02.2026

[0561] CX-L1-A1^

[0562] si

[0563] P1 — F1 — 11 -J1 -C3-L3-A3-S3-TE-S5-G

[0564] / S2

[0565] CY-L2-A2

[0566] CX-L1

[0567] P 1 - F 1 - 11 - J 1 — TZ— L4-S4-T E-S5-G

[0568] ±3 S2

[0569] ^A2

[0570]

[0571] CY-L2

[0572] P1-F1— I1-J1-C1-L1-A1-S1

[0573] / TL-S5-G

[0574] P2-F2— I2-J2-C2-L2-A2-S2

[0575] P1 -F1 — 11 -J1 — C1 — L1 — A1 — S1

[0576] / TL-S5— G

[0577] CY-L2— A2— S2

[0578] C1 — L1— A1— S1xP3-F3-I3— J3— JT^ZTL— S5— G and

[0579]

[0580] C2— L2— A2— S2 CX-L1-A1

[0581] S1

[0582] C3_L3

[0583] P3-F3-I3-J3-JT\,: TL-L4-S4-TE-S5-G

[0584] C3— L3

[0585] S2

[0586] CY-L2-A2

[0587] wherein G is a radical of a first bioorthogonal click-reactant, and

[0588] - PD has the structure

[0589] Gc— S6— Ch or Gc— S6— LR

[0590] wherein

[0591] - Gc is a radical of a second bioorthogonal click-reactant, - S6 is absent or a bivalent spacer radical,

[0592] - Ch is a radical of a chelator for complexation of a radioisotope, - LR is a radical configured

[0593] - as a leaving group for substitution with a radioisotope, or38 / 126 pma25 10.02.2026

[0594] as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope,

[0595] and

[0596] - G and Gc are configured to react with each other and form a covalent bond under physiological conditions.

[0597] - Pl, P2, P3 independently of one another are radicals comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 radicals selected independently of one another from the group comprising -CH2-, — C(=O)—, -CH(-CH3)-, -O-, -NH-, -N(-CH3)-, -CH=CH-, -CH(-CH2COOH)-, -CH2CH2O– , –C(=O)–CH2–N(–CH3)– , and radicals of 4- to 10-membered aryl, substituted 4- to 10-membered aryl, 4- to 10-membered heteroaryl, substituted 4- to 10-membered heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.

[0598] - Pl, P2, P3 independently of one another are radicals comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 radicals selected independently of one another from the group comprising -CH2-, — C(=O)—, -O-, -N(-CH3)-, -CH(-CH2COOH)-, -CH2CH2O-, -C(=O)-CH2-N(-CH3)-, and radicals of arginine, histidine, asparagine, serine, aspartic acid, threonine, cysteine, lysine, tryptophan, glutamine, tyrosine, glutamic acid, alcohols, aminoalkylcarboxylic acids. - Pl, P2, P3 independently of one another are radicals comprising 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 radicals selected independently of one another from the group comprising -CH2-, -C(=O)-, -CH(-CH3)-, -O-, -NH-, -N(-CH3)-, -CH=CH-, -CH(-CH2COOH)-, -CH2CH2O-, — C(=O)— CH2— N(— CH3)—, and radicals of 4- to 10-membered aryl, substituted 4- to 10-membered aryl, 4- to 10-membered heteroaryl, substituted 4- to 10- membered heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.

[0599] - Pl, P2, P3 independently of one another comprise a radical of a linear or branched ethylene glycol (— (CH2)2O— ) or sarcosine (— N (C)CH2C(=O)— ) oligomer.

[0600] - Pl, P2, P3 independently of one another comprise a radical of a linear or branched heterooligomer of ethylene glycol (— (CH2)2O— ) and sarcosine (— N(C)CH2C(=O)— ).

[0601] - Pl, P2, P3 independently of one another comprise one, two, three or more aspartic acid radicals.39 / 126 pma25 10.02.2026

[0602] Pl, P2, P3 independently of one another comprise a radical selected from the group comprising

[0603]

[0604] Fl, F2, F3 independently of one another comprise a radical selected from the group comprising

[0605]

[0606] wherein the terminal carbonyl radical is conjugated to the terminal amine radical of a radical having the structure40 / 126 pma25 10.02.2026

[0607]

[0608] wherein X = H or CH3, Y1= H or F , Y2= H or F .

[0609] - Fl, F2, F3 independently of one another comprise a radical selected from the group comprising

[0610] and

[0611]

[0612] - Fl, F2, F3 independently of one another comprise a peptide radical selected from the group comprising -Gly-Pro-Ser-, -Gly-Pro-Ser-GIn-, -Gly-Pro-Ser-GIn-Gly-, -Gly-Pro-Ser-GIn-Gly-Lys-, -Gly-Pro-Ser-GIn-Gly-Lys-COO-,

[0613] -Gly-Pro-Ser-Gln-Gly-Lys(COOH)-, -Val-Gly-Pro-Ser-, -Val-Gly-Pro-Ser-GIn-, -Val-Gly-Pro-Ser-GIn-Gly-, -Val-Gly-Pro-Ser-GIn-Gly-Lys-,41 / 126 pma25 10.02.2026

[0614] -Val-Gly-Pro-Ser-Gln-Gly-Lys-COO- and -Val-Gly-Pro-Ser-Gln-Gly-Lys(COOH)-, wherein -Lys(COOH)- represents -CH(=O)-CH(NH-COOH)-(CH2)4NH-.

[0615] Fl, F2, F3 independently of one another comprise a peptide radical selected from the group comprising -(D-Ala)-Pro-Ser-, -(D-Ala)-Pro-Ser-Gln-,

[0616] -(D-Ala)-Pro-Ser-Gln-Gly-, -(D-Ala)-Pro-Ser-Gln-Gly-Lys-,

[0617] -(D-Ala)-Pro-Ser-Gln-Gly-Lys-COO-, -(D-Ala)-Pro-Ser-Gln-Gly-Lys(COOH)-, -Val-(D-Ala)-Pro-Ser-, -Val-(D-Ala)-Pro-Ser-Gln-, -Val-(D-Ala)-Pro-Ser-Gln-Gly-, -Val-(D-Ala)-Pro-Ser-Gln-Gly-Lys-, -Val-(D-Ala)-Pro-Ser-Gln-Gly-Lys-COO- and -Val-(D-Ala)-Pro-Ser-Gln-Gly-Lys(COOH)-, wherein -Lys(COOH)- represents -CH(=O)-CH(NH-COOH)-(CH2)4NH-.

[0618] Fl, F2, F3 independently of one another comprise a peptide radical selected from the group comprising -Gly-Pro-Val-, -Gly-Pro-Val-Ala, -Gly-Pro-Val-Ala-Asp-, -Ser-Gly-Pro-Val-, -Ser-Ser-Gly-Pro-Val-, -Ser-Gly-Pro-Val-Ala-,

[0619] -Ser-Gly-Pro-Val-Ala-Asp- and -Ser-Ser-Gly-Pro-Val-Ala-Asp-.

[0620] 11, 12, 13 independently of one another are absent or comprise a radical selected from the group comprising

[0621]

[0622] 42 / 126 pma25 10.02.2026

[0623] and

[0624]

[0625] wherein the terminal amine radical is bound to Fl, F2 or F3, Bl is an amine, oxy or sulfide radical, and P4 is a pharmacokinetic modulator radical.

[0626] - 11, 12, 13 independently of one another are absent or comprise a radical having the structure

[0627]

[0628] 11, 12, 13 independently of one another are absent or comprise a radical selected from the group comprising

[0629]

[0630] wherein the terminal amine radical is bound to Fl, F2 or F3, Bl is an amine, oxy or sulfide radical, B2 is an amine or oxy radical and B3 is a radical selected from the group comprising

[0631]

[0632] - 11, 12, 13 independently of one another are absent or comprise a radical selected from the group comprising

[0633]

[0634] 43 / 126 pma25 10.02.2026

[0635]

[0636] wherein the terminal amine radical is bound to Fl, F2 or F3 and P4 is a pharmacokinetic modulator radical.

[0637] - 11, 12, 13 independently of one another are absent or comprise a radical selected from the group comprising

[0638]

[0639] 11, 12, 13 independently of one another are absent or comprise a radical selected from the group comprising

[0640]

[0641] wherein P4 is a pharmacokinetic modulator radical.

[0642] - 11, 12, 13 independently of one another are absent or comprise a radical having the structure

[0643]

[0644] wherein P4 is a pharmacokinetic modulator radical.44 / 126 pma25 10.02.2026

[0645] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0646]

[0647] 45 / 126 pma25 10.02.2026

[0648]

[0649] 46 / 126 pma25 10.02.2026

[0650]

[0651] wherein the terminal amine, oxy or sulfide radical is bound to Fl, F2, F3, 11, 12 or 13, Bl is an amine, oxy or sulfide radical, and P4 is a pharmacokinetic modulator radical.

[0652] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0653]

[0654] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0655]

[0656] 47 / 126 pma25 10.02.2026

[0657]

[0658] wherein P4 is a pharmacokinetic modulator radical.

[0659] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0660]

[0661] P4

[0662] wherein P4 is a pharmacokinetic modulator radical.

[0663] - JI, J2, J3 independently of one another are absent or comprise a radical having the structure

[0664]

[0665] wherein P4 is a pharmacokinetic modulator radical.

[0666] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0667]

[0668] 48 / 126 pma25 10.02.2026

[0669]

[0670] wherein the terminal amine radical is bound to Fl, F2 or F3 and P4 is a pharmacokinetic modulator radical.

[0671] - JI, J2, J3 independently of one another are absent or comprise a radical selected from the group comprising

[0672]

[0673] O O49 / 126 pma25 10.02.2026

[0674]

[0675] wherein a terminal methylene radical is bound to 11, 12 or 13 and P4 is a pharmacokinetic modulator radical.

[0676] - PC comprises a radical selected from the group comprising

[0677]

[0678] O50 / 126 pma25 10.02.2026

[0679]

[0680] wherein P4 is a pharmacokinetic modulator radical.

[0681] - JT is a radical of a trivalent self-immolative linker or a radical of a trivalent self-immolative linker subunit and comprises a radical having the structure

[0682]

[0683] O51 / 126 pma25 10.02.2026

[0684]

[0685] wherein

[0686] - M1is an amine, oxy or sulfide radical,

[0687] - M2is a carbon (C), nitrogen (N) or carbonitro (C-NO2) radical,

[0688] - M3is a carbon (C), nitrogen (N) or carbonitro (C-NO2) radical,

[0689] - M4is a -H, -OH, -COOH, -NO2, -C(=O)CH2N(C)OH, -N(C)CH2COOH, -(OCH2CH2)mOH, -(CH2OCH2)mOH, alkyl, heteroalkyl, substituted alkyl or substituted heteroalkyl radical with m = 1, 2 or 3, and

[0690] - M1is bound to F3, 13 or J3.

[0691] - P4 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 radicals selected independently of one another from the group comprising -CH2-, -C(=O)-, -CH(-CH3)-, -O-, -NH-, -N(-CH3)-, -CH=CH-, -CH(-CH2COOH)-, -CH2CH2O– , –C(=O)–CH2–N(–CH3)– , and radicals of 4- to 10-membered aryl, substituted 4- to 10-membered aryl, 4- to 10-membered heteroaryl, substituted 4- to 10-membered heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.

[0692] - P4 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 radicals selected independently of one another from the group comprising -CH2-, -C(=O)-, -O-, -N(-CH3)-, -CH(-CH2COOH)-, -CH2CH2O-, -C(=O)-CH2-N(-CH3)-, and radicals of arginine, histidine, asparagine, serine, aspartic acid, threonine, cysteine, lysine, tryptophan, glutamine, tyrosine, glutamic acid, alcohols, aminoalkylcarboxylic acids. - P4 comprises a radical of a linear or branched ethylene glycol (–(CH₂)₂O–) or sarcosine (–N(C)CH₂C(O)–) oligomer.

[0693] - P4 comprises a radical of a linear or branched hetero-oligomer of ethylene glycol (–(CH₂)₂O–) and sarcosine (–N(C)CH₂C(O)–).

[0694] - P4 comprises one, two, three or more aspartic acid radicals.52 / 126 pma25 10.02.2026

[0695] - P4 comprises a radical selected from the group comprising

[0696]

[0697] - PC has the structure

[0698] / C1— L1— A1 — S1\

[0699] P3-F3-I3-J3— JT^ / TL— S5— Ch

[0700] C2— L2— A2— S2

[0701] C1~ L1— A1 — S1x

[0702] P3-F3-I3-J3-JT\ / TL— S5— LR

[0703] C2— L2— A2— S2

[0704] C1 — L1 — A1 — S1\

[0705] P3-F3-I3— J3— JT^ZTL— S5— G

[0706]

[0707] C2— L2— A2— S2

[0708] CX-L1-A1

[0709] S1

[0710] C3— L3

[0711] P3-F3-I3-J3-JT\ ': TL- L4- S4- TE- S5- Ch

[0712] C3— L3

[0713] S2

[0714] CY-L2-A2

[0715] CX-L1 -A1

[0716] S1

[0717] C3— L3

[0718] P3-F3-I3-J3-JT\: TL-L4-S4-TE-S5-LR

[0719] C3— L3Z

[0720] S2

[0721] CY-L2-A2

[0722] CX-L1-A1^

[0723] ZS1

[0724] C3— L3

[0725] P3-F3-I3-J3-JT TL-L4-S4-TE-S5-G

[0726] XC3— L3X

[0727] / S2

[0728]

[0729] CY-L2-A253 / 126 pma25 10.02.2026

[0730] and comprises a radical having the structure

[0731]

[0732] wherein

[0733] - M1is an amine, oxy or sulfide radical,

[0734] - M2is a carbon (C), nitrogen (N) or carbonitro (C-NO2) radical,

[0735] - M3is a carbon (C), nitrogen (N) or carbonitro (C-NO2) radical,

[0736] - M4is a -H, -OH, -COOH, -NO2, -C(=O)CH2N(C)OH, -N(C)CH2COOH, -(OCH2CH2)mOH, -(CH2OCH2)mOH, alkyl, heteroalkyl, substituted alkyl or substituted heteroalkyl radical with m = 1, 2 or 3,

[0737] - M5is an amine, oxy or sulfide radical, and

[0738] - M1is bound to F3, 13 or J3.

[0739] - PC has the structure

[0740] / C1— L1— A1— S1\

[0741] P3-F3-I3-J3— JT^ / TL— S5— Ch

[0742] C2— L2— A2— S2

[0743] C1~ L1— A1— S1x

[0744] P3-F3-I3-J3-JT\ / TL— S5— LR or

[0745] C2— L2— A2— S2

[0746] C1 — L1 — A1 — S1\

[0747] P3-F3-I3— J3— JT^ZTL— S5— G

[0748]

[0749] C2— L2— A2— S254 / 126 pma25 10.02.2026

[0750] and comprises the radicals

[0751] and

[0752]

[0753] - PC has the structure

[0754] CX-L1-A1 CX-L1-A1

[0755] P1 — F1 — D1 — TE-S5-Ch P1 — F1 — D1 — TE-S5— LR

[0756] / S2 / S2

[0757] CY-L2-A2 CY-L2-A2

[0758] CX-L1-A1^ CX-L1-A1^

[0759] S1 S1

[0760] I

[0761] P1-F1-D1— TE-S5-G P1 -F1 -D1 -S3-TE-S5— Ch

[0762] I

[0763] / S2 / S2

[0764] CY-L2-A2 CY-L2-A2

[0765] CX-L1-A1^ CX-L1-A1^

[0766] S1 S1

[0767] P1 -F1 -D1 -S3-TE-S5— LR or P1-F1-D1-S3-TE-S5-G

[0768] / S2 / S2

[0769]

[0770] CY-L2-A2 CY-L2-A2

[0771] wherein –D1– represents –I1–, –J1– or –I1–J1– and includes the pharmacokinetic modulator radical P4.

[0772] - Cl, C2, C3 independently of one another are selected from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxy- cholesterol, 7a-hydroxycholesterol, 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP) with the proviso that Cl, C2, C3 independently of one another comprise a terminal radical selected from the group comprising

[0773]

[0774] and the four nearest neighbor radicals of said terminal radical are selected independently of one another from the group comprising

[0775]

[0776] 55 / 126 pma25 10.02.2026

[0777]

[0778] 56 / 126 pma25 10.02.2026

[0779]

[0780] wherein the amine, oxy or sulfide radical is bound to Fl, F2, F3, 11, 12, 13, JI, J2, J3 or JT, and p = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0781] - Cl, C2, C3 independently of one another comprise a radical selected from the group comprising

[0782]

[0783] wherein the amine, oxy or sulfide radical is bound to Fl, F2, F3, 11, 12, 13, JI, J2, J3 or JT. - Cl, C2, C3 independently of one another comprise a radical selected from the group comprising

[0784]

[0785] wherein the amine, oxy or sulfide radical is bound to Fl, F2, F3, 11, 12, 13, JI, J2, J3 or JT.57 / 126 pma25 10.02.2026

[0786] - Cl, C2, C3 independently of one another comprise a radical selected from the group

[0787] comprising

[0788]

[0789] N58 / 126 pma25 10.02.2026

[0790]

[0791] 59 / 126 pma25 10.02.2026

[0792]

[0793] - CX, CY, CZ independently of one another comprise a radical selected from the group comprising

[0794]

[0795] - CR is selected from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl, substituted heteroalkylaryl, cholesterol, 25-hydroxycholesterol, 24(S)-hydroxycholesterol, 7a-hydroxycholesterol,

[0796] 27-hydroxycholesterol, 22(R)-hydroxycholesterol, guanidine, cell penetrating peptides (CPP) with the proviso that CR comprises a terminal radical selected from the group comprising

[0797]

[0798] and the four nearest neighbor radicals of said terminal radical are selected independently of one another from the group comprising

[0799] bCHd

[0800]

[0801] 60 / 126 pma25 10.02.2026

[0802]

[0803] - CR comprises a radical selected from the group comprising

[0804]

[0805] wherein the amine, oxy or sulfide radical is bound to Fl, F2, F3, 11, 12, 13, JI, J2, J3 or JT.61 / 126 pma25 10.02.2026

[0806] - LR is conjugated to an aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, heteroalkylaryl or substituted heteroalkylaryl radical of CR.

[0807] - LI, L2, L3, L4 independently of one another comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 methylene radicals (-CH2-).

[0808] - LI, L2, L3, L4 independently of one another comprise 1, 2, 3, 4, 5, 6, 7 or 8 methylene radicals (-CH2-).

[0809] - LI, L2, L3, L4 independently of one another comprise 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 methylene radicals (–CH2–).

[0810] - LI, L2, L3, L4 independently of one another comprise 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 methylene radicals (-CH2-).

[0811] - LI, L2 are branched and independently of one another comprise a radical having the structure

[0812] g

[0813]

[0814] wherein g = 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0815] - LI, L2, L3, L4 independently of one another comprise a terminal radical having the structure

[0816]

[0817] - LI, L2, L3, L4 independently of one another comprise 1, 2, 3 or 4 alkene radicals (-CH=CH-).

[0818] - LI, L2, L3, L4 independently of one another comprise 1, 2, 3, 4, 5 or 6 radicals selected independently of one another from the group comprising radicals of aryl, substituted aryl, heteroaryl and substituted heteroaryl.

[0819] - LI, L2, L3, L4 independently of one another comprise 1, 2, 3, 4, 5 or 6 radicals selected independently of one another from the group comprising

[0820] '2

[0821]

[0822] 62 / 126 pma25 10.02.2026

[0823] - L4 comprises a radical having the structure

[0824]

[0825] - LI, L2, L3, L4 independently of one another have the structure

[0826]

[0827] m

[0828] wherein m = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0829] - LI, L2, L3, L4 independently of one another have the structure

[0830]

[0831] m

[0832] wherein m = 1, 2, 3, 4, 5, 6, 7 or 8.

[0833] - LI, L2, L3, L4 independently of one another have the structure

[0834]

[0835] m

[0836] wherein m = 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[0837] - LI, L2, L3, L4 independently of one another have the structure

[0838]

[0839] m

[0840] wherein m = 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0841] - LI, L2, L3, L4 independently of one another have the structure

[0842]

[0843] k

[0844] wherein k = 1, 2, 3, 4, 5, 6, 7 or 8.

[0845] - Al, A2, A3 independently of one another are radicals of peptides composed of one, two, three or more amino acids.63 / 126 pma25 10.02.2026

[0846] - Al, A2, A3 independently of one another comprise a radical selected from the group comprising

[0847]

[0848] 64 / 126 pma25 10.02.2026

[0849]

[0850] - AT comprises a radical selected from the group comprising

[0851]

[0852] 65 / 126 pma25 10.02.2026

[0853] - Al, A2, A3, AT independently of one another comprise a covalent linker radical CW selected from the group comprising -S7-U-V-(W1=)S(=W2)-F, -S7-C(=O)-BT, -S7-C(=O)-NA,-S7-C(=O)-ML and -S7-C(=O)-NP, wherein

[0854] - S7 is a bivalent spacer radical,

[0855] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,

[0856] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0857] - W1 is =0 or =NH,

[0858] - W2 is =0 or =NH,

[0859] - BT is a substituted or unsubstituted benzotriazole radical,

[0860] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0861] O

[0862]

[0863] O

[0864] - Al, A2, A3, AT independently of one another comprise a covalent linker radical CW selected from the group comprising -S7-CH[CH(CH3)2]-O-C(=O)-BT,

[0865] -S7-CH[CH(CH3)2]-O-C(=O)-NA, -S7-CH[CH(CH3)2]-O-C(=O)-ML and

[0866] -S7-CH[CH(CH3)2]-O-C(=O)-NP.

[0867] - SI, S2, S3, S4, S5, S6, S7 independently of one another are radicals of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, 20-, 21-, 22-, 23-, 24-, 25-, 26-, 27-, 28-, 29-, 30-, 31-, 32-, 33-, 34-, 35-, 36-, 37-, 38-, 39- or 40-membered alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl.

[0868] - SI, S2, S3, S4, S5, S6, S7 independently of one another are radicals of 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-membered alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl.

[0869] - SI, S2, S3, S4, S5, S6, S7 independently of one another are radicals comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 radicals selected independently of one another from the group comprising -CH2-, -C(=O)-, -CH(-CH3)-, -O-, -NH-, -N(-CH3)-, -CH=CH-, -CH(-CH2COOH)-, -CH2CH2O– , –C(=O)–CH2–N(–CH3)– , and radicals of 4- to 10-membered aryl, substituted 4- to 10-membered aryl, 4- to

[0870] 10-membered heteroaryl, substituted 4- to 10-membered heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.66 / 126 pma25 10.02.2026

[0871] - SI, S2, S3, S4, S5, S6, S7 independently of one another comprise radicals having the structure

[0872]

[0873] u

[0874] wherein u = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0875] - SI, S2, S3, S4, S5, S6, S7 independently of one another comprise radicals having the structure

[0876]

[0877] wherein u = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30.

[0878] - SI, S2, S3, S4, S5, S6, S7 independently of one another comprise radicals having the structure

[0879] O

[0880]

[0881] wherein u = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 and w = 1, 2, 3, 4, 5 or 6.

[0882] - SI, S2, S3, S4, S5, S6, S7 independently of one another comprise radicals having the structure

[0883] O

[0884]

[0885] wherein u = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 and w = 1, 2, 3, 4, 5 or 6.67 / 126 pma25 10.02.2026

[0886] - TL comprises one, two, three or more radicals selected independently of one another from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, alcohol, aminoalkylcarboxylic acid, amino acid or peptide composed of 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids.

[0887] - TL comprises a covalent linker radical CW selected from the group comprising

[0888] -S7-U-V-(W1=)S(=W2)-F, -S7-C(=O)-BT, -S7-C(=O)-NA, -S7-C(=O)-ML and

[0889] -S7-C(=O)-NP, wherein

[0890] - S7 is a bivalent spacer radical,

[0891] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,

[0892] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0893] - W1 is =0 or =NH,

[0894] - W2 is =0 or =NH,

[0895] - BT is a substituted or unsubstituted benzotriazole radical,

[0896] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0897]

[0898] - TL comprises a covalent linker radical CW selected from the group comprising

[0899] -S7-CH[CH(CH3)2]-O-C(=O)-BT, -S7-CH[CH(CH3)2]-O-C(=O)-NA,

[0900] -S7-CH[CH(CH3)2]-O-C(=O)-ML and -S7-CH[CH(CH3)2]-O-C(=O)-NP.

[0901] - TL comprises one, two, three or more radicals of substituted or unsubstituted polycyclic aromatic hydrocarbons.

[0902] - TL comprises one, two, three or more radicals selected independently of one another from the group comprising radicals of substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, substituted or unsubstituted pyrene and substituted or unsubstituted perylene.

[0903] - TL comprises a radical selected from the group comprising

[0904]

[0905] 68 / 126 pma25 10.02.2026

[0906]

[0907] - TL comprises a radical having the structure

[0908] Q1—Q2—Q3 or Q1-Q2—Q3-Q4-Q5

[0909]

[0910] wherein

[0911] - Q1 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl,

[0912] - Q2 is a radical of a 2-, 3-, 4- or 5-membered alkyl or heteroalkyl,

[0913] - Q3 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl,

[0914] - Q4 is a radical of a 2-, 3-, 4- or 5-membered alkyl or heteroalkyl, and

[0915] - Q5 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl.

[0916] - TL comprises a radical having the structure

[0917] Q1— Q2— Q3 or Q1-Q2— Q3-Q4-Q5

[0918]

[0919] wherein

[0920] Q1, Q3 and Q5 independently of one another are selected from the group comprising

[0921]

[0922] 69 / 126 pma25 10.02.2026

[0923] 0 -J- i

[0924]

[0925] 70 / 126 pma25 10.02.2026

[0926]

[0927] and Q2 and Q4 independently of one another are selected from the group comprising

[0928]

[0929] - TL is selected from the group of trivalent radicals comprising

[0930]

[0931] 71 / 126 pma25 10.02.2026

[0932]

[0933] a chlorine, iodine or perchlorate salt thereof.

[0934] - TE comprises one, two, three or more radicals selected independently of one another from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, alcohol, aminoalkylcarboxylic acid, amino acid or peptide composed of 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids.

[0935] - TE comprises a covalent linker radical CW selected from the group comprising

[0936] -S7-U-V-(W1=)S(=W2)-F, -S7-C(=O)-BT, -S7-C(=O)-NA, -S7-C(=O)-ML and

[0937] -S7-C(=O)-NP, wherein

[0938] - S7 is a bivalent spacer radical,

[0939] - U is absent, a substituted or unsubstituted alkyl or heteroalkyl, or a substituted or unsubstituted C4 to C10 aryl or heteroaryl,

[0940] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0941] - W1 is =0 or =NH,

[0942] - W2 is =0 or =NH,

[0943] - BT is a substituted or unsubstituted benzotriazole radical,

[0944] - NA is a substituted or unsubstituted N-methyl-N-arylmethanesulfonamide radical, - ML is a substituted or unsubstituted malolactone radical, and

[0945] O

[0946]

[0947] O

[0948] - TE comprises a covalent linker radical CW selected from the group comprising

[0949] -S7-CH[CH(CH3)2]-O-C(=O)-BT, -S7-CH[CH(CH3)2]-O-C(=O)-NA,

[0950] -S7-CH[CH(CH3)2]-O-C(=O)-ML and -S7-CH[CH(CH3)2]-O-C(=O)-NP.72 / 126 pma25 10.02.2026

[0951] - TE comprises one, two, three or more radicals of substituted or unsubstituted polycyclic aromatic hydrocarbons.

[0952] - TE comprises one, two, three or more radicals of substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, substituted or unsubstituted pyrene and substituted or unsubstituted perylene.

[0953] - TE comprises a radical selected from the group comprising

[0954]

[0955] - TE comprises a radical having the structure

[0956] Q1-Q2-Q3-Q4-Q5-

[0957]

[0958] Q1 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl,73 / 126 pma25 10.02.2026

[0959] - Q2 is a radical of a 2-, 3-, 4- or 5-membered alkyl or heteroalkyl,

[0960] - Q3 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl,

[0961] - Q4 is a radical of a 2-, 3-, 4- or 5-membered alkyl or heteroalkyl, and

[0962] - Q5 is a radical of 6- to 13-membered aryl, substituted 6- to 13-membered aryl, 6- to 13-membered heteroaryl or substituted 6- to 13-membered heteroaryl.

[0963] TE comprises a radical having the structure

[0964] Q1-Q2-Q3-Q4-Q5-

[0965]

[0966] Q1, Q3 and Q5 independently of one another are selected from the group comprising

[0967]

[0968] 74 / 126 pma25 10.02.2026

[0969]

[0970] and Q2 and Q4 independently of one another are selected from the group comprising

[0971]

[0972] 75 / 126 pma25 10.02.2026

[0973]

[0974] - TE is selected from the group of tetravalent radicals comprising

[0975]

[0976] a chlorine, iodine or perchlorate salt thereof.

[0977] - The covalent linker radical CW comprises a radical selected from the group comprising -O-C(=O)-BT, -O-C(=O)-NA, -O-C(=O)-ML and -O-C(=O)-NP.

[0978] - The covalent linker radical CW comprises a radical selected from the group comprising -CH[CH(CH3)2]-O-C(=O)-BT, -CH[CH(CH3)2]-O-C(=O)-NA, -CH[CH(CH3)2]-O-C(=O)-ML and -CH[CH(CH3)2]-O-C(=O)-NP.

[0979] - The radical -U-V-(W1=)S(=W2)-F has the structure

[0980] 2 1

[0981] \ A / RF

[0982] <, AA

[0983] ? — r -j — V \\, wherein

[0984] W2

[0985] _3 ^R4

[0986]

[0987] RR

[0988] - V is absent, -CH2-, =CH-, -O-, -NH- or -C(=O)-,

[0989] - W1 is =NH or =0,

[0990] - W2 is =NH or =0,

[0991] A is a C4-C10 aryl, C4-C10 substitued aryl, C4-C10 heteroaryl or substitued C4-C10 heteroaryl,76 / 126 pma25 10.02.2026

[0992] - R1is absent, H, NH2, NH, OH, O, linear or branched alkyl, or linear or branched substituted alkyl,

[0993] - R2is absent, H, NH2, NH, OH, O, linear or branched alkyl, or linear or branched substituted alkyl,

[0994] - R3is absent, H, NH2, NH, OH, O, linear or branched alkyl, or linear or branched substituted alkyl, and

[0995] - R4is absent, H, NH2, NH, OH, O, linear or branched alkyl, or linear or branched substituted alkyl.

[0996] - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[0997]

[0998] 77 / 126 pma25 10.02.2026

[0999]

[1000] - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[1001]

[1002] - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[1003]

[1004] - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[1005]

[1006] - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[1007]

[1008] 78 / 126 pma25 10.02.2026

[1009]

[1010] O - The radical -U-V-(W1=)S(=W2)-F is selected from the group comprising

[1011]

[1012] - BT is a benzotriazole radical selected from the group comprising

[1013]

[1014] 79 / 126 pma25 10.02.2026

[1015]

[1016] - NA is a N-methyl-N-arylmethanesulfonamide radical selected from the group comprising

[1017]

[1018] 80 / 126 pma25 10.02.2026

[1019] , wherein

[1020]

[1021] - Z1is absent or selected from the group comprising -F, -Cl, -Br and -NO2;

[1022] - Z2is absent or selected from the group comprising -F, -Cl, -Br and -NO2;

[1023] - Z3is absent or selected from the group comprising -F, -Cl, -Br and -NO2.

[1024] - ML is a malolactone radical selected from the group comprising

[1025]

[1026] wherein Hl is a radical of a linear or branched alkyl.81 / 126 pma25 10.02.2026

[1027] - TZ comprises one, two, three or more radicals selected independently of one another from the group comprising radicals of alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, alcohol, aminoalkylcarboxylic acid, amino acid or peptide composed of 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids.

[1028] - TZ comprises one, two, three or more radicals of substituted or unsubstituted polycyclic aromatic hydrocarbons.

[1029] - TZ comprises one, two, three or more radicals selected independently of one another from the group comprising radicals of substituted or unsubstituted naphthalene and substituted or unsubstituted anthracene.

[1030] - TZ comprises a terminal radical selected from the group comprising

[1031]

[1032] - TZ comprises a radical selected from the group comprising

[1033]

[1034] 82 / 126 pma25 10.02.2026

[1035] wherein Z1is an amine (-NH-), oxy (-O-) or sulfide (-S-) radical.

[1036] - Ch comprises a radical selected from the group comprising

[1037]

[1038] wherein F1 is -OH or -NH2, F2 is -OH or -NH2, F3 is -OH or -NH2, F4 is -OH or -NH2. - Ch comprises a radical selected from the group comprising radicals (I), (II), (III), (IV), (V) and (VI) having structures

[1039]

[1040] (HI) (IV)83 / 126 pma25 10.02.2026

[1041]

[1042] - Ch comprises a radical selected from the group comprising radicals (VII), (VIII), (IX) and (X) having structures

[1043]

[1044] 84 / 126 pma25 10.02.2026

[1045] - Ch comprises a radical selected from the group comprising radicals (XI), (XII), (XIII) and (XIV) having structures

[1046]

[1047] (XIII) (XIV)

[1048] - Ch comprises a radical selected from the group comprising radicals of DOTAM (1,4,7,10- Tetrakis(carbamoylmethyl)-l,4,7,10-tetraazacyclododecane), DOTAM-mono-acid (l,4,7,10-Tetraazacyclododecane-l,4,7-tri(carbamoylmethyl)-10-acetic acid) or DOTAM- bis-acid (l,4,7,10-Tetraazacyclododecane-l,7-bis(acetate)-4,10-bis(acetamide) ).

[1049] - Ch comprises a radical selected from the group comprising radicals (XV), (XVI), (XVII) and (XVIII) having structures

[1050]

[1051] 85 / 126 pma25 10.02.2026

[1052]

[1053] (XVII) (XVIII)

[1054] wherein U1 is –OH or –NH2, U2 is –OH or –NH2, U3 is –OH or –NH2, U4 is –OH or –NH2, and at least one of U1, U2 and U3 is –NH2or at least one of U1, U2, U3 and U4 is –NH2. Ch comprises the radical

[1055] Ch comprises the radical

[1056]

[1057] (XX)

[1058] - Ch comprises the radical

[1059]

[1060] (XXI)86 / 126 pma25 10.02.2026

[1061] - Ch comprises a radical selected from the group comprising

[1062]

[1063] - Ch comprises a radical selected from the group comprising radicals of H4pypa, EDTA (Ethylenediamine tetraacetate), EDTMP (Ethylenediaminetetra(methylenephosphonic acid)), DTPA (Diethylenetriamine pentaacetate) and derivatives thereof, NOTA (1,4,7- triazacyclononane-l,4,7-triacetic acid) and derivatives thereof, such as NODAGA (1,4,7- triazacyclononane,l-glutaric acid-4, 7-acetic acid), TRAP (Triazacyclononane-phosphinic acid), NOPO (l,4,7-triazacyclononane-l,4-bis[methylene-(hydroxymethyl)-phosphinic acid]-7-[methylene-(2-carboxyethyl)-phosphinic acid]), DOTPH(1,4,7,10-tetraaza- cyclododecane-l,4,7,10-tetrakis[methylenephosphinic acid]) and derivatives thereof, such as DOTPI (l,4,7,10-tetraazacyclododecane-l,4,7,10-tetrakis[methylene(2- carboxyethylphosphinic acid)]) and DOTPI(azid)4, TRITA (Trideca-l,4,7,10-tetraamine- tetraacetate), TETA (Tetradeca-l,4,8,ll-tetraamine-tetraacetate) and derivatives87 / 126 pma25 10.02.2026

[1064] thereof, PEPA (Pentadeca-l,4,7,10,13-pentaamine pentaacetate), HEHA (Hexadeca- 1,4,7,10,13,16-hexaamine-hexaacetate) and derivatives thereof, HBED (N, N'-Bis- (2-hydroxybenzyl) ethylene-diamine-N, N'-diacetate) and derivatives thereof such as HBED-CC (N, N'-Bis-[2-hydroxy-5-carboxyethyl)benzyl)ethylene-diamine-N, N'-diacetate), DEDPA and derivatives thereof, such as H2dedpa (l,2-[ [6-(Ca rboxy I) pyrid i ne-2- yl]methylamine]ethane) and H4octapa (l,2-[[6-(Carboxyl)pyridine-2- yl]methylamine]ethane-N, N'-diacetate), DFO (Deferoxamine) and derivatives thereof, Trishydroxypyridinone (THP) and derivatives thereof, such as HsTHP-Ac and HsTHP-mal (YM103), TEAP (Tetraazycyclodecane-phosphinic acid) and derivatives thereof, Sarcophagin SAR (l-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosan- 1,8-diamine) and derivatives thereof, such as (NH₂)₂SAR (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane), N4 (3-[(2'-Aminoethyl)amino]-2-[(2"-aminoethyl) aminomethyl] propionic acid) and other ISU-derivates, PnAO (6-(4-lsothiocyanatobenzyl)- 3,3,9,9,-tetramethyl-4,8-diaza-undecane-2,10-dione-dioxime) and derivatives thereof, such as BMS181321 (3,3'-(l,4-Butanediyldiamino)-bis(3-methyl-2-butanone)dioxime), MAG2 (Mercaptoacetyl-glycyl-glycine) and derivatives thereof, MAG3 (Mercaptoacetyl- glycyl-glycyl-glycine) and derivatives thereof, such as N3S-adipate, MAS3 (Mercaptoacetyl-seryl-seryl-serine) and derivatives thereof, MAMA (N-(2- Mercaptoethyl)-2-[(2-mercaptoethyl)amino]acetamide) and derivatives thereof, EC (Ethylene dicysteine) and derivatives thereof, dmsa (Dimercaptosuccinic acid) and derivatives thereof, DADT (Diamine dithiol), DADS (Diamine disulfide), N2S2-chelators and derivatives thereof, Aminothiol and derivatives thereof; salts of the preceding chelators; HYNIC (Hydrazinonicotinamide) and derivatives thereof.

[1065] - LR is selected from the group comprising radicals of dinitrogen, dialkyl ether, perfluoroalkylsulfonates, triflate, iodide, tosylates, mesylates, sulfonates, bromide, hydrogen, alcohols, chloride, nitrate, phosphate, inorganic esters, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, hydroxide, alkoxides, amides, hydride, arenide, alkanide and sulfur fluorides.

[1066] - LR is selected from the group comprising radicals of azide, tetrazine, cyclopentadienone, amine, hydrazine and thiol.

[1067] - LR is selected from the group comprising radicals of alkyne, trans-cyclooctene (TCO), dibenzoazacyclooctyne (DIBAC), biarylazacyclooctynone (BARAC), bicyclo[6.1.0]non-4- yne (BCN), norbonene, epoxide, aziridine, aldehyde, ketone, maleimide, phosphine, alkene and 3-isocyanopropyl.

[1068] - G is a radical of a first bioorthogonal click-reactant, Gc is a radical of a second bioorthogonal click-reactant, and G and Gc are configured to react with each other and form a covalent bond under physiological conditions.

[1069] - G comprises a tetrazine radical and Gc comprises a trans-cyclooctene radical.88 / 126 pma25 10.02.2026

[1070] G comprises a trans-cyclooctene radical and Gc comprises a tetrazine radical.

[1071] G comprises a radical having the structure

[1072]

[1073] and Gc comprises a radical having the structure

[1074]

[1075] G comprises a radical having the structure

[1076]

[1077] and Gc comprises a radical having the structure

[1078]

[1079] 89 / 126 pma25 10.02.2026

[1080]

[1081] - Gc comprises a radical selected from the group comprising

[1082]

[1083] 90 / 126 pma25 10.02.2026

[1084] - Gc comprises a radical selected from the group comprising

[1085]

[1086] - Pl and P2 have the same structure.

[1087] - Fl and F2 have the same structure.

[1088] - I1 and I2 have the same structure.

[1089] - J1 and J2 have the same structure.

[1090] - Cl and C2 have the same structure.

[1091] - CX and CY have the same structure.

[1092] - L1 and L2 have the same structure.

[1093] - A1 and A2 have the same structure.

[1094] - S1 and S2 have the same structure.

[1095] - The radicals -Al-Sl- and -A2-S2- have the same structure.

[1096] - The radicals -L1-A1-S1- and -L2-A2-S2- have the same structure.

[1097] - The radicals -C1-L1-A1-S1- and -C2-L2-A2-S2- have the same structure.

[1098] The radicals CX-L1-A1-S1- and CY-L2-A2-S2- have the same structure.91 / 126 pma25 10.02.2026

[1099] - The radicals -J1-C1-L1-A1-S1- and -J2-C2-L2-A2-S2- have the same structure. - The radicals -I1-J1-C1-L1-A1-S1- and -I2-J2-C2-L2-A2-S2- have the same structure.

[1100] - The radicals -F1-I1-J1-C1-L1-A1-S1- and -F2-I2-J2-C2-L2-A2-S2- have the same structure.

[1101] - The radicals P1-F1-I1-J1-C1-L1-A1-S1- and P2-F2-I2-J2-C2-L2-A2-S2- have the same structure.

[1102] The invention has the further object to provide a radiopharmaceutical kit for cancer diagnosis and treatment.

[1103] This object is achieved through a radiopharmaceutical kit comprising

[1104] - the compound PC including a first bioorthogonal click-reactant G and the delivery compound PD including a second bioorthogonal click-reactant Gc wherein PD further includes

[1105] - a chelator radical Ch for complexation of a radioisotope or radioactive compound selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,90Nb,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,203Pb,212Pb,213Bi,225Ac and18FAl,

[1106] - a radical LR configured as a leaving group for substitution with a radioisotope selected from the group comprising18F,123l,124l,125l,131l and211At,

[1107] or

[1108] - a radical LR configured as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope selected from the group comprising18F,123l,124l,125l,131l and211At.

[1109] The invention has the further object to provide a radioligand RT for cancer diagnosis and treatment.

[1110] This object is achieved through a radioligand RT comprised of

[1111] - the compound PC including a chelator radical Ch and a therewith complexed radioisotope or radioactive compound selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,90Nb,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,203Pb,212Pb,213Bi,225Ac and18FAl,

[1112] - the compound PC wherein the radical LR is substituted with a radioisotope selected from the group comprising18F,123l,124l,125l,131l and211At,

[1113] or92 / 126 pma25 10.02.2026

[1114] - the compound PC wherein the radical LR is substituted with a conjugate obtained by clickconjugating a first coupling group with a second coupling group that includes a radioisotope selected from the group comprising18F,123l,124l,125l,131l and211At, wherein - the first coupling group is selected from the group comprising radicals of azide, tetrazine, cyclopentadienone, amine, hydrazine and thiol,

[1115] - the second coupling group comprises a radical selected from the group comprising radicals of alkyne, trans-cyclooctene (TCO), dibenzoazacyclooctyne (DIBAC), biarylaza- cyclooctynone (BARAC), bicyclo[6.1.0] non-4-yne (BCN), norbonene, epoxide, aziridine, aldehyde, ketone, maleimide, phosphine, alkene and 3-isocyanopropyl,

[1116] or vice versa.

[1117] Expedient embodiments of the invention are characterized by one of the following features or a combination of the following features insofar the combined features are not mutually exclusive or contradictory and according to which:

[1118] - G comprises a tetrazine radical and Gc comprises a trans-cyclooctene radical.

[1119] - G comprises a trans-cyclooctene radical and Gc comprises a tetrazine radical.

[1120] - The radioisotope is68Ga.

[1121] - The radioisotope is161Tb.

[1122] - The radioisotope is177Lu.

[1123] - The radioisotope is212Pb.

[1124] - The radioisotope is225Ac.

[1125] - The radioactive compound is18FAI (aluminum fluoride).

[1126] - The chelator Ch comprises a radical having the structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) and the radioisotope is selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,86Y,90Y,90Nb,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,203Pb,212Pb,213Bi and225Ac.

[1127] - The chelator Ch comprises a radical having the structure (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) and the radioisotope is selected from the group comprising68Ga,177Lu,203Pb,212Pb and225Ac.

[1128] - The chelator Ch comprises a radical having the structure (VII), (VIII), (IX) or (X) and the radioisotope is selected from the group comprising66Ga,67Ga and68Ga.

[1129] - The chelator Ch comprises a radical having the structure (XI), (XII), (XIII) or (XIV) and the radioactive compound is18FAI (aluminum fluoride).

[1130] The chelator Ch comprises a radical having the structure (XV), (XVI), (XVII) or (XVIII) and the radioisotope is selected from the group comprising203Pb,212Pb and213Bi.93 / 126 pma25 10.02.2026

[1131] - The chelator Ch comprises a radical having the structure (XIX) and the radioisotope is selected from the group comprising62Cu,64Cu and67Cu.

[1132] - The chelator Ch comprises a radical having the structure (XX) or (XXI) and the radioisotope is225Ac.

[1133] The content of all prior art documents cited in this patent application is incorporated by reference. In particular, the chemical synthesis methods described in the cited prior art, scientific articles and corresponding supplementary information are used directly or in an analogous, suitably adapted manner to prepare the pharmaceutical compounds of the present invention.

[1134] The compounds of the present invention are prepared, using known synthetic strategies and protocols, that are routinely employed by the person skilled in organic and medicinal chemistry. The synthetic methods comprise the use of orthogonal protecting groups, solidphase peptide synthesis (SPPS, https: / / en.wikipedia.org / wiki / Peptide_synthesis) and ring-closing metathesis (RCM) using Hoveyda-Grubbs catalysts.

[1135] Macrocycles are prepared by the synthetic routes described, for example in

[1136] - Bechtler C, Lamers C. Macrocyclization strategies for cyclic peptides and peptidomimetics.

[1137] RSC Med Chem. 2021 Jun 29;12(8):1325-1351. https: / / pubs.rsc.org / en / content / articlelanding / 2021 / md / dlmd00083g, and

[1138] - WO 2025 / 037249 Al.

[1139] WO 2023 / 133645 Al, EP 4537851 Al and WO 2023 / 247487 Al describe synthetic routes for the preparation of FAP inhibitor ligands that comprise a radical having the structure

[1140]

[1141] which can be readily adapted to obtain analogous FAP substrate ligand radicals that comprise an amide radical in lieu of nitrile, as detailed in above cited US 10,245,248 B2 and scientific articles by De Decker et al. (doi: 10.1021 / acsmedchemlett.9b00191) and Luo et al. (doi: 10.7150 / thno.70308).

[1142] The compounds of the present invention can also be prepared by retrosynthetic routes devised by software that implements expert-coded rules and uses libraries comprising millions of commercially available starting materials and building blocks. Retrosynthesis software and related chemical synthesis services are commercially available, for example from Merck Synthia® Lab (https: / / www.synthiaonline.com).94 / 126 pma25 10.02.2026

[1143] In the present invention and application

[1144] - the term "radical" refers to a monovalent, bivalent, trivalent or multivalent atom, molecule, residue, chemical group, chemical unit, chemical structure or chemical moiety that is covalently coupled to or covalently conjugated with one, two, three or more radicals of atoms, molecules, chemical groups, chemical units, chemical structures or chemical moieties of the same or different types;

[1145] - radicals can be conjugated by one, two, three or more single covalent bonds, each with two shared electrons, or by one, two, three or more double covalent bonds, each with four shared electrons;

[1146] - radicals of atoms, molecules, chemical groups or chemical units are specified by structural formulas or by letters, digits, brackets, hyphens and equal signs;

[1147] - unless otherwise indicated, the symbols C, F, H, N and S have their usual meaning according to standard chemical notation and refer to a carbon, fluorine, hydrogen, nitrogen or sulfur atom or radical;

[1148] - radicals can also be denoted by symbols and hyphens, for example -NH- or -NH2 for amine radicals, -CH2- for methylene radicals, and -CO-, — C(O)—, -C=O-, -O=C-, — C(=O)— or — O(=C)— for carbonyl radicals, wherein a terminal hyphen corresponds to one shared electron of a single covalent bond or one "half' of a single covalent bond, and a terminal equal sign corresponds to two shared electrons of a double covalent bond or one "half' of a double covalent bond;

[1149] - the term "amine radical" refers to a radical having the structure

[1150]

[1151] the term "oxy radical" refers to a radical having the structure

[1152]

[1153] - the term "sulfide radical" refers to a radical having the structure

[1154]

[1155] S

[1156] - the terms "radioligand" and "radiotracer" have the same meaning and are used interchangeably.

[1157] Fig. 1 illustrates the invention and its mechanism of action. The pharmaceutical compound of Fig. 1 comprises a radioisotope, a cell surface binder radical, a self-immolative spacer radical and a radical of a substrate ligand of fibroblast activation protein (FAP) as main components. The FAP substrate ligand radical is conjugated to the cell surface binder radical via the self-immolative spacer radical and prevents the cell surface binder from attaching to95 / 126 pma25 10.02.2026

[1158] the plasma membrane of cells. The mechanism of action comprises four steps which are indicated in Fig. 1 by circled numbers 1, 2, 3 and 4. Subsequent to intravenous injection, systemic distribution via blood circulation and extravasation, the pharmaceutical compound reaches a FAP molecule expressed by a cancer-associated fibroblast (CAF) present in tumor tissue (step 1). The FAP substrate ligand binds to the enzymatic pocket of FAP and is cleaved (step 2). The self-immolative spacer disintegrates and the cell surface binder with the thereto bound radioisotope dissociates from the FAP substrate ligand (step 3). The cell surface binder partitions to the surface of a proximal cell and is inserted into the plasma membrane (step 4). Depending on the cell's reproductive and life cycle the cell surface binder with the thereto bound radioisotope remains inserted in the plasma membrane for an extended period of time of up to 6 months or permeates into the cytosol. Quiescent cancer stem cells have life spans of several months and do not reproduce. Incidental insertion of the cell surface binder with a thereto appended radioisotope, such as Terbium-161, Lutetium-177, Lead-212 or Actinium-225 into the plasma membrane of a long-lived cancer stem cell significantly increases the probability of causing severe and potentially lethal radiation damage to the latter. This applies in particular, when a-emitting Actinium-225 is chosen as the therapeutic radioisotope. The invention may thus enable eradication of cancer stem cells.

[1159] EXAMPLES

[1160] Synthesis of the precursor compound PC3

[1161] Scheme 3a depicts a radioligand RT3 according to the present invention which comprises a precursor compound PC3 specified by the SMILES string:

[1162] CN(CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N( C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N(C)CC(=O)N)C( =O)CN(C)C(=O)CN(C)C(=O)CN(C)C(=O)CN(C)CCOCCOCCOCCOclcc2c(ccl)nccc2C(=O)NCC(=O) NlCC(F)(F)CClC(=O)Nclccc(ccl)COC(=O)Nclccc(ccl)CCCCCCCCCCCCCCCCCC[N+](C)(CCCS(=O )(=O)[O-])CCCNC(=O)CN1CCN(CC(=O)O)CCN(CCN(CC(=O)O)CC1)CC(=O)O

[1163] The precursor compound PC3 is obtained by conjugation and deprotection of intermediate compounds Al, A2, A3 shown beneath in Schemes Al, A2 and A3.96 / 126 pma25 10.02.2026

[1164]

[1165] Scheme Al: Intermediate Al comprising four t-Bu protecting groups

[1166]

[1167] Scheme A2: Intermediate A2 comprising one benzyl protecting group

[1168]

[1169] Scheme A3: Intermediate A3

[1170] Intermediate A2 is conjugated to Al via a carbamate group to obtain intermediate A4, as depicted in Schemes A4 and A5.

[1171] DIPEA

[1172] A1 + A2 - ► A4 + NHS

[1173] DMF, 40°C

[1174] Scheme A4: Synthesis of intermediate A497 / 126 pma25 10.02.2026

[1175]

[1176] The benzyl protecting group of A4 is removed to obtain intermediate A4', and A3 is conjugated to A4' to obtain the t-Bu protected analog A5 of PC3, as depicted in Scheme A6.

[1177] H2, Pd / C

[1178] (i) A4 - ► A4' + PhCH3

[1179] THF / MeOH

[1180] Cs2CO3, KI

[1181] (ii) A3 + A4' - ► A5

[1182] DMF, RT

[1183] Scheme A6: Removal of the benzyl protecting group of A4 to obtain intermediate A4' and conjugation of A3 to A4' to obtain intermediate A5

[1184] The four t-Bu protecting groups of intermediate A5 are removed to obtain the precursor compound PC3, as depicted in Scheme A7.

[1185] TFA, TIPS, H2O

[1186] A5 - ► PC3 + 4 x isobutylene

[1187] RT, 2-4 h

[1188] Scheme A7: Removal of the t-Bu protecting groups of A5 to obtain the precursor compound PC3

[1189] The synthesis of intermediates Al, A2 and A3 is described beneath.98 / 126 pma25 10.02.2026

[1190]

[1191] Scheme Bl: Synthesis of Phth and t-Bu protected intermediate Bl

[1192]

[1193] Br-(CH2)18-Ph-NH-Boc

[1194] 4M HCI

[1195] (ii) Br-(CH2)18-Ph-NH-Boc Br-(CH2)18-Ph-NH2

[1196] 1,4-dioxane

[1197] DIPEA

[1198] (iii) Br-(CH2)18-Ph-NH2+ Alloc-CI - ► Br-(CH2)18-Ph-NH-Alloc DCM, 0°C-RT

[1199] N2atm

[1200] Scheme B2: Synthesis of the intermediate B2 (Br-(CH2)i8-Ph-NH-Alloc)99 / 126 pma25 10.02.2026

[1201] Nal B1 + B2 DMF, 70°C

[1202]

[1203] Scheme B3: Synthesis of intermediate B3

[1204]

[1205] Scheme B4: (i) Phth deprotection of B3 and (ii) conjugation with DOTA-(t-Bu)3 to obtain intermediate B4

[1206] Pd(PPh3)4 / PhSiH3(1:3.5)

[1207] B4 - ► A1

[1208] DCM

[1209] Scheme B5: Alloc deprotection of B4 to obtain intermediate Al

[1210]

[1211] Scheme Cl: Synthesis of intermediate Cl100 / 126 pma25 10.02.2026

[1212] Scheme C2: Synthesis of intermediate C2

[1213] 15% TFA, 2% TIPS (i) C2 - ► C2'

[1214] DCM, 0°C

[1215] (iii)

[1216] ^TBDPS

[1217]

[1218] Scheme C3: (i) Boc deprotection of C2, (ii) conjugation with Boc-Gly and

[1219] (iii) Boc deprotection to obtain intermediate C3

[1220]

[1221] (1.05 eq) (1.0 eq)

[1222] Scheme C4: Bn protection of 6-hydroxyquinoline-4-carboxylic acid

[1223] to obtain intermediate C4

[1224] TBDPS HATU / DIPEA (1.1:2.0) + C4

[1225] DMF

[1226]

[1227] Scheme C5: Conjugation of C3 to C4 to obtain intermediate C5101 / 126 pma25 10.02.2026

[1228] 1M TBAF

[1229] DIPEA / DMAP (2.0:0.1)

[1230] A2

[1231] ACN

[1232]

[1233] Scheme C7: (i) TBDPS deprotection and (ii) reaction with DSC to obtain intermediate A2

[1234] Intermediate A3 is prepared by solid-phase peptoid synthesis (SPPS) as depicted in Schemes DI and D2. First, a Sar2o peptoid is synthesized using rink amide resin and alternating steps of

[1235] (i) acylation with bromoacetic acid and DIC ( / V, / V'-Diisopropylcarbodiimide), and

[1236] (ii) nucleophilic displacement with methylamine,

[1237] as shown in Scheme DI.

[1238]

[1239] Scheme DI: SPPS of Sar peptoid

[1240] After 20 iterations of the two-step sequence (i) and (ii), the N-terminal secondary amine of the Sar2o peptoid is reacted with Br–PEG4–Br (Br[(CH2)2O]3(CH2)2Br), as depicted in Scheme D2.102 / 126 pma25 10.02.2026

[1241]

[1242] Scheme D2: Conjugation of Br-PEG4-Br to the Sar2o peptoid The obtained -NH-Sar2o-PEG3-(CH2)2-Br peptoid radical is cleaved from the rink amide resin using a mixture of 95%TFA, 2.5% H2O, and 2.5% TIPS (triisopropylsilane) to obtain the intermediate A3.

[1243] Compounds 1 to 28 according to the invention

[1244] The below presented exemplary embodiments 1 to 28 of the compound PC and PD according to the present invention can be easily modified by the skilled person in numerous trivial and obvious ways without notably altering their chemical function and pharmacology. Many replacements for functional subunits of PC and PD, in particular linkers and spacers, are known in the prior art and are available from commercial suppliers or can be readily synthesized. The below Schemes El to E28 show exemplary embodiments 1 to 28 of the invention. Exemplary embodiments 22, 23, 28 pertain to compounds PC comprising a bromine leaving group that is suited for substitution with a radioisotope, such as18F,131l or211At. The remaining exemplary embodiments 1 to 21, 24 to 27 employ a DOTA chelator for complexation of radioisotopes, such as68Ga,161Tb,177Lu,212Pb and225Ac. DOTA and bromine can be substituted with one of the above recited chelators and leaving groups. Chelators comprising a radical having the structure (XV), (XVI), (XVII) or (XVIII) are better suited for complexation of the radioisotope212Pb than DOTA. Chelators comprising a radical having the structure (XX) or (XXI) are better suited for complexation of the radioisotope225Ac than DOTA.

[1245] Exemplary embodiments 7, 22, 24, 28 comprise radicals having the structure

[1246] O O I

[1247] s II s II U

[1248] j- (CH2)18OPO(CH2)2N Me3or |-(CH2)18OPO(CH2)2N-|,

[1249]

[1250] 0“ O~ I

[1251] the orientation and polarity of which are consistent with the phosphatidylcholine, respectively phosphorylcholine head groups of phospholipids in the outer leaflet of plasma membranes. This can affect anchoring and retention in the plasma membrane and facilitate permeation into the cytosol.

[1252] Exemplary embodiments 17, 23 and 25 comprise radicals having the structure103 / 126 pma25 10.02.2026

[1253] I o I O

[1254] S L II s L H e

[1255] |-(CH2)18N (CH2)2OPOH or H (CH2)18N (CH2)2OPO— |

[1256]

[1257] I o’ I o’

[1258] the orientation and polarity of which are opposed to the phosphatidylcholine, respectively phosphorylcholine head groups of phospholipids in the outer leaflet of plasma membranes. Therefore, the surface binder components of exemplary embodiments 17, 23 and 25 tend to form ionic bonds with phosphatidylcholine or phosphorylcholine head groups and remain in the outer leaflet of plasma membranes. Similar applies to the cell surface binder of exemplary embodiments 1, 2, 6, 9, 11 to 21, 26, 27, which comprise anchor radicals having the structure

[1259] — N (CH2)3SO voA / v Q

[1260]

[1261] Scheme El.l: Exemplary embodiment 1 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1262]

[1263] Scheme El.2: Radioligand according to exemplary embodiment 1 of PC complexed with radioisotope177Lu and after cleavage by FAP104 / 126 pma25 10.02.2026

[1264]

[1265] Scheme E2.1: Exemplary embodiment 2 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1266]

[1267] Scheme E2.2: Radioligand according to exemplary embodiment 2 of PC complexed with radioisotope177Lu and after cleavage by FAP

[1268]

[1269] Scheme E3.1: Exemplary embodiment 3 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50105 / 126 pma25 10.02.2026

[1270]

[1271] Scheme E3.2: Radioligand according to exemplary embodiment 3 of PC complexed with radioisotope177Lu and after cleavage by FAP

[1272]

[1273] Scheme E4.1: Exemplary embodiment 4 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50

[1274]

[1275] Scheme E4.2: Radioligand according to exemplary embodiment 4 of PC complexed with radioisotope177Lu and after cleavage by FAP106 / 126 pma25 10.02.2026

[1276]

[1277] Scheme E5.1: Exemplary embodiment 5 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50

[1278]

[1279] Scheme E5.2: Radioligand according to exemplary embodiment 5 of PC complexed with radioisotope177Lu and after cleavage by FAP107 / 126 pma25 10.02.2026

[1280]

[1281] Scheme E6.1: Exemplary embodiment 6 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50

[1282]

[1283] Scheme E6.2: Radioligand according to exemplary embodiment 6 of PC complexed with radioisotope177Lu and after cleavage by FAP108 / 126 pma25 10.02.2026

[1284]

[1285] Scheme E7.1: Exemplary embodiment 7 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 10 and 40

[1286]

[1287] Scheme E7.2: Radioligand according to exemplary embodiment 7 of PC complexed with radioisotope177Lu and after cleavage by FAP109 / 126 pma25 10.02.2026

[1288]

[1289] Scheme E8.1: Exemplary embodiment 8 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50

[1290]

[1291] Scheme E8.2: Radioligand according to exemplary embodiment 8 of PC complexed with radioisotope177Lu and after cleavage by FAP

[1292]

[1293] Scheme E9.1: Exemplary embodiment 9 of the compound PC wherein m = 3, 4, 5, 6, 7, 8,

[1294] 9 or 10 and n is a number between 5 and 30110 / 126 pma25 10.02.2026

[1295]

[1296] Scheme E9.2: Radioligand according to exemplary embodiment 9 of PC complexed with radioisotope177Lu and after cleavage by FAP

[1297]

[1298] Scheme E10.1: Exemplary embodiment 10 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1299]

[1300] Scheme E10.2: Radioligand according to exemplary embodiment 10 of PC complexed with radioisotope177Lu and after cleavage by FAP111 / 126 pma25 10.02.2026

[1301]

[1302] Scheme E11.1: Exemplary embodiment 11 of the compound PC comprising a bioorthogonal tetrazine radical and wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1303]

[1304] Scheme E11.2: Exemplary embodiment 11 of PC after cleavage by FAP

[1305]

[1306] Scheme E11.3: Exemplary embodiment 11 of the delivery compound PD comprising a bioorthogonal trans-cyclooctene radical112 / 126 pma25 10.02.2026

[1307]

[1308] Scheme E12.1: Exemplary embodiment 12 of the compound PC comprising a bioorthogonal trans-cyclooctene radical and wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1309]

[1310] Scheme E12.2: Exemplary embodiment 12 of PC after cleavage by FAP

[1311]

[1312] Scheme E12.3: Exemplary embodiment 12 of the delivery compound PD comprising a bioorthogonal tetrazine radical

[1313]

[1314] Scheme E13.1: Exemplary embodiment 13 of the compound PC comprising a bioorthogonal tetrazine radical and wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40113 / 126 pma25 10.02.2026

[1315]

[1316] Scheme E13.2: Exemplary embodiment 13 of PC after cleavage by FAP

[1317]

[1318] Scheme E13.3: Exemplary embodiment 13 of the delivery compound PD comprising a bioorthogonal trans-cyclooctene radical

[1319]

[1320] Scheme E14: Exemplary embodiment 14 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1321]

[1322] Scheme E15: Exemplary embodiment 15 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50114 / 126 pma25 10.02.2026

[1323]

[1324] Scheme E16: Exemplary embodiment 16 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1325]

[1326] Scheme E17: Exemplary embodiment 17 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5, p = 0, 1, 2, 3, 4 or 5, n is a number between 10 and 40 and q is a number between 5 and 20115 / 126 pma25 10.02.2026

[1327]

[1328] Scheme E18: Exemplary embodiment 18 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40

[1329]

[1330] Scheme E19: Exemplary embodiment 19 of the compound PC comprising a 24(S)-hydroxycholesterol radical and wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50116 / 126 pma25 10.02.2026

[1331]

[1332] Scheme E20: Exemplary embodiment 20 of the compound PC comprising a radical of a Di-8-ANEPPS derivative and wherein

[1333] m = 0, 1, 2, 3, 4 or 5 and n is a number between 20 and 50

[1334]

[1335] Scheme E21: Exemplary embodiment 21 of the compound PC wherein

[1336] m = 0, 1, 2, 3, 4 or 5 and n is a number between 15 and 40117 / 126 pma25 10.02.2026

[1337]

[1338] Scheme E22: Exemplary embodiment 22 of the compound PC comprising a radical of an Iopofosine I-131 derivative with a bromine leaving group for substitution with a radioisotope wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 10 and 30

[1339]

[1340] Scheme E23: Exemplary embodiment 23 of the compound PC comprising a radical of an Iopofosine I-131 derivative with a bromine leaving group for substitution with a radioisotope wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 10 and 30

[1341]

[1342] Scheme E24: Exemplary embodiment 24 of the compound PC comprising a radical of an Iopofosine I-131 derivative wherein m = 0, 1, 2, 3, 4 or 5 and

[1343] n is a number between 10 and 30118 / 126 pma25 10.02.2026

[1344]

[1345] Scheme E25: Exemplary embodiment 25 of the compound PC comprising a radical of an Iopofosine I-131 derivative wherein m = 0, 1, 2, 3, 4 or 5 and

[1346] n is a number between 10 and 30

[1347]

[1348] Scheme E26: Exemplary embodiment 26 of the compound PC wherein m = 0, 1, 2, 3, 4 or 5 and n is a number between 10 and 30119 / 126 pma25 10.02.2026

[1349]

[1350] Scheme E27: Exemplary embodiment 27 of the compound PC comprising a radical of a Di-8-ANEPPS derivative wherein m = 0, 1, 2, 3, 4 or 5

[1351] and n is a number between 15 and 40

[1352]

[1353] Scheme E28: Exemplary embodiment 28 of the compound PC comprising a radical of a cell penetrating peptide (CPP) with a bromine leaving group for substitution with a radioisotope wherein m = 0, 1, 2, 3, 4 or 5

[1354] and n is a number between 20 and 50

Claims

120 / 126 pma25 10.02.2026Claims1. A compound PC or a salt thereof, alone or as part of a radiopharmaceutical kit comprises a cell surface binder radical CSB conjugated to either an activator radical ARI, two activator radicals ARI and AR2, or an activator radical AR3, wherein- CSB comprises a lipophilic membrane-inserting radical,- CSB comprises one of- a chelator radical Ch for complexation of a radioisotope,- a radical LR configured- as a leaving group for substitution with a radioisotope, or- as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope,or- a radical G of a first bioorthogonal click-reactant that includes a radical of triazine or trans-cyclooctene,- CSB comprises one or two terminal radicals selected independently of one another from amine, oxy or sulfide radicals,- AR1 comprises a fibroblast activation protein (FAP) substrate ligand radical F1 and a hydrophilic pharmacokinetic modulator radical P1,- AR2 comprises a FAP substrate ligand radical F2 and a hydrophilic pharmacokinetic modulator radical P2,- AR3 comprises a FAP substrate ligand radical F3, a hydrophilic pharmacokinetic modulator radical P3 and a trivalent self-immolative spacer radical SI3 conjugated to a first radical of F3 via an amine radical and to terminal amine, oxy or sulfide radicals of CSB, wherein SI3 is configured to disintegrate and release CSB upon FAP-mediated cleavage of F3 from SI3,- Fl, F2, F3 independently of one another comprise- a radical having the structureX121 / 126 pma25 10.02.2026wherein X = H or CH3, Y1= H or F, Y2= H or F,or- a radical selected from the group comprising peptide radicals -Gly-Pro-Ser-, -Ala-Pro-Ser and -Gly-Pro-Val-.

2. The compound PC according to claim 1, characterized in that Fl, F2, F3 independently of one another comprisea first radical having the structureand a second radical selected from the group comprisingandwherein X = H or CH3, Y1= H or F, Y2= H or F, and the terminal carbonyl radical of the second radical is conjugated to the terminal amine radical of the first radical.122 / 126 pma25 10.02.20263. The compound PC according to claim 1 or 2, characterized in that CSB comprises one or more radicals selected from the group comprising radicals of aliphatic chains -(CH2)n- with n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 substituted or unsubstituted mono- and polycyclic aromatic hydrocarbons, and conjugates of substituted or unsubstituted mono- or polycyclic aromatic hydrocarbons with aliphatic chains.

4. The compound PC according to claim 1, 2 or 3, characterized in that the first radical of Fl is conjugated to a terminal amine radical of CSB.

5. The compound PC according to claim 1, 2 or 3, characterized in that the first radicals of Fl and F2 are each conjugated to terminal amine radicals of CSB.

6. The compound PC according to claim 1, 2 or 3, characterized in that ARI comprises a bivalent self-immolative spacer radical Sil conjugated to the first radical of Fl via an amine radical and to a terminal amine, oxy or sulfide radical of CSB and Sil is configured to disintegrate and release CSB upon FAP-mediated cleavage of Fl from Sil.

7. The compound PC according to claim 6, characterized in that AR2 comprises a bivalent self-immolative spacer radical SI2 conjugated to the first radical of F2 via an amine radical and to a terminal amine, oxy or sulfide radical of CSB and SI2 is configured to disintegrate and release CSB upon FAP-mediated cleavage of F2 from SI2.

8. The compound PC according to any one of claims 1 to 7, characterized in that Pl, P2, P3 independently of one another are radicals comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 radicals selected independently of one another from the group comprising -CH2-, — C(=O)—, -CH(-CH3)-, -O-, -NH-, -N(- CH3)-, -CH=CH-, -CH(-CH2COOH)-, -CH2CH2O– , –C(=O)–CH2–N(–CH3)– , and radicals of 4- to 10-membered aryl, substituted 4- to 10-membered aryl, 4- to 10-membered heteroaryl, substituted 4- to 10-membered heteroaryl, alanine, glycine, phenylalanine, arginine, histidine, proline, asparagine, isoleucine, serine, aspartic acid, leucine, threonine, cysteine, lysine, tryptophan, glutamine, methionine, tyrosine, glutamic acid, ornithine, valine, alcohols, aminoalkylcarboxylic acids.123 / 126 pma25 10.02.20269. The compound PC according to any one of claims 1 to 8, characterized in that it comprises a chelator radical Ch selected from the group comprisingwherein F1 is -OH or -NH2, F2 is -OH or -NH2, F3 is -OH or -NH2, F4 is -OH or -NH2and D1is H, CH3 or NH2.

10. The compound PC according to any one of claims 1 to 8, characterized in that PC comprises a radical LR selected from- the group comprising radicals of dinitrogen, dialkyl ether, perfluoroalkylsulfonates, triflate, iodide, tosylates, mesylates, sulfonates, bromide, hydrogen, alcohols, chloride, nitrate, phosphate, inorganic esters, thioether, amines, ammonia, fluoride, carboxylate, phenoxides, hydroxide, alkoxides, amides, hydride, arenide, alkanide and sulfur fluorides,124 / 126 pma25 10.02.2026the group comprising radicals of azide, tetrazine, cyclopentadienone, amine, hydrazine and thiol,or- the group comprising radicals of alkyne, trans-cyclooctene (TCO), dibenzoazacyclo- octyne (DIBAC), biarylazacyclooctynone (BARAC), bicyclo[6.1.0]non-4-yne (BCN), norbonene, epoxide, aziridine, aldehyde, ketone, maleimide, phosphine, alkene and 3-isocyanopropyl.

11. A radiopharmaceutical kit comprising the compound PC according to any one of claims 1 to 8 and a delivery compound PD, characterized in that PC comprises a first bioorthogonal click-reactant G, PD comprises a second bioorthogonal click-reactant Gc, G comprises a triazine radical and Gc comprises a trans-cyclooctene radical or vice versa and Gc further comprises a chelator radical Ch for complexation of a radioisotope, or a radical LR configured as a leaving group for substitution with a radioisotope or as a first coupling group adapted for click-conjugation with a second coupling group that includes a radioisotope.

12. A radioligand RT comprising- the compound PC of claim 9 complexed with a radioisotope or radioactive compound selected from the group comprising44Sc,47Sc,55Co,62Cu,64Cu,67Cu,66Ga,67Ga,68Ga,89Zr,86Y,90Y,90Nb,111In,135Sm,140Pr,159Gd,149Tb,160Tb,161Tb,165Er,166Dy,166Ho,175Yb,177Lu,203Pb,212Pb,213Bi,225Ac and18FAI, or- the compound PC of claim 10, wherein LR is substituted with a radioisotope or with a group obtained by click-conjugating the first coupling group with a second coupling group that includes a radioisotope, wherein the radioisotope is selected from the group comprising18F,123l,124l,125l,131l and211At.

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