EP4637826A1 - Conjugate compounds and their use in cancer treatment and diagnosis - Google Patents

Conjugate compounds and their use in cancer treatment and diagnosis

Info

Publication number
EP4637826A1
EP4637826A1 EP23837651.1A EP23837651A EP4637826A1 EP 4637826 A1 EP4637826 A1 EP 4637826A1 EP 23837651 A EP23837651 A EP 23837651A EP 4637826 A1 EP4637826 A1 EP 4637826A1
Authority
EP
European Patent Office
Prior art keywords
lys
asp
ruc
phe
psma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23837651.1A
Other languages
German (de)
French (fr)
Inventor
Ali Azhdarinia
Sukhen C. Ghosh
Susanne KOSSATZ
Beatrice Stefanie LUDWIG
Wolfgang Weber
Lena KOLLER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Technische Universitaet Muenchen
University of Texas System
University of Texas at Austin
Original Assignee
Technische Universitaet Muenchen
University of Texas System
University of Texas at Austin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technische Universitaet Muenchen, University of Texas System, University of Texas at Austin filed Critical Technische Universitaet Muenchen
Publication of EP4637826A1 publication Critical patent/EP4637826A1/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Conjugate compounds and their use in cancer treatment and diagnosis The present invention relates to conjugate compounds comprising a disease-targeting moiety and at least one PARP inhibitor moiety and pharmaceutical compositions comprising the conjugate compounds.
  • the present invention relates to the use of the conjugate compounds for use in the treatment of cancer.
  • the present invention further relates to methods of treatment of cancer and for patient selection.
  • BACKGROUND OF THE INVENTION Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths in men worldwide with an estimated 360,000 deaths in 2018 (Bray et al., 2018). Most of these deaths are associated with metastatic castration-resistant PCa (mCRPC), a lethal form of PCa that arises from progression and spread of the disease during androgen deprivation therapy.
  • mCRPC metastatic castration-resistant PCa
  • PSMA prostate-specific membrane antigen
  • NETs Neuroendocrine tumors
  • this object is solved by a conjugate compound comprising a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof.
  • a pharmaceutical composition comprising at least one conjugate compound of the present invention and optionally pharmaceutically acceptable carrier and/or excipient(s).
  • this object is solved by providing the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to, wherein said cells are preferably tumor cells.
  • this object is solved by providing the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors.
  • this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in medicine.
  • this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in the treatment of cancer.
  • this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in patient selection.
  • this object is solved by a method of treatment of cancer comprising the administration of a therapeutically effective amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient.
  • this object is solved by a method of patient selection comprising the administration of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient and performing molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the present invention provides a conjugate compound.
  • the conjugate compound of the present invention comprises a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof.
  • the disease-targeting moiety (T) preferably comprises a peptide or small molecule, which internalizes upon binding to a cell surface biomarker.
  • the term “peptides” as used herein refer to peptides comprising natural and/or non-natural amino acids, L- and/or D-amino acids as well as peptidomimetics.
  • Said peptide or small molecule preferably targets the prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), ⁇ v ⁇ 6-integrin, ⁇ v ⁇ 8-integrin, ⁇ 5 ⁇ 1-integrin, ⁇ v ⁇ 1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R).
  • PSMA prostate-specific membrane antigen
  • SSTR subtypes 2, 3, and 5 gastrin-releasing peptide receptor
  • CXCR4 C-X-C motif chemokine receptor 4
  • ⁇ v ⁇ 6-integrin ⁇ v ⁇ 8-integrin
  • FR folate receptor
  • NTSR1 neurotensin receptor 1
  • M1R melanocortin receptor 1
  • the disease-targeting moiety (T) comprises monomers or multimers.
  • the disease-targeting moiety (T) can comprise further component(s).
  • Said further component(s) can be additional structural components to optimize the pharmacokinetic properties of the disease-targeting moiety, including but not limited to PEG linker(s), albumin-binding domain(s), amino acid(s) or amino acid sequence(s) and/or peptidomimetics.
  • the disease-targeting moiety (i) targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad).
  • the disease-targeting moiety (i) targets somatostatin receptor (SSTR), preferably SSTR2.
  • SSTR somatostatin receptor
  • the disease-targeting moiety (i) preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics.
  • TOC is an octreotide analog (Tyr 3 -octreotide) having/consisting of the amino acid sequence D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr(ol) [SEQ ID NO.15].
  • TOC binds to somatostatin receptors which are overexpressed on the surface of tumor cells, in particular of neuroendocrine tumors (NET).
  • TATE is an octreotate or octreotide acid analog (Tyr 3 -octreotate) having/consisting of the amino acid sequence D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH [SEQ ID NO.16].
  • TATE binds to somatostatin receptors which are overexpressed on the surface of tumor cells, in particular of neuroendocrine tumors (NET).
  • - PARP inhibitor moiety P
  • the PARP inhibitor moiety (P) comprises or consists of rucaparib, olaparib, talazoparib, niraparib or analogs thereof.
  • An analog refers to a PARP inhibitor moiety (P) that has been modified for conjugation and/or cleavage.
  • the PARP inhibitor moiety (P) can comprise parts of the cleavable bond, such as a thiol group after cleavage.
  • the conjugate compounds comprise two or more PARP inhibitor moieties (P), such as 2 or 3.
  • the PARP inhibitor moiety (P) can be connected via an anchor unit (A), such as a lysine or cysteine, to the conjugate compound.
  • the PARP inhibitor moiety (P) is preferably connected via the cleavable linker (X) to said anchor unit (A).
  • - cleavable linker (X) The PARP moiety (P) is preferably connected via the cleavable linker (X) to the conjugate compound.
  • the cleavable linker (X) allows intracellular or extracellular release of the PARP moiety (P) upon enzymatic cleavage or redox reaction.
  • the cleavable linker (X) preferably comprises a substrate for enzyme cleavage or redox reaction. Examples for such substrates are a substrate for substrate for prostate specific antigen (PSA), caspases or cathepsins or proteases or peptidases or for the antioxidant glutathione. Examples for cathepsin B linker are valine-citrulline-p-aminobenzyloxycarbonyl (PABC) and valine-alanine-PABC.
  • the conjugate compounds of the present invention selectively deliver PARP inhibitor(s) to target-positive cells, such as PSMA-positive tumor cells or SSTR-expressing tumor cells.
  • the cleavable linker is preferably cleaved intracellularly, i.e. after uptake of the conjugate compound into the target tumor cell, thereby releasing the PARP inhibitor.
  • the cleavable linker comprises a disulfide bridge
  • the cleavage is carried out intracellularly by glutathione (GSH) for release of the PARP inhibitor(s).
  • the conjugate compounds of the present invention serve as vehicles for the specific delivery of the PARP inhibitor(s) to target-expressing cells, such as PSMA-positive or SSTR- expressing cells, in particular tumor-targeted delivery of PARP inhibitor(s).
  • - Chelating agent (C) The conjugate compound preferably comprises a chelating agent (C).
  • the chelating agent (C) is a macrocyclic chelator or a non-cyclic chelating agent.
  • macrocyclic chelators are: 1,4,7,10-tetraazacyclododecane (cyclen), 2-(7-(4-aminobutyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)pentanedioic acid (MMC), 2,2',2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (DOTAGA), 2,2',2",2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 2,2',2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 2-[1,4,7,10
  • the chelating agent (C) is preferably selected from the group consisting of cyclen, MMC, DOTAGA, DOTA, NOTA, NODAGA, DOTPI, HBED, HBED-CC, DOTAM, TRAP, NOPO, PCTA and EDTA and derivatives thereof.
  • the chelating agent (C) can comprise or contain a radionuclide.
  • the radionuclide is preferably selected from 44 Sc, 45 Ti, 47 Sc, 59 Fe, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 89 Sr, 90 Y, 94m Tc, 99m Tc, 111 In, 149 Pm, 153 Gd, 153 Sm, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 203 Pb, 211 At, 212 Bi, 212 Pb or 225 Ac.
  • the conjugate compound of the present invention has the general formula (I) or (II) wherein T is said disease-targeting moiety, as defined herein, S is a functional spacer, m is 0 or 1, C is said chelating agent, as defined herein, n is 0 or 1, A is an anchor unit, such as lysine or cysteine, X is said cleavable linker, as defined herein, P is said PARP inhibitor moiety, as defined herein, o is at least 1, preferably 1, 2 or 3, or a salt, solvate or tautomer thereof.
  • T said disease-targeting moiety
  • S is a functional spacer
  • m is 0 or 1
  • C is said chelating agent, as defined herein
  • n is 0 or 1
  • A is an anchor unit, such as lysine or cysteine
  • X is said cleavable linker
  • P is said PARP inhibitor moiety, as defined herein
  • o is at least 1, preferably
  • the functional spacer (S) comprises at least two amino acids or amino acid derivatives, preferably non-natural amino acids, such as aminohexanoic acid (Ahx), naphthylalanine (Nal), trans-4- (aminomethyl)-cyclohexanecarboxylic acid (TXA), D-amino acids, such as D-phenylalanine, D-tyrosine, D-aspartic acid, D-lysine, ⁇ -amino acids, such as ⁇ -alanine ( ⁇ A), and combinations thereof, and/or the functional spacer (S) comprises polyethylenglycol (PEG), preferably (PEG)n wherein n is 1 to 24.
  • PEG polyethylenglycol
  • PEG polyethylenglycol
  • the functional spacer is (PEG) n wherein n is 4.
  • the functional spacer (S) can comprise 2 to 10 amino acids or amino acid derivatives, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the functional spacer (S) preferably comprises or consists of an amino acid sequence selected from TXA-L-Nal, D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.1], D-Lys-D-Asp- ⁇ -Ala-TXA-L-Nal [SEQ ID NO.2], D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.3], D-Lys-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.4], D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-
  • conjugate compound of the present invention has a linear structure and has the general formula (I) wherein, preferably, T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined herein above, n is 1 and C is as defined herein above, X comprises a substrate for glutathione.
  • T targets PSMA preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad)
  • P comprises or consists of
  • the conjugate compounds of general formula I have one of the following structures PSMARuc-14: Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE (Ruc-SS-MMC – SEQ ID NO.6 – KUE), PSMARuc-15: Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (Ruc-SS-MMC – SEQ ID NO.7 – KUE), or PSMARuc-18: Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys-EuE (Ruc-SS-MMC – SEQ ID NO.10 – KUE), or a salt, solvate or tautomer thereof.
  • PSMARuc-14 Ruc-SS-MMC-D
  • PSMARuc-14 (((1S)-5-((2S)-2-((1R,4S)-4-((3-((2R)-2-((2R)-2-(4-(4,10-bis(carboxymethyl)- 7-(4-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4-carboxybutanamido)-3-carboxypropanamido)-3- carboxypropanamido)propanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2- yl)
  • conjugate compound of the present invention has a branched structure and has the general formula (II) wherein, preferably, T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined herein above, n is 1 and C is as defined herein above, X comprises a substrate for glutathione.
  • T targets PSMA preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad)
  • P comprises or
  • the conjugate compounds of general formula II have one of the following structures PSMARuc-9: DOTAGA-D-Lys(Ruc-SS)-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE (DOTAGA – SEQ ID NO.2 – KuE, wherein Lys of SEQ ID NO.2 has Ruc-SS attached), PSMARuc-10: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA – SEQ ID NO.3 – KuE, wherein Lys of SEQ ID NO.3 has Ruc-SS attached), PSMARuc-11: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA – SEQ ID NO.4 – KuE, wherein Ly
  • PSMARuc-9 (((1S)-1-carboxy-5-((2S)-2-(4-((3-((2R)-3-carboxy-2-((2R)-2-(4-carboxy-4- (4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)-6-(3-((3-((4-(8- fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3- oxopropyl)disulfaneyl)propanamido)hexanamido)propanamido)propanamido)methyl)cyclohe xane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)pentyl)
  • conjugate compound of the present invention has a linear structure and has the general formula (I) wherein, preferably, T targets SSTR, such as SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics, P comprises or consists of rucaparib and o is 1, m is 0, n is 1 and C is as defined herein above, X comprises a substrate for glutathione.
  • the conjugate compounds of general formula I have one of the following structures: Ruc-SS-MMC-TOC (Ruc-SS-MMC – SEQ ID NO.15) or Ruc-SS-(PEG)4-MMC-TOC (Ruc-SS-(PEG)4-MMC – SEQ ID NO.15) or Ruc-SS-MMC-TATE (Ruc-SS-MMC – SEQ ID NO.16) or Ruc-SS-(PEG) 4 -MMC-TATE (Ruc-SS-(PEG) 4 -MMC – SEQ ID NO.15) or a salt, solvate or tautomer thereof.
  • Ruc-SS-MMC-TOC Ruc-SS-MMC – SEQ ID NO.15
  • Ruc-SS-(PEG)4-MMC-TOC Ruc-SS-(PEG)4-MMC – SEQ ID NO.15
  • Ruc-SS-MMC-TATE Ruc-SS-(PEG)
  • Ruc-SS-MMC-TOC 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3- yl)methyl)-10-(4-aminobutyl)-4-(((2S,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-16-(4- hydroxybenzyl)-7-((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(3-(3- ((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro
  • compositions and medical uses provides a pharmaceutical composition comprising at least one conjugate compound of the present invention and, optionally, pharmaceutically acceptable carrier and/or excipient(s).
  • the pharmaceutical compositions according to the present invention are very well suited for all the uses and methods described herein.
  • a "pharmaceutically acceptable carrier or excipient” refers to any vehicle wherein or with which the pharmaceutical compositions according to the invention may be formulated. It includes a saline solution such as phosphate buffer saline. In general, a diluent or carrier is selected based upon the mode and route of administration, and standard pharmaceutical practice.
  • the present invention provides the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to.
  • Said target cells are preferably tumor cells.
  • the present invention provides the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA- positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors.
  • the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8- positive cells and tumors has general formula I, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2.
  • PSMARuc-14 Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE
  • PSMARuc-15 Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE
  • PSMARuc-18 Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys-EuE, or a salt, solvate or tautomer thereof.
  • the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8- positive cells and tumors has general formula II, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, preferably having one of the following structures PSMARuc-9: DOTAGA-D-Lys(Ruc-SS)-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE, PSMARuc-10: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-D-D-
  • the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to SSTR-expressing cells and tumors has general formula I, wherein T targets SSTR, such as SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics,
  • P comprises or consists of rucaparib and o is 1.
  • o is 1. preferably having one of the following structures Ruc-SS-MMC-TOC or Ruc-SS-(PEG) 4 -MMC-TOC or Ruc-SS-MMC-TATE or Ruc-SS-(PEG)4-MMC-TATE or a salt, solvate or tautomer thereof.
  • the present invention provides the compound or the pharmaceutical composition of the present invention for use in medicine.
  • the present invention provides the compound or the pharmaceutical composition of the present invention for use in the treatment of cancer.
  • the cancer to be treated is preferably - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), ⁇ v ⁇ 6-integrin, ⁇ v ⁇ 8- integrin, ⁇ 5 ⁇ 1-integrin, ⁇ v ⁇ 1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor 1 (GRPR), gastri
  • a “PSMA-positive tumor” or “PSMA-expressing tumor” as used herein refers to a tumor that expresses PSMA as determined by standard of care clinical tests, including immunohistochemistry and a PSMA-PET or SPECT scan.
  • a PSMA-positive tumor or cancer is preferably prostate cancer, such as castration sensitive metastatic prostate cancer (mCRPC), primary prostate cancer.
  • mCRPC castration sensitive metastatic prostate cancer
  • Tumors expressing the target refers to all tumors in patients that have been tested positive for the respective target, preferably via histology or imaging.
  • a “tumor expressing SSTR”, preferably SSTR2, as used herein refers to a tumor that expresses SSTR, preferably SSTR2, as determined by standard of care clinical tests, including immunohistochemistry of tumor tissue and nuclear medicine imaging procedures (e.g. [ 68 Ga]Ga-DOTA-TATE PET scan).
  • a tumor expressing SSTR, preferably SSTR2 is preferably neuroendocrine tumors (NET), gastroenteropancreatic NET (GEP-NET), small cell lung cancer, pituitary tumors, insulinomas, breast cancers and pancreatic cancers.
  • Target Avb1: cancer-associated fibroblasts in various tumor types
  • Target folate receptor: e.g. breast, cervical, colorectal, renal, nasopharyngeal, ovarian, and endometrial (in general epithelial cancers)
  • Target neurotensin-1: e.g. pancreatic, lung, breast, prostate cancers and colon cancer
  • Target melanocortin-1: melanoma.
  • the cancer treatment can be several cycles of treatment, such as daily applications. Exemplary doses can be similar or lower than clinically used doses of PARPi.
  • Preferred routes of administration are intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal.
  • the use for cancer treatment is in combination with another therapy, preferably - - chemotherapy, - - hormonal therapy, such as hormonal therapy of mCRPC, - - immune-checkpoint blockade, - - DNA damage response (DDR) inhibiting agents, such as ATR/ATM inhibitors, AR targeting agents, DNA damaging agents, AKT inhibitors, - antiangiogenic agents, - tubulin inhibitors, such as MMAE (maytansine) and mertansine (DM1) or further conjugates of agents wherein the agents themselves are to toxic for systemic application (e.g.
  • chemotherapeutic agent refers to all chemotherapeutic and cytotoxic agents comprising the clinically approved chemotherapeutic agents.
  • the use for cancer treatment is in combination with external beam radiation therapy.
  • the cancer treatment is in combination with endoradiotherapy, e.g.
  • RLT targeted radioligand therapy
  • PRRT peptide receptor radiotherapy
  • said therapeutic isotopes being selected from 47 Sc, 67 Cu, 67 Ga, 89 Sr, 90 Y, 149 Pm, 149 Tb, 153 Sm, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, 212 Bi, 212 Pb or 225 Ac in RLT or PRRT agents.
  • the conjugate compounds, not radiolabeled or cold-labeled (labeled with a stable isotope)
  • can be given as single dose or treatment cycles, in combination with single or multiple cycles of endoradiotherapy e.g.
  • RLT or PRRT
  • both compounds have the same target, e.g. PSMA, SSTR2, or others.
  • RLT could be treatment with PSMA-targeting ligands, such as [177Lu]-PSMA-617 or [177Lu]-rhPSMA, which are typically given in several cycles with intervals of six to eight weeks in between each application.
  • PRRT could be treatment with SSTR2-targetings ligands, such as [177Lu]- DOTA-TATE or [177Lu]-DOTA-LM3, which are typically given in several cycles with intervals of six to eight weeks in between each application.
  • the present invention provides the compound or the pharmaceutical composition of the present invention for use in patient selection.
  • Said use preferably comprises molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) with said compound or said pharmaceutical composition.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • “Patient selection” as used herein refers to the determination whether the patient will likely benefit from the treatment with a compound or pharmaceutical composition of the present invention.
  • the procedure for “patient selection” will consist of administering a sub- pharmacologic dose of the radiolabeled form of the compound and confirming accumulation in tumors, preferably by PET or SPECT.
  • the present invention provides a method of treatment of cancer comprising the administration of a therapeutically effective amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient.
  • the cancer to be treated is preferably - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), ⁇ v ⁇ 6-integrin, ⁇ v ⁇ 8- integrin, ⁇ 5 ⁇ 1-integrin, ⁇ v ⁇ 1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor
  • GRPR gastrin-
  • a “PSMA-positive tumor” or “PSMA-expressing tumor” as used herein refers to a tumor that expresses PSMA as determined by standard of care clinical tests, including immunohistochemistry and a PSMA-PET or SPECT scan.
  • a PSMA-positive tumor or cancer is preferably prostate cancer, such as castration sensitive metastatic prostate cancer (mCRPC), primary prostate cancer.
  • mCRPC castration sensitive metastatic prostate cancer
  • Tumors expressing the target refers to all tumors in patients that have been tested positive for the respective target, preferably via histology or imaging.
  • a “tumor expressing SSTR”, preferably SSTR2, as used herein refers to a tumor that expresses SSTR, preferably SSTR2, as determined by standard of care clinical tests, including immunohistochemistry of tumor tissue and nuclear medicine imaging procedures, as discussed above.
  • a tumor expressing SSTR, preferably SSTR2 is preferably neuroendocrine tumors (NET), gastroenteropancreatic NET (GEP-NET), small cell lung cancer, pituitary tumors, insulinomas, breast cancers and pancreatic cancers.
  • NET neuroendocrine tumors
  • GEP-NET gastroenteropancreatic NET
  • small cell lung cancer pituitary tumors
  • insulinomas insulinomas
  • breast cancers pancreatic cancers.
  • the cancer treatment can be several cycles of treatment, such as daily applications.
  • Exemplary doses can be similar or lower than clinically used doses of PARPi.
  • Preferred routes of administration are intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal.
  • the use for cancer treatment is in combination with another therapy, preferably - - chemotherapy, - - hormonal therapy, such as hormonal therapy of mCRPC, - - immune-checkpoint blockade, - - DNA damage response (DDR) inhibiting agents, such as ATR/ATM inhibitors, AR targeting agents, DNA damaging agents, AKT inhibitors, - antiangiogenic agents, - tubulin inhibitors, such as MMAE (maytansine) and mertansine (DM1) or further conjugates of agents wherein the agents themselves are to toxic for systemic application (e.g.
  • the cancer treatment is in combination with external beam radiation therapy.
  • the cancer treatment is in combination with targeted radioligand therapy (RLT) or peptide receptor radiotherapy (PRRT), preferably comprising using therapeutic isotopes in RLT or PRRT agent(s), said therapeutic isotopes being selected from 47 Sc, 67 Cu, 67 Ga, 89 Sr, 90 Y, 149 Pm, 149 Tb, 153 Sm, 161 Tb, 166 Ho, 177 Lu, 186 Re, 188 Re, 211 At, 212 Bi, 212 Pb or 225 Ac in RLT or PRRT agents.
  • RLT radioligand therapy
  • PRRT peptide receptor radiotherapy
  • a “therapeutically effective amount” of a conjugate compound of the present invention refers to the amount which has to be administered to a subject in need thereof in order to achieve a desired therapeutic result or outcome.
  • Therapeutically effective amounts and suitable administration regimen will be determined from preclinical and clinical studies designed by qualified medical personnel.
  • the conjugate compounds not radiolabeled or cold-labelled (labelled with a stable isotope) can be given as single dose or treatment cycles, in combination with single or multiple cycles of endoradiotherapy (e.g. RLT or PRRT) with targeted alpha- or beta-emitting ligands.
  • both compounds have the same target, e.g. PSMA, SSTR2, or others.
  • RLT could be treatment with PSMA-targeting ligands, such as [177Lu]-PSMA-617 or [177Lu]-rhPSMA, which are typically given in several cycles with intervals of six to eight weeks in between each application.
  • PSMA-targeting ligands such as [177Lu]-PSMA-617 or [177Lu]-rhPSMA
  • PRRT could be treatment with SSTR2-targetings ligands, such as [177Lu]- DOTA-TATE or [177Lu]-DOTA-LM3, which are typically given in several cycles with intervals of six to eight weeks in between each application.
  • the present invention provides a method of patient selection comprising the administration of a sub-pharmacologic amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient and performing molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • molecular imaging such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • PARP inhibitors as mono- and combination therapy agents in prostate cancer.
  • Inhibitors of the DNA repair enzyme Poly(ADP-ribose)Polymerase 1/2 (PARP) have been approved for treatment of numerous indications in patients with breast, ovarian, pancreatic and prostate cancer, among others.
  • PSMA Prostate-specific membrane antigen
  • PSMA Prostate-specific membrane antigen
  • PC cells compared to normal prostate epithelial cells.
  • the vast majority of prostate cancers overexpress PSMA at the cell surface.
  • PSMA overexpression has been found to be even higher with increasing de-differentiation or castration-resistant disease, making it an attractive biomarker for targeted probe development (Ghosh et al., 2004). Indeed, a multitude of high-affinity, PSMA-directed small molecules have been translated into patients over the last decade.
  • radiolabeled PSMA analogs with gallium-68 ( 68 Ga) or Fluorine-18
  • PET positron emission tomography
  • Ruc is the only one with an indole-based fluorochrome embedded in its structure, rendering it a potent anti-cancer drug and a biocompatible fluorophore at the same time (Kossatz et al., 2018). This allows direct imaging to track the delivery, target-engagement, distribution, and clearance of Ruc without the need of external labeling techniques ( Figure 1).
  • Ruc fluorescence can become integral in understanding and optimizing Ruc-based treatment strategies. In the present case, Ruc fluorescence allows to straightforwardly validate and monitor PSMA-dependent delivery of PARPi.
  • PSMA-targeted radioligand therapy for combination with Ruc.
  • PSMA is also the target structure for PSMA-targeted 177 Lu-RLT, which was recently granted breakthrough therapy designation by the FDA, after publication of the VISION trial data, which showed prolonged median overall survival (15.3 vs.11.3 months) in late stage mCRPC patients compared to standard therapy (Sartor et al., 2021).
  • the VISION trial employed PSMA-617, a PSMA analog of particular importance because of its versatile drug design that provides 68 Ga-PET and therapeutic utility with the same PSMA-targeting motif (Benesova et al., 2015; Fendler et al., 2017).
  • 177 Lu-PSMA-617 (“Pluvicto”) was FDA approved for treatment of metastatic castration-resistant prostate cancer on March 23 rd , 2022 (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto- metastatic-castration-resistant-prostate-cancer).
  • Other 177 Lu-labelled PSMA-targeting agents are currently in phase III clinical evaluation.
  • beta-emitting radionuclide, lutetium-177 ( 177 Lu)
  • precise systemic delivery of cytotoxic radiation to tumors is achieved (Heinzel et al., 2019; Yadav et al., 2019).
  • the new conjugate compounds can substantially reduce the hematotoxicity of PARP inhibitors because PSMA is not expressed by hematopoietic cells.
  • tumor specific delivery of PARP inhibitors can facilitate the use of this therapy in earlier stages of prostate cancer, for example in combination with hormonal therapy of castration sensitive metastatic prostate cancer (mCRPC) or in combination with external beam radiotherapy of primary prostate cancer. This appears feasible because DNA repair defects are often present already at the time of prostate cancer diagnosis.
  • this invention leads not only to a more effective palliative radionuclide therapy of advanced mCRPC, but can also serve for novel treatment approaches that result in long-term remissions in mCRPC and increase the likelihood of cure for high-risk localized prostate cancer.
  • Our invention centers on the development of a selective drug delivery system for PARPi to PC cells that express the prostate specific membrane antigen (PSMA).
  • PSMA prostate specific membrane antigen
  • PSMA prostate specific membrane antigen
  • somatostatin receptor SSTR subtypes 2, 3, and 5
  • gastrin-releasing peptide receptor GRPR
  • CXCR4 C-X-C motif chemokine receptor 4
  • ⁇ v ⁇ 6-integrin ⁇ v ⁇ 8-integrin
  • NTSR1 neurotensin receptor 1
  • M1R melanocortin receptor 1
  • conjugates of PARPi with molecules targeting the aforementioned targets will be employed alone or in combination with other therapeutic agents for the respective disease entities.
  • the chemical composition of the conjugates include - PSMA-targeting vectors based on EuK and EuE urea analogs (Robu et al., 2018; Petrov et al., 2021; Kelly et al., 2017; Hensbergen et al., 2020), - different linkers for affinity/pharmacokinetic (PK) optimization, and - different chelators (DOTAGA or multimodality chelator (MMC), leading to branched or linear conjugates, respectively, that allow direct radiolabeling for quantitative assessment of binding and biodistribution.
  • PK affinity/pharmacokinetic
  • MMC multimodality chelator
  • PSMA-Ruc conjugates only induced cytotoxic effects in PSMA+ cells, where the cell viability was 50-60% compared to untreated cells. In PSMA- negative cells, cell viability was >80% and similar to the untreated controls. Importantly, the non-cleavable control (conjugate 13), did not show cytotoxic effects in PSMA+ cells, demonstrating the need for intracellular release of Ruc to exert cytotoxic effects. Hence, PSMA-Ruc conjugates showed PSMA-selective cytotoxicity, while free Ruc did not. Differences in potency of monotherapies potentially arise from saturation of PSMA at the high concentrations of Ruc needed to exert cytotoxic effects in monotherapy. PSMA-Ruc in combination with 177 Lu-PSMA treatment in vitro.
  • PET/CT imaging revealed 68 Ga-PSMA-Ruc-11 uptake in PSMA+ PC3-PIP tumors and no accumulation in PSMA- PC3-Flu tumors at 60 min p.i. ( Figure 9A). These findings demonstrate retention of PSMA-targeting properties after payload conjugation.
  • biodistribution profile of 68 Ga-PSMA-Ruc-11 was similar to 68 Ga-PSMA-617, with uptake limited to PSMA-expressing tumors and kidneys, and fundamentally different from the typical biodistribution of PARPi (e.g., 18 F-Olaparib, Wilson et al.2019), which is characterized by low tumor uptake and high gut uptake.
  • PSMA-Ruc conjugates with 2 Ruc moieties in combination with 177 Lu-PSMA treatment in vitro We tested if conjugates containing two Ruc moieties can increase the cytotoxic effects of 177 Lu-PSMA treatment (10Lys/PSMA-Ruc(2)-10, 11Lys/ PSMA-Ruc(2)-11, 12Lys/ PSMA- Ruc(2)-12, 16Lys/ PSMA-Ruc(2)-16 and 17Lys/ PSMA-Ruc(2)-17).
  • SSTR2-targeting PARPi conjugates - rationale Neuroendocrine tumors (NETs) have an increasing incidence rate.
  • NETs neuroendocrine tumors
  • SSTR2 somatostatin receptor type 2
  • SSTR2 is often overexpressed in NETs, therefore it is already a clinically validated biomarker in most NETs.
  • a selective delivery of PARPi e.g.
  • rucaparib to SSTR2 expressing tumor cells via peptide-drug conjugates could trigger synthetic lethality through combination therapies only in the cancer cells, but not in healthy cells.
  • Such an effective radiosensitizer would improve the therapeutic index of peptide receptor radionuclide therapy (PRRT) by maintaining potency with lower administered doses per cycle, and potentially extend the duration of treatment benefit.
  • PRRT peptide receptor radionuclide therapy
  • Ruc-TOC was internalized into HCT-116SSTR2 expressing cells, whereas it showed nearly no uptake in HCT-116 wildtype cells ( Figure 13, first and second row).
  • free Ruc 5 ⁇ M was used and showed nuclear accumulation in both cell lines.
  • octreotide 500 ⁇ M
  • no Ruc signal was observed in the cells, indicating SSTR2-mediated uptake ( Figure 13, last row):
  • a similar experiment with Ruc-(PEG)4-TATE also showed SSTR2-specific uptake via fluorescence detection of Ruc ( Figure 14).
  • Radioligand uptake assay To determine the SSTR2-mediated internalization, a radioactive uptake assay was performed (see Example 11). We measured the relative uptake of the compound at two different concentrations (0.6 nM or 6 nM) with and without octreotide blocking . After 1 h of incubation with [ 68 Ga]Ga-Ruc-(PEG) 4 -TATE, a specific uptake of 3.95 % ⁇ 1.76 % (6 nM ligand concentration) and 3.62 % ⁇ 0.59 % (0.6 nM ligand concentration) was observed (Figure 16). These results reflect SSTR2-specific cell binding and internalization of [ 68 Ga]Ga- Ruc-(PEG) 4 -TATE.
  • Time–activity curves of tumor, heart, kidney and muscle showed a rapid clearance from the blood pool (heart) as well as rapid background clearance (muscle) and low non-specific accumulation. Renal excretion was characterized by a sharp peak 2 min post injection and subsequent clearance over time. Importantly, the tumoral accumulation of [ 68 Ga]Ga-Ruc-(PEG) 4 -TATE was higher than blood pool within 20 min and showed a continuous increase over 90 min .
  • a conjugate compound comprising a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof.
  • T disease-targeting moiety
  • the disease-targeting moiety comprises a peptide or small molecule, which internalizes upon binding to a cell surface biomarker, wherein said peptide or small molecule preferably targets the prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), ⁇ v ⁇ 6-integrin, ⁇ v ⁇ 8-integrin, ⁇ 5 ⁇ 1-integrin, ⁇ v ⁇ 1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R).
  • PSMA prostate-specific membrane antigen
  • SSTR subtypes 2, 3, and 5 gastrin-releasing peptide receptor
  • CXCR4 C-X-C motif chemokine receptor 4
  • ⁇ v ⁇ 6-integrin ⁇ v ⁇ 8-integrin
  • FR
  • T disease-targeting moiety
  • the disease-targeting moiety comprises monomers or multimers, and/or comprises further components, such as PEG linker(s), albumin-binding domain(s), further amino acid(s), and/or peptidomimetics.
  • T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), or wherein the disease-targeting moiety (T) targets SSTR, preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics.
  • the disease-targeting moiety (T) targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), or wherein the disease-targeting moiety (T) targets SSTR, preferably SSTR2, and preferably
  • the cleavable linker (X) comprises a substrate for enzyme cleavage or redox reaction, such as a substrate for prostate specific antigen (PSA), caspases or cathepsins, proteases or peptidases, or for the antioxidant glutathione.
  • the functional spacer (S) comprises at least two amino acids or amino acid derivatives, preferably non-natural amino acids, such as aminohexanoic acid (Ahx), naphthylalanine (Nal), trans-4- (aminomethyl)-cyclohexanecarboxylic acid (TXA), D-amino acids, such as D-phenylalanine, D-tyrosine, D-aspartic acid, D-lysine, ⁇ -amino acids, such as ⁇ -alanine ( ⁇ A), and combinations thereof, and/or wherein the functional spacer (S) comprises polyethylenglycol (PEG), preferably (PEG)n wherein n is 1 to 24, such as n is 4.
  • PEG polyethylenglycol
  • D-Lys-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.4]
  • D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.5]
  • D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal [SEQ ID NO.6]
  • viii. D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.7], ix.
  • D-Lys-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys [SEQ ID NO.8], x. D-Lys-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys [SEQ ID NO.9], xi. D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys [SEQ ID NO.10], xii.
  • D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.11], xiii. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.12], xiv. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx, [SEQ ID NO.13], and xv.
  • T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad),
  • P comprises or consists of rucaparib and o is 1 or 2
  • m is 1 and S is as defined in items 9 and 10
  • n is 1 and C is as defined in item 7
  • X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-Ku
  • T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad),
  • P comprises or consists of rucaparib and o is 1 or 2
  • m is 1 and S is as defined in items 9 and 10
  • n is 1 and C is as defined in item 7
  • X comprises a substrate for glutathione, preferably having one of the following structures DOTAGA-D-Lys(Ruc-SS)-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, D
  • T targets SSTR preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics
  • P comprises or consists of rucaparib and o is 1, m is 0, n is 1 and C is as defined in item 7
  • X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-TOC, Ruc-SS-(PEG) 4 -MMC-TOC, Ruc-SS-MMC-TATE, Ruc-SS-(PEG)4-MMC-TATE, or a salt, solvate or tautomer thereof.
  • a pharmaceutical composition comprising at least one conjugate compound of any one of items (1) to (13) and, optionally, pharmaceutically acceptable carrier and/or excipient(s).
  • the compound of any one of items (1) to (13) as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to, wherein said cells are preferably tumor cells, preferably, as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors, or, preferably as vehicle for the specific delivery of at least one PARP inhibitor moiety to SSTR-expressing cells and tumors.
  • the cancer is - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), ⁇ v ⁇ 6 integrin, ⁇ v ⁇ 8 integrin, ⁇ 5 ⁇ 1 integrin, ⁇ v ⁇ 1 integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocort
  • GRPR gastrin-releasing peptide receptor
  • CXCR4 C-X-C motif chemokine receptor 4
  • another therapy preferably chemotherapy, hormonal therapy, immune-checkpoint blockade, DNA damage response (DDR) inhibiting agents, antiangiogenic agents,
  • Ruc free Rucaparib
  • 7-12 branched PSMA-Ruc conjugates
  • 13 non-cleavable control
  • 14- 15 linear PSMA-Ruc conjugates. All cells were pretreated with 10 mM GSH and contained 0,2% DSMO.
  • Figure 7. Cell viability in PSMA+ and PSMA- cell lines. Cells (PSMA+: LNCaP, C42; PSMA-: DU145, PC3) were treated for 72 h with 1 ⁇ M free Ruc, 1 ⁇ M Conj.15, 0.1875 MBq RLT( 177 Lu-PSMA-I&T) or the combination of both. Viability was assessed via Alamar Blue assay and calculated relative to untreated control.
  • PSMA+ LNCaP, C42, PC3-PiP; PSMA-: DU145, PC3
  • RLT 177 Lu-PSMA-I&T
  • Viability was assessed via Alamar Blue assay and calculated relative to untreated control, which contained 0.2 % DMSO.
  • HCT-116 SSTR2 cells after pre-treatment with octreotide for blocking and treatment with Ruc-TOC. left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay).
  • Figure 14 SSTR2-specific cellular uptake of Ruc-PEG-(TATE)4.
  • First row HCT-116 SSTR2 cells after treatment with Ruc-(PEG)4-TATE (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay).
  • HCT-116 SSTR2 cells after pre-treatment with octreotide for blocking and treatment with Ruc-(PEG)4-TATE (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay).
  • Figure 15 In vitro treatment of H69 cells Analysis of the viability of H69 cells after treatment with 5 ⁇ M Ruc-TOC or 5 ⁇ M Ruc- (PEG)4-TATE compared to untreated cells (medium only) and medium containing 0.5% DMSO (similar to DMSO concentration in treatment groups). Cell viability was determined via 10% AlamarBlue TM HS incubation at 37 °C for 3h and fluorescence measurement at 570 nm.
  • Viability values were set relative to cell viability of untreated cells (Medium only).
  • Figure 16. SSTR2-mediated internalization of [ 68 Ga]Ga-Ruc-(PEG) 4 -TATE, shown as percentage of applied activity after incubation in H69 cells at 37 °C for 1 h. Blocking was performed with octreotide (10 ⁇ M).
  • Figure 17. PET Imaging in H69 tumor bearing mice.
  • Rucaparib was obtained from Selleckchem (Berlin, Germany), and PSMA-617 from MedChemExpress (Sollentuna, Sweden), respectively. All solvents were purchased from Sigma-Aldrich (Munich, Germany), VWR (Darmstadt, Germany), Carl Roth (Karlsruhe, Germany) or Iris Biotech, of analytical, for synthesis, peptide or HPLC grade and used without further purification. Unless otherwise noted, all other used chemicals and reagents for the performed syntheses were obtained from Sigma-Aldrich, VWR, Merck (Darmstadt, Germany), abcr (Karlsruhe, Germany) or Alfa Aesar.
  • Solid phase syntheses were performed in 20 mL plastic syringes from B. Braun, which were equipped with a frit from Roland Vetter Labor position (Ammerbuch, Germany). By drawing up the syringe, reaction or wash solutions were added to the resin. Complete mixing was accomplished on a rotating unit. The equivalents (eq.) of amino acids were referred to the theoretical loading given by the manufacturer. Column chromatography was performed using a 100-fold excess of silica gel (40-63 ⁇ m grain size, Si 60, 230-400 mesh ASTM) from Merck at 1 bar overpressure. The respective eluent ratios were described in the experimental procedures.
  • TLC thin- layer reaction controls
  • silica gel 60 F254 obtained from Merck using different mixtures of organic solvents.
  • the respective eluent ratios were described in the experimental procedures as well. Via UV absorption at 254 nm the substances were hereby detected.
  • Semi-preparative reversed phase high-performance liquid chromatography (RP-HPLC) was realized on the following devices: a) Waters (Milford, USA) instrument including a Waters 2545 (Binary Gradient Module), Waters SFO (System Fluidics Organizer), Waters 2996 (Photodiode Array Detector), and Waters 2767 (Sample Manager), respectively.
  • the applied flow rate was 40 mL/min.
  • Shimadzu Shimadzu Kunststoff GmbH, Neufahrn, Germany
  • RP-HPLC system including a CBM-20A communications bus module, SPD-M20A prominence diode array detector, LC-20AP prominence preparative liquid chromatograph (for both pumps).
  • the applied flow rate was 20 mL/min.
  • the LC-MS spectra were acquired on two devices: a) UltiMate 3000 UHPLC (Dionex, Sunnyvale, USA) equipped with a LCQ Fleet mass spectrometer (ThermoFisher Scientific, Waltham, USA) and two different C18 columns (Hypersil Gold aQ 175 ⁇ , 3 ⁇ m, 150 mm ⁇ 2.1 mm or Accucore C18, 80 ⁇ , 2.6 ⁇ m, 50 x 2.1 mm, constant flow 0.9 mL/min) from Thermo Scientific.
  • trypsin-EDTA (10 ⁇ ), Roswell Park Memorial Institute-1640 Medium (RPMI-1640), fetal calf serum (FCS), and phosphate buffered saline (1 ⁇ , PBS; pH 7.4) were purchased from Gibco, ThermoFisher.
  • Poly-L-lysine solution (0.01% in sterile water) was purchased from Merck, bovine serum albumin (BSA) from Carl Roth, and alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively.
  • BSA bovine serum albumin
  • alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively.
  • the following cell lines were used: prostate carcinoma cell lines LNCaP, PC3, PC3-PiP, C42, and DU145, respectively.
  • the cell lines were purchased from American Type Culture Collection (ATCC, Manassas, USA) and from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany). All cell lines were cultured in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated FCS (v/v) (Gibco, ThermoFisher Scientific) and 1% (v/v) penicillin/streptomycin (10,000 U/mL, Gibco, ThermoFisher Scientific) in a 37 °C incubator with a 5% (g/v) CO 2 atmosphere.
  • FCS v/v
  • penicillin/streptomycin 10,000 U/mL, Gibco, ThermoFisher Scientific
  • GP-2 On-resin Fmoc-deprotection: The resin was treated with a solution of 20% (v/v) Piperidin in DMF (1 ⁇ 15 min, 1 ⁇ 10 min) at RT. Afterwards, the resin was washed with DMF (8 ⁇ ).
  • GP-3 On-resin peptide synthesis with HATU/HOBt: A solution (0.1-0.2 M ) of Fmoc-AA- OH (2.0 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 2.0 eq.), 1-hydroxybenzotriazole (HOBt ⁇ H2O; 2.0 eq.), and DIPEA (5.0 eq.), respectively, in DMF was stirred for 15 min at RT. The pre-activated solution was added to the resin-bound, free amine and shaken for 1 h at RT.
  • GP-4 Cleavage of linear peptides from the resin: For complete cleavage, the resin was first washed with DCM (3 ⁇ ) and then treated with a solution of 20% (v/v) hexafluoroisopropanol in DCM (1 ⁇ 15 min, 2 ⁇ 10 min). In a next step, the solvent was evaporated under reduced pressure.
  • GP-5 Trityl-, Pbf-, Boc-, and t Bu-deprotection in solution: The starting material was dissolved in a mixture of TFA/DCM/triisopropylsilane (TIPS)/H2O/DCM (90/5/2.5/2.5, v/v/v) and stirred for 60 min at RT.
  • TIPS TFA/DCM/triisopropylsilane
  • GP-7 Standard amino acid coupling in solution: The corresponding acid (1.2 eq.), HOBt ⁇ H2O (1.2 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.2 eq) as well as DIPEA (5.0 eq.) were dissolved in DMF (0.12 M ), and incubated for 15 min at RT. The pre-activated solution was added to the deprotected, free amine (1.0 eq.), dissolved in a small amount of DMF. After stirring the reaction solution for 16-24 h at RT, the solvent was evaporated.
  • GP-10 Preparation of non-radioactive nat Ga-complexed PSMA-ligands: A solution of the PSMA-inhibitor (2.0 mM; 10 ⁇ L) in dimethyl sulfoxide (DMSO) and a solution of Ga(NO 3 ) 3 (2.0 mM; 10 ⁇ L) in H2O/DMSO (16% H2O (v/v)) were mixed and heated at 45 °C for 40 min under shaking. Chelate formation was analyzed via RP-HPLC and ESI-MS. The resulting 1.0 mM solution was used without further purification in in vitro experiments.
  • DMSO dimethyl sulfoxide
  • Ga(NO 3 ) 3 2.0 mM; 10 ⁇ L
  • H2O/DMSO 16% H2O (v/v)
  • Rucaparib containing building blocks 3-((3-((4-(8-Fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)- (methyl)amino)-3-oxopropyl)disulfaneyl)propanoic acid (Ruc-SS-OH) (1): To a solution of rucaparib*HCl (40.0 mg, 112 ⁇ mol, 1.0 eq.) in DMF (15 mL), 3,3- dithiopropionic acid (47.0 mg, 222 ⁇ mol, 2.0 eq.) was added (GP-7).
  • 2-CTC resin (2.00 g, 1.93 mmol, 1.0 eq; resin loading: 0.97 mmol/g resin) was loaded with Fmoc-L-Lys(Dde)-OH (1.30 g, 2.32 mmol, 1.2 eq.) according to GP-1.
  • Fmoc-removal GP-2
  • a solution of 6 (1.37 g, 3.87 mmol, 2.0 eq.
  • NEt 3 700 ⁇ L, 450 mg, 4.45 mmol, 2.3 eq.
  • DCE dichloroethane
  • 2-CTC resin (2.00 g, 1.93 mmol, 1.0 eq; resin loading: 1.03 mmol/g resin) was loaded with Fmoc-D-Lys(Dde)-OH (1.30 g, 2.32 mmol, 1.2 eq.) according to GP-1.
  • Fmoc-removal GP-2
  • the resin was treated with a solution of 8 (1.42 g, 2.90 mmol, 1.5 eq.) according to GP-3.
  • Resin-bound 9 was used for the generation of EuE-based PSMA- ligands according to solid phase peptide synthesis/standard Fmoc-strategy.
  • the Fmoc-deprotected resin was treated with a solution of DOTAGA anhydride (4.0 eq.) and DIPEA (10 eq.) in DMSO (0.07 m M ) for 48 h. Subsequently, the PSMA ligand was cleaved from the resin according to GP-4. After global deprotection of the acid labile protection groups, performed after GP-5, the ligands were purified via semipreparative RP-HPLC. Finally, the Ruc-derivative was coupled under basic conditions according to GP-6 and the product was obtained after RP-HPLC purification. The peptide sequence was synthesized according to the general synthesis procedure.
  • R UC -SS-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (Ruc-SS-dyff-Ahx-KuE) (PSMARuc-8) 11 was synthesized as 10 by coupling Fmoc-6-Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, and Fmoc-D-Asp(O t Bu)-OH to 7 (100 mg resin, 96.9 ⁇ mol, 1.0 eq.).
  • DOTAGA-D-Lys(Ruc-SS)-D-Asp- ⁇ -Ala-TXA-L-Nal-KuE (DOTAGA-k(Ruc-SS)-d- ⁇ A- TXA-Nal-KuE) (PSMARuc-9) (12): As already described for 10, the following amino acid sequence was coupled to 7 (100 mg resin, 96.9 ⁇ mol, 1.0 eq.): Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc- ⁇ -Ala-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively.
  • DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA-k(Ruc-SS)- dyff-Ahx-KuE) (PSMARuc-10) (13): The synthesis of 13 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D- Lys(Boc)-OH, and DOTAGA-anhydride, respectively.
  • DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA-k(Ruc-SS)- dyf-Nal-Ahx-KuE) (PSMARuc-11) (14): The synthesis of 14 was accomplished in similarity to 10, using Fmoc-6-Ahx- OH, Fmoc-L- Nal-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D- Lys(Boc)-OH, and DOTAGA-anhydride, as amino acid analogues.
  • DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (DOTAGA-k(Ruc- SS)-dyff-Ahx-Ahx-KuE) (PSMARuc-12) (15): The synthesis of 15 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-6- Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)- OH, Fmoc-D-Lys(Boc)-OH, and DOTAGA-anhydride.
  • Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (Ruc-SS-MMC-ddyff- Ahx-Ahx-KuE) (PSMARuc-15) (18): The synthesis was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-6-Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc- D-Asp(O t Bu)-OH, and MMC(O t Bu)3-NH(Boc), respectively.
  • DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA- k(k(Ruc-SS)2)-ddyff-Ahx-KuE) (PSMARuc-10Lys2) (19): The synthesis of 19 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D- Asp(O t Bu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively.
  • the synthesis was accomplished in accordance with 10, using Fmoc-6-Ahx-OH, Fmoc-6-Ahx- OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DOTAGA- anhydride, respectively.
  • the peptide structures for the synthesis of the PSMA-targeting ligands were achieved according to GP-2, GP-3, GP-4, GP-5, and GP-9, respectively, via standard solid phase peptide synthesis.
  • K(Dde)-(O t Bu)EuE(O t Bu) 2 (9) was Dde- deprotected according to GP-9.
  • the coupling of further amino acid analogues or amino acids was achieved according to GP-2 and GP-3 following Fmoc-strategy.
  • the Fmoc-deprotected resin was treated with a solution of DOTAGA anhydride (4.0 eq.) and DIPEA (10 eq.) in DMSO (0.07 mM) for 48 h. Afterwards, the PSMA ligand was cleaved from the resin according to GP-4 and globally deprotected according to GP-5. The crude ligands were purified via semipreparative RP-HPLC. After coupling of the Ruc-derivative according to GP-6, the final product was acquired after semipreparative RP-HPLC purification.
  • Ruc-SS-MMC-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys-EuE (Ruc-SS-MMC-dd- ⁇ A-TXA- Nal-k-EuE) (PSMARuc-18) (25): The synthesis was accomplished in similarity to 23, using Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc- ⁇ -Ala-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, and MMC(O t Bu)3-NH(Boc), respectively.
  • DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp- ⁇ -Ala-TXA-L-Nal-D-Lys-EuE (DOTAGA- k(k(Ruc-SS) 2 )-dd- ⁇ A-TXA-Nal-k-EuE) (PSMARuc-16-Lys 2 ) (26): The synthesis of the title compound was accomplished in similarity to 23, using Fmoc-L-Nal- OH, Fmoc-TXA, Fmoc- ⁇ -Ala-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D-Asp(O t Bu)-OH, Fmoc-D- Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DBCO-acid, respectively.
  • Radiolabeled product was finally eluted with EtOH/H2O (1:1 (v/v)) and the cartridge was purged with PBS (1 mL; pH 7.4) and H 2 O (1 mL), respectively. After evaporation of EtOH under reduced pressure, the tracer was used without further purification in in vitro and in vivo experiments. Radiochemical purity was controlled using Radio-TLC (1.0 M sodium citrate buffer and 0.06 M NH4OAc/MeOH buffer (1/1 ; v/v)).
  • PSMA-Ruc conjugates show PSMA-specific internalization and high affinity to PSMA-expressing cells
  • LNCaP cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in 5% BSA (w/v)/RPMI medium (100 ⁇ L/well) and incubated for 30 min at 37 °C. Afterwards, solutions (25 ⁇ L/well) of either 5% BSA (w/v)/RPMI medium or of 2-PMPA (final concentration: 10 ⁇ M) in 5% BSA (w/v)/RPMI medium for blockade were added.
  • the cells were treated in a next step with ice-cold 2-PMPA-solution (10 ⁇ M in PBS; 150 ⁇ L/well; 15 min on ice), centrifuged (600 g, 3 min), and washed with ice-cold PBS (150 ⁇ L/well). The fractions were again combined.
  • the fractions of a 1.0 N NaOH (150 ⁇ L/well; 10 min on ice) treatment as well as a concomitant washing step with 1.0 N NaOH (150 ⁇ L/well) were pooled. Free, surface bound, and internalized activity, respectively, was measured in a ⁇ -counter.
  • LNCaP cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in 1% BSA (w/v)/HBSS (Hank’s balanced salt solution, ThermoFisher Scientific; 100 ⁇ L/well) and incubated for 15 min on ice. In the meantime, dilution series of the compounds were prepared in 1% BSA (w/v)/HBSS in a separate 96 U- bottom deep well plate ranging from 12 ⁇ M to 153.6 pM in 1:5 dilution steps.
  • the cells were then washed with ice-cold HBSS (150 ⁇ L/well), centrifuged (600 g, 3 min), and the supernatant as well as the washing fraction were combined, representing the amount of free, unbound radioligand.
  • Bound radioligand was obtained by lysis of the cells with 1.0 N NaOH (150 ⁇ L/well; 10 min on ice). Afterwards, the plate was washed a second time with 1.0 N NaOH (150 ⁇ L/well). Hereby, the washing step was combined with the NaOH fraction. The quantification of bound and free radioligand was finally accomplished via measuring the samples in a ⁇ -counter. Lipophilicity of the conjugates was determine after radiolabeling with 68 Ga.
  • PSMA-Ruc conjugates show PSMA-dependent uptake of Ruc Microscopy + flow
  • black clear-bottom 96 well cell culture plates with cover-glass bottom ⁇ plate 96 well black; ibidi
  • poly-L-lysine 0.01% (w/v) in sterile water.
  • Cells were seeded at a density of 20-40,000 cells/well and cultured for 24 h at 37 °C.
  • the PSMA ligands (1 ⁇ M; 100 ⁇ L/well) were directly added with or without blocking and ligand treatment was accomplished for 5, 60 or 180 min at 37 °C, while in case of GSH preincubation, GSH-OEt (10 mM; 100 ⁇ L/well) was applied for 1 h at 37 °C prior to ligand treatment.
  • GSH-OEt 10 mM; 100 ⁇ L/well
  • the PSMA ligands (1 ⁇ M, 100 ⁇ L/well) were added after removal of the GSH containing medium and the incubation time was 60 min at 37 °C.
  • PSMA-Ruc conjugates induce selective cytotoxicity in vitro Black, clear-bottom 96 well culture plates were coated with poly-L-lysine. Afterwards, the plates were washed with PBS (1 ⁇ 100 ⁇ L), cells were seeded (2000 cells/well for PC3, 10000 cells/well for LNCaP), and cultured for 24 h (PC3) or 48 h (LNCaP) at 37 °C.
  • the plates were washed with PBS (1 ⁇ 100 ⁇ L), cells were seeded (2000 cells/well for PC3, 10000 cells/well for LNCaP), and cultured for 24 h to 48 h at 37 °C.
  • the culture medium was removed and fresh medium containing 10 mM GSH-OEt (for PSMA-Ruc-conjugate treatment; treatment for 1 h at 37 °C), 0.1875 MBq RLT ( 177 Lu-PSMA-I&T; treatment for 72 h) or rucaparib (0.1 - 1 ⁇ M) or both was added. After a total incubation time of 72 h, the cell viability was tested by use of Alamar Blue.
  • PSMA-617, PSMA-Ruc-9, PSMA-Ruc-16 and PSMA-Ruc-18 (15 nmol each) were dissolved in 0.2 M sodium acetate buffer (pH 4.2; 100 ⁇ L), mixed with 68 Ga (155-296 MBq; 100-150 ⁇ L), radiolabeled for 15 min at 95°C and purified using an activated Sep-Pak Light C18 (Waters) cartridge.
  • Athymic nude mice were subcutaneously injected with 4 ⁇ 10 6 PC3-PIP (PSMA+) and 3 ⁇ 10 6 PC3-Flu (PSMA-) cells to produce a bilateral tumor model.
  • Conjugate 11 Mice were injected with 7.4 MBq of 68 Ga-PSMA-Ruc-11 or 68 Ga-PSMA-617 (positive control) via the tail vein and PET/CT imaging was performed 1 hour post-injection. At the completion of the imaging study, mice were euthanized and organs were resected, weight, and analyzed by gamma counting to determine tracer biodistribution. Data are ported as percentage of injected activity per gram of tissue (%IA/g). Results are shown in Figure 9.
  • mice were euthanized and organs were resected, weighted, and analyzed by gamma counting to determine tracer biodistribution. Biodistribution data are reported as percentage of injected dose per gram of tissue (%ID/g). Results are shown in Figure 10.
  • EXAMPLE 9 PSMA-Ruc conjugates with 2 Ruc moieties in combination with 177 Lu- PSMA treatment in vitro Black, clear-bottom 96 well culture plates were coated with poly-L-lysine. Afterwards, the plates were washed with PBS (1 ⁇ 100 ⁇ L), cells were seeded and cultured for 24 h at 37 °C.
  • Seeding cell density was adapted to the cell line (C42: 1000 cells/well; DU145: 1500 cells/well; LNCaP: 5000 cells/well PC3 and PC3-PIP: 500 cells/well).
  • Treatment consisted of 24 h treatment with 0.1875 MBq [ 177 Lu]Lu-PSMA I&T. Then, the culture medium containing the radioligand was removed and 10 mM GSH-OEt was added for 1 h, subsequently GSH was removed and either medium (monotreatment control), 1 ⁇ M Rucaparib or 1 ⁇ M of a PSMA- Ruc(2)-ligand (combination treatment) was added and incubated for 47 h.
  • the H-L-Thr(tBu)-ol-2CT resin and the H-L-Thr(tBu)-2CT resin were obtained from Iris Biotech (Marktredwitz, Germany). Rucaparib was obtained from MedChemExpress (Sollentuna, Sweden). All solvents were purchased from Merck (Munich, Germany), VWR (Darmstadt, Germany), Carl Roth (Karlsruhe, Germany) or Iris Biotech (Marktredwitz, Germany), of analytical, for synthesis, peptide or HPLC grade and used without further purification.
  • RP-HPLC Semi-preparative reversed phase high-performance liquid chromatography
  • LC-MS spectra were acquired on the following device: ISQ EM Vanquish mass spectrometer (ThermoFisher Scientific, Waltham, USA) with a C18 column (ReproSil-Pur 120 C18-AQ, 5 ⁇ m, 150 x 4 mm, Dr. Maisch, Ammerbuch-Entringen, Germany).
  • Poly-L-lysine solution (0.01% in sterile water) was purchased from Merck, bovine serum albumin (BSA) from Carl Roth, and alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively.
  • BSA bovine serum albumin
  • alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively.
  • All cell lines were cultured in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated FCS (v/v) (Gibco, ThermoFisher Scientific) and 1% (v/v) penicillin/streptomycin (10,000 U/mL, Gibco, ThermoFisher Scientific) in a 37 °C incubator with a 5% (g/v) CO2 atmosphere.
  • v/v heat inactivated FCS
  • penicillin/streptomycin 10,000 U/mL, Gibco, ThermoFisher Scientific
  • GP-2 On-resin peptide synthesis with TBTU/HOBt: A solution of Fmoc-AA-OH (1.5 eq.), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.5 eq.), 1-hydroxybenzotriazole (HOBt ⁇ H 2 O; 1.5 eq.), and DIPEA (4.5 eq.), respectively, in DMF was stirred for 15 min at RT. The pre-activated solution was added to the resin-bound, free amine and shaken for 1.5 h at RT.
  • GP-6 Coupling of Ruc-SS-COOH on resin: A solution of Ruc-SS-COOH (1.5 eq.), 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.5 eq.), 1-hydroxybenzotriazole (HOBt ⁇ H 2 O; 1.5 eq.), and DIPEA (4.0 eq.), respectively, in DMF was stirred for 15 min at rt. The pre-activated solution was added to the resin-bound, free amine and shaken for 1.5 h at rt.
  • TBTU 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate
  • HOBt ⁇ H 2 O 1.5 eq.
  • DIPEA 4.0 eq.
  • GP-9 Radiolabeling: 68 Ga-labeling: The SSTR2-targeting compounds were radiolabeled according to the literature (Weineisen et al., 2014; Notni et al., 2011) using a fully automated synthesis module (GallElut+ from Scintomics GmbH, Germany). The following reaction steps were controlled by a computer program from Scintomics (Scintomics Control Center). In a first step, the 68 Ge/ 68 Ga-generator with SnO 2 matrix (iTHEMBA labs, South Africa) was eluted with 0.1 M aq. HCl. Hereby, a fraction of 1.25 mL containing ca.80% of the entire activity (ca.
  • Radiochemical purity was controlled using Radio-TLC (1.0 M sodium citrate buffer).
  • PET/MR imaging was performed with a Nano Scan PET/MRI 3T (Mediso, Budapest, Hungary). Static measurements were performed 45 min p.i. for 15 min. A dynamic scan was performed for 90 min upon tracer injection. As software for image reconstruction NuclineTM (Mediso, Budapest, Hungary) was used. Radioligand uptake assay H69 cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in medium (120 ⁇ L/well). Afterwards, solutions (15 ⁇ L/well) of either RPMI medium or of octreotide (final concentration: 10 ⁇ M) in DMSO for blockade were added.
  • J Med Chem 57, no.6 (2014): 2657-69. Benesova, M., Schafer, M., Bauder-Wust, U., Afshar-Oromieh, A., Kratochwil, C., Mier, W., Haberkorn, U., Kopka, K., and Eder, M.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to conjugate compounds comprising a disease-targeting moiety and at least one PARP inhibitor moiety and pharmaceutical compositions comprising the conjugate compounds. The present invention relates to the use of the conjugate compounds for use in the treatment of cancer. The present invention further relates to methods of treatment of cancer and for patient selection.

Description

Conjugate compounds and their use in cancer treatment and diagnosis The present invention relates to conjugate compounds comprising a disease-targeting moiety and at least one PARP inhibitor moiety and pharmaceutical compositions comprising the conjugate compounds. The present invention relates to the use of the conjugate compounds for use in the treatment of cancer. The present invention further relates to methods of treatment of cancer and for patient selection. BACKGROUND OF THE INVENTION Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths in men worldwide with an estimated 360,000 deaths in 2018 (Bray et al., 2018). Most of these deaths are associated with metastatic castration-resistant PCa (mCRPC), a lethal form of PCa that arises from progression and spread of the disease during androgen deprivation therapy. Currently approved life-prolonging treatments for mCRPC include taxanes (docetaxel and cabazitaxel), an immunotherapeutic agent (sipuleucel-T), androgen receptor pathway inhibitors (abiraterone, enzalutamide), and a bone targeting alpha-emitting radionuclide (radium-223 chloride) (Gillessen et al., 2015). Despite the different mechanisms of action of these therapies, patients with mCRPC inevitably progress and develop resistance. Thus, there is a critical need for new treatment options that improve outcomes and quality of life for these patients. In PCa, prostate- specific membrane antigen (PSMA) has emerged as a target for imaging and therapeutic purposes due to a 100 to 1000-fold higher expression in cancerous tissue of the prostate compared to normal cells. Several glutamate-ureido-based small molecules that target PSMA have been linked to radionuclides are used clinically, but durable responses remain a major challenge in the field. Neuroendocrine tumors (NETs) represent a heterogeneous group of generally indolent neoplasms that primarily arise from the diffuse endocrine system of the lungs, gastrointestinal tract, and pancreas. For patients with localized NETs, surgery is curative, and the median overall survival rate is more than 30 years; however, the majority of patients present with metastatic disease at the time of diagnosis, emphasizing the importance of systemic therapies for this disease. Expression of somatostatin receptor subtype2 (SSTR2) is a hallmark of most NETs, and its clinical role in the targeted delivery of radionuclides for imaging and therapy is well-established. Despite the availability of treatment options that include somatostatin analogs, targeted therapies, and peptide receptor radionuclide therapy (PRRT), advanced NETs inevitably progress and are universally incurable and life-limiting. There is a need in the art for improved means and methods which allow for a targeted treatment of cancer, in particular cancers that express PSMA and SSTR2. SUMMARY OF THE INVENTION According to the present invention this object is solved by a conjugate compound comprising a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof. According to the present invention this object is solved by a pharmaceutical composition comprising at least one conjugate compound of the present invention and optionally pharmaceutically acceptable carrier and/or excipient(s). According to the present invention this object is solved by providing the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to, wherein said cells are preferably tumor cells. According to the present invention this object is solved by providing the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors. According to the present invention this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in medicine. According to the present invention this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in the treatment of cancer. According to the present invention this object is solved by providing the conjugate compound of the present invention or the pharmaceutical composition of the present invention for use in patient selection. According to the present invention this object is solved by a method of treatment of cancer comprising the administration of a therapeutically effective amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient. According to the present invention this object is solved by a method of patient selection comprising the administration of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient and performing molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION Before the present invention is described in more detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For the purpose of the present invention, all references cited herein are incorporated by reference in their entireties. Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "1 to 21" should be interpreted to include not only the explicitly recited values of 1 to 21, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 1, 2, 3, 4, 5 ….17, 18, 19, 20, 21 and sub-ranges such as from 2 to 10, 8 to 15, etc. This same principle applies to ranges reciting only one numerical value, such as "at least 90%". Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. Conjugate compounds As outlined above, the present invention provides a conjugate compound. The conjugate compound of the present invention comprises a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof. - disease-targeting moiety (T) The disease-targeting moiety (T) preferably comprises a peptide or small molecule, which internalizes upon binding to a cell surface biomarker. The term “peptides” as used herein refer to peptides comprising natural and/or non-natural amino acids, L- and/or D-amino acids as well as peptidomimetics. Said peptide or small molecule preferably targets the prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8-integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R). Examples of such peptides or small molecules are - urea derivatives targeting prostate specific membrane antigen (PSMA), - somatostatin analogs (SSTR), - bombesin analogs (GRPR), - ligands for CXCR4, - RGD-motif containing peptides (αvβ6, αvβ8, α5β1 or αvβ1 integrins), - folic acid analogs, - neurotensin analogs and/or - melanocortin analogs. In one embodiment, the disease-targeting moiety (T) comprises monomers or multimers. The disease-targeting moiety (T) can comprise further component(s). Said further component(s) can be additional structural components to optimize the pharmacokinetic properties of the disease-targeting moiety, including but not limited to PEG linker(s), albumin-binding domain(s), amino acid(s) or amino acid sequence(s) and/or peptidomimetics. In one embodiment, the disease-targeting moiety (i) targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad). In one embodiment, the disease-targeting moiety (i) targets somatostatin receptor (SSTR), preferably SSTR2. The disease-targeting moiety (i) preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics. TOC is an octreotide analog (Tyr3-octreotide) having/consisting of the amino acid sequence D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr(ol) [SEQ ID NO.15]. It is preferably a peptide comprising a cyclic part: D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Thr- Cys]-Thr(ol). TOC binds to somatostatin receptors which are overexpressed on the surface of tumor cells, in particular of neuroendocrine tumors (NET). TATE is an octreotate or octreotide acid analog (Tyr3-octreotate) having/consisting of the amino acid sequence D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH [SEQ ID NO.16]. It is preferably a peptide comprising a cyclic part: D-Phe-cyclo[Cys-Tyr-D-Trp-Lys-Thr- Cys]-Thr-OH. TATE binds to somatostatin receptors which are overexpressed on the surface of tumor cells, in particular of neuroendocrine tumors (NET). - PARP inhibitor moiety (P) Preferably, the PARP inhibitor moiety (P) comprises or consists of rucaparib, olaparib, talazoparib, niraparib or analogs thereof. An analog refers to a PARP inhibitor moiety (P) that has been modified for conjugation and/or cleavage. For example, the PARP inhibitor moiety (P) can comprise parts of the cleavable bond, such as a thiol group after cleavage. In some embodiments, the conjugate compounds comprise two or more PARP inhibitor moieties (P), such as 2 or 3. In some embodiments, the PARP inhibitor moiety (P) can be connected via an anchor unit (A), such as a lysine or cysteine, to the conjugate compound. Thereby, the PARP inhibitor moiety (P) is preferably connected via the cleavable linker (X) to said anchor unit (A). - cleavable linker (X) The PARP moiety (P) is preferably connected via the cleavable linker (X) to the conjugate compound. The cleavable linker (X) allows intracellular or extracellular release of the PARP moiety (P) upon enzymatic cleavage or redox reaction. The cleavable linker (X) preferably comprises a substrate for enzyme cleavage or redox reaction. Examples for such substrates are a substrate for substrate for prostate specific antigen (PSA), caspases or cathepsins or proteases or peptidases or for the antioxidant glutathione. Examples for cathepsin B linker are valine-citrulline-p-aminobenzyloxycarbonyl (PABC) and valine-alanine-PABC. Preferably, the conjugate compounds of the present invention selectively deliver PARP inhibitor(s) to target-positive cells, such as PSMA-positive tumor cells or SSTR-expressing tumor cells. The cleavable linker is preferably cleaved intracellularly, i.e. after uptake of the conjugate compound into the target tumor cell, thereby releasing the PARP inhibitor. In the embodiment where the cleavable linker comprises a disulfide bridge, the cleavage is carried out intracellularly by glutathione (GSH) for release of the PARP inhibitor(s). Thus, the conjugate compounds of the present invention serve as vehicles for the specific delivery of the PARP inhibitor(s) to target-expressing cells, such as PSMA-positive or SSTR- expressing cells, in particular tumor-targeted delivery of PARP inhibitor(s). - Chelating agent (C) The conjugate compound preferably comprises a chelating agent (C). In one embodiment, the chelating agent (C) is a macrocyclic chelator or a non-cyclic chelating agent. Preferred examples of macrocyclic chelators are: 1,4,7,10-tetraazacyclododecane (cyclen), 2-(7-(4-aminobutyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)pentanedioic acid (MMC), 2,2',2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (DOTAGA), 2,2',2",2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 2,2',2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 2-[1,4,7-triazacyclononan-1-yl-4,7-bis(tBu-ester)]-1,5-pentanedioic acid (NODAGA), 1,4,7,10-tetraazacyclo- dodecane-1,4,7,10-tetrakis[methylene(2- carboxyethyl)phosphinic acid] (DOTPI), N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid monohydrochloride (HBED), N,N’-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid (HBED-CC), 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), 3,3′,3”-(((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(hydroxyphosphoryl)) tripropanoic acid (TRAP), 3-(((4,7-bis((hydroxy(hydroxymethyl)phosphoryl)methyl)-1,4,7-triazonan-1- yl)methyl)(hydroxy)phosphoryl)propanoic acid (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), and ethylenediaminetetraacetic acid (EDTA), and derivatives thereof. The chelating agent (C) is preferably selected from the group consisting of cyclen, MMC, DOTAGA, DOTA, NOTA, NODAGA, DOTPI, HBED, HBED-CC, DOTAM, TRAP, NOPO, PCTA and EDTA and derivatives thereof. The chelating agent (C) can comprise or contain a radionuclide. The radionuclide is preferably selected from 44Sc, 45Ti, 47Sc, 59Fe, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 89Sr, 90Y, 94mTc, 99mTc, 111In, 149Pm, 153Gd, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 203Pb, 211At, 212Bi, 212Pb or 225Ac. In a preferred embodiment, the conjugate compound of the present invention has the general formula (I) or (II) wherein T is said disease-targeting moiety, as defined herein, S is a functional spacer, m is 0 or 1, C is said chelating agent, as defined herein, n is 0 or 1, A is an anchor unit, such as lysine or cysteine, X is said cleavable linker, as defined herein, P is said PARP inhibitor moiety, as defined herein, o is at least 1, preferably 1, 2 or 3, or a salt, solvate or tautomer thereof. The conjugate compounds with general formula I have a linear structure. The conjugate compounds with general formula II have a branched structure. - Functional spacer (S) Preferably the functional spacer (S) comprises at least two amino acids or amino acid derivatives, preferably non-natural amino acids, such as aminohexanoic acid (Ahx), naphthylalanine (Nal), trans-4- (aminomethyl)-cyclohexanecarboxylic acid (TXA), D-amino acids, such as D-phenylalanine, D-tyrosine, D-aspartic acid, D-lysine, β-amino acids, such as β-alanine (βA), and combinations thereof, and/or the functional spacer (S) comprises polyethylenglycol (PEG), preferably (PEG)n wherein n is 1 to 24. In a preferred embodiment the functional spacer is (PEG)n wherein n is 4. The functional spacer (S) can comprise 2 to 10 amino acids or amino acid derivatives, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10. The functional spacer (S) preferably comprises or consists of an amino acid sequence selected from TXA-L-Nal, D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.1], D-Lys-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.2], D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.3], D-Lys-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.4], D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.5], D-Asp-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.6], D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.7], D-Lys-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.8], D-Lys-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys [SEQ ID NO.9], D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.10], D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.11], D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.12], D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx, [SEQ ID NO.13], and D-Lys(D-Lys)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.14]. In one embodiment, conjugate compound of the present invention has a linear structure and has the general formula (I) wherein, preferably, T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined herein above, n is 1 and C is as defined herein above, X comprises a substrate for glutathione. Preferably, the conjugate compounds of general formula I have one of the following structures PSMARuc-14: Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-KuE (Ruc-SS-MMC – SEQ ID NO.6 – KUE), PSMARuc-15: Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (Ruc-SS-MMC – SEQ ID NO.7 – KUE), or PSMARuc-18: Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE (Ruc-SS-MMC – SEQ ID NO.10 – KUE), or a salt, solvate or tautomer thereof. PSMARuc-14: (((1S)-5-((2S)-2-((1R,4S)-4-((3-((2R)-2-((2R)-2-(4-(4,10-bis(carboxymethyl)- 7-(4-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4-carboxybutanamido)-3-carboxypropanamido)-3- carboxypropanamido)propanamido)methyl)cyclohexane-1-carboxamido)-3-(naphthalen-2- yl)propanamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid PSMARuc-15: (3S,7S,28R,31R,34R,37R,40R)-28,31-dibenzyl-45-(4,10-bis(carboxymethyl)- 7-(4-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-1,4,7,10- tetraazacyclododecan-1-yl)-37,40-bis(carboxymethyl)-34-(4-hydroxybenzyl)- 5,13,20,27,30,33,36,39,42-nonaoxo-4,6,12,19,26,29,32,35,38,41-decaazapentatetracontane- 1,3,7,45-tetracarboxylic acid, PSMARuc-18: (3S,10R,15S,19S)-1-((1R,4S)-4-((8R,11R)-16-(4,10-bis(carboxymethyl)-7- (4-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-1,4,7,10- tetraazacyclododecan-1-yl)-16-carboxy-8,11-bis(carboxymethyl)-3,7,10,13-tetraoxo-2,6,9,12- tetraazahexadecyl)cyclohexyl)-3-(naphthalen-2-ylmethyl)-1,4,12,17-tetraoxo-2,5,11,16,18- pentaazahenicosane-10,15,19,21-tetracarboxylic acid. In one embodiment conjugate compound of the present invention has a branched structure and has the general formula (II) wherein, preferably, T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined herein above, n is 1 and C is as defined herein above, X comprises a substrate for glutathione. Preferably, the conjugate compounds of general formula II have one of the following structures PSMARuc-9: DOTAGA-D-Lys(Ruc-SS)-D-Asp-β-Ala-TXA-L-Nal-KuE (DOTAGA – SEQ ID NO.2 – KuE, wherein Lys of SEQ ID NO.2 has Ruc-SS attached), PSMARuc-10: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA – SEQ ID NO.3 – KuE, wherein Lys of SEQ ID NO.3 has Ruc-SS attached), PSMARuc-11: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA – SEQ ID NO.4 – KuE, wherein Lys of SEQ ID NO.4 has Ruc-SS attached), PSMARuc-12: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (DOTAGA – SEQ ID NO.5 – KuE, wherein Lys of SEQ ID NO.2 has Ruc-SS attached), PSMARuc-16: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, (DOTAGA – SEQ ID NO.8 – EuE, wherein the first Lys of SEQ ID NO.8 has Ruc-SS attached), PSMARuc-17: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys- EuE (DOTAGA – SEQ ID NO.9 – EuE, wherein the first Lys of SEQ ID NO.9 has Ruc-SS attached), PSMARuc2-10 (10Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D- Phe-Ahx-KuE (DOTAGA – SEQ ID NO.11 – KuE, wherein the D-Lys(D-Lys) of SEQ ID NO.11 each have Ruc-SS attached), PSMARuc2-11 (11Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-L- Nal-Ahx-KuE (DOTAGA – SEQ ID NO.12 – KuE, wherein the D-Lys(D-Lys) of SEQ ID NO.12 each have Ruc-SS attached), PSMARuc2-12 (12Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D- Phe-Ahx-Ahx-KuE (DOTAGA – SEQ ID NO.13 – KuE, wherein the D-Lys(D-Lys) of SEQ ID NO.13 each have Ruc-SS attached), PSMARuc2-16 (16Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-β-Ala-TXA-L- Nal-D-Lys-EuE (DOTAGA – SEQ ID NO.14 – EuE, wherein the D-Lys(D-Lys) of SEQ ID NO.14 each have Ruc-SS attached), or PSMARuc2-17 (17Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D- Phe-Ahx-D-Lys-EuE (DOTAGA – SEQ ID NO.11 – EuE, wherein the D-Lys(D-Lys) of SEQ ID NO.11 each have Ruc-SS attached), or a salt, solvate or tautomer thereof. PSMARuc-9: (((1S)-1-carboxy-5-((2S)-2-(4-((3-((2R)-3-carboxy-2-((2R)-2-(4-carboxy-4- (4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)-6-(3-((3-((4-(8- fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3- oxopropyl)disulfaneyl)propanamido)hexanamido)propanamido)propanamido)methyl)cyclohe xane-1-carboxamido)-3-(naphthalen-2-yl)propanamido)pentyl)carbamoyl)-L-glutamic acid, PSMARuc-10: (3S,7S,21R,24R,27R,30R,33R)-21,24-dibenzyl-30-(carboxymethyl)-33-(4-(3- ((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-27-(4- hydroxybenzyl)-5,13,20,23,26,29,32,35-octaoxo-38-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,12,19,22,25,28,31,34-nonaazaoctatriacontane-1,3,7,38- tetracarboxylic acid, PSMARuc-11: (3S,7S,21S,24R,27R,30R,33R)-24-benzyl-30-(carboxymethyl)-33-(4-(3-((3- ((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-27-(4- hydroxybenzyl)-21-(naphthalen-2-ylmethyl)-5,13,20,23,26,29,32,35-octaoxo-38-(4,7,10- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-4,6,12,19,22,25,28,31,34- nonaazaoctatriacontane-1,3,7,38-tetracarboxylic acid, PSMARuc-12: (3S,7S,28R,31R,34R,37R,40R)-28,31-dibenzyl-37-(carboxymethyl)-40-(4-(3- ((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-34-(4- hydroxybenzyl)-5,13,20,27,30,33,36,39,42-nonaoxo-45-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,12,19,26,29,32,35,38,41-decaazapentatetracontane-1,3,7,45- tetracarboxylic acid, PSMARuc-16: (3S,10R,15S,19S)-1-(4-((16R,19R,22R)-16-(4-carboxy-4-(4,7,10- tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)-19,22- bis(carboxymethyl)-1-(4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)phenyl)-2-methyl-3,10,17,20,23,27-hexaoxo-6,7-dithia-2,11,18,21,24,28- hexaazanonacosan-29-yl)cyclohexyl)-3-(naphthalen-2-ylmethyl)-1,4,12,17-tetraoxo- 2,5,11,16,18-pentaazahenicosane-10,15,19,21-tetracarboxylic acid, PSMARuc-17: (3S,7S,12R,26R,29R,32R,35R,38R,41R)-26,29-dibenzyl-35,38- bis(carboxymethyl)-41-(4-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3- cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)butyl)-32-(4- hydroxybenzyl)-5,10,18,25,28,31,34,37,40,43-decaoxo-46-(4,7,10-tris(carboxymethyl)- 1,4,7,10-tetraazacyclododecan-1-yl)-4,6,11,17,24,27,30,33,36,39,42- undecaazahexatetracontane-1,3,7,12,46-pentacarboxylic acid, PSMARuc2-10 (10Lys): (3S,7S,21R,24R,27R,30R,33R,36R)-21,24-dibenzyl-30,33- bis(carboxymethyl)-36-((R)-16-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H- azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)- 1-(4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl- 3,10,17-trioxo-6,7-dithia-2,11,18-triazadocosan-22-yl)-27-(4-hydroxybenzyl)- 5,13,20,23,26,29,32,35,38-nonaoxo-41-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,12,19,22,25,28,31,34,37-decaazahentetracontane-1,3,7,41- tetracarboxylic acid, PSMARuc2-11 (11Lys): (3S,7S,21R,24R,27R,30R,33R,36R)-24-benzyl-30,33- bis(carboxymethyl)-36-((R)-16-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H- azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)- 1-(4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl- 3,10,17-trioxo-6,7-dithia-2,11,18-triazadocosan-22-yl)-27-(4-hydroxybenzyl)-21-(naphthalen- 2-ylmethyl)-5,13,20,23,26,29,32,35,38-nonaoxo-41-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,12,19,22,25,28,31,34,37-decaazahentetracontane-1,3,7,41- tetracarboxylic acid, PSMARuc2-12 (12Lys): (3S,7S,28R,31R,34R,37R,40R,43R)-28,31-dibenzyl-37,40- bis(carboxymethyl)-43-((R)-16-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H- azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)- 1-(4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl- 3,10,17-trioxo-6,7-dithia-2,11,18-triazadocosan-22-yl)-34-(4-hydroxybenzyl)- 5,13,20,27,30,33,36,39,42,45-decaoxo-48-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,12,19,26,29,32,35,38,41,44-undecaazaoctatetracontane- 1,3,7,48-tetracarboxylic acid, PSMARuc2-16 (16Lys): (3S,10R,15S,19S)-1-((1R,4S)-4-((16R,23R,26R,29R)-23-(4- carboxy-4-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)butanamido)- 26,29-bis(carboxymethyl)-16-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3- cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)-1-(4-(8-fluoro- 1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl- 3,10,17,24,27,30,34-heptaoxo-6,7-dithia-2,11,18,25,28,31,35-heptaazahexatriacontan-36- yl)cyclohexyl)-3-(naphthalen-2-ylmethyl)-1,4,12,17-tetraoxo-2,5,11,16,18- pentaazahenicosane-10,15,19,21-tetracarboxylic acid, PSMARuc2-17 (17Lys): (3S,7S,12R,26R,29R,32R,35R,38R,41R)-26,29-dibenzyl-35,38- bis(carboxymethyl)-41-((R)-16-(3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H- azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)- 1-(4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl- 3,10,17-trioxo-6,7-dithia-2,11,18-triazadocosan-22-yl)-32-(4-hydroxybenzyl)- 5,10,18,25,28,31,34,37,40,43-decaoxo-46-(4,7,10-tris(carboxymethyl)-1,4,7,10- tetraazacyclododecan-1-yl)-4,6,11,17,24,27,30,33,36,39,42-undecaazahexatetracontane- 1,3,7,12,46-pentacarboxylic acid. In one embodiment, conjugate compound of the present invention has a linear structure and has the general formula (I) wherein, preferably, T targets SSTR, such as SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics, P comprises or consists of rucaparib and o is 1, m is 0, n is 1 and C is as defined herein above, X comprises a substrate for glutathione. Preferably, the conjugate compounds of general formula I have one of the following structures: Ruc-SS-MMC-TOC (Ruc-SS-MMC – SEQ ID NO.15) or Ruc-SS-(PEG)4-MMC-TOC (Ruc-SS-(PEG)4-MMC – SEQ ID NO.15) or Ruc-SS-MMC-TATE (Ruc-SS-MMC – SEQ ID NO.16) or Ruc-SS-(PEG)4-MMC-TATE (Ruc-SS-(PEG)4-MMC – SEQ ID NO.15) or a salt, solvate or tautomer thereof. Ruc-SS-MMC-TOC: 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3- yl)methyl)-10-(4-aminobutyl)-4-(((2S,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-16-(4- hydroxybenzyl)-7-((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(3-(3- ((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)propanoyl)-1,4,7,10- tetraazacyclododecane-1,7-diyl)diacetic acid, Ruc-SS-(PEG)4-MMC-TOC: 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol- 3-yl)methyl)-10-(4-aminobutyl)-4-(((2S,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-16-(4- hydroxybenzyl)-7-((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(1-(4- (8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl-3,10,26- trioxo-14,17,20,23-tetraoxa-6,7-dithia-2,11,27-triazatriacontan-30-oyl)-1,4,7,10- tetraazacyclododecane-1,7-diyl)diacetic acid, Ruc-SS-MMC-TATE: 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3- yl)methyl)-10-(4-aminobutyl)-4-(((1R,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4- hydroxybenzyl)-7-((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(3-(3- ((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5- yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanamido)propanoyl)-1,4,7,10- tetraazacyclododecane-1,7-diyl)diacetic acid, Ruc-SS-(PEG)4-MMC-TATE: 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H- indol-3-yl)methyl)-10-(4-aminobutyl)-4-(((1R,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)- 16-(4-hydroxybenzyl)-7-((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentaazacycloicosan-19-yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(1-(4- (8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl-3,10,26- trioxo-14,17,20,23-tetraoxa-6,7-dithia-2,11,27-triazatriacontan-30-oyl)-1,4,7,10- tetraazacyclododecane-1,7-diyl)diacetic acid. Pharmaceutical compositions and medical uses As outlined above, the present invention provides a pharmaceutical composition comprising at least one conjugate compound of the present invention and, optionally, pharmaceutically acceptable carrier and/or excipient(s). The pharmaceutical compositions according to the present invention are very well suited for all the uses and methods described herein. A "pharmaceutically acceptable carrier or excipient" refers to any vehicle wherein or with which the pharmaceutical compositions according to the invention may be formulated. It includes a saline solution such as phosphate buffer saline. In general, a diluent or carrier is selected based upon the mode and route of administration, and standard pharmaceutical practice. As outlined above, the present invention provides the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to. Said target cells are preferably tumor cells. As outlined above, the present invention provides the conjugate compound of the present invention as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA- positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors. Preferably, the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8- positive cells and tumors: has general formula I, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2. preferably having one of the following structures PSMARuc-14: Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-KuE, PSMARuc-15: Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, or PSMARuc-18: Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, or a salt, solvate or tautomer thereof. Preferably, the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8- positive cells and tumors: Has general formula II, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, preferably having one of the following structures PSMARuc-9: DOTAGA-D-Lys(Ruc-SS)-D-Asp-β-Ala-TXA-L-Nal-KuE, PSMARuc-10: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, PSMARuc-11: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE, PSMARuc-12: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, PSMARuc-16: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys- EuE, PSMARuc-17: DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D- Lys-EuE, PSMARuc2-10 (10Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D- Phe-D-Phe-Ahx-KuE, PSMARuc2-11 (11Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D- Phe-L-Nal-Ahx-KuE, PSMARuc2-12 (12Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D- Phe-D-Phe-Ahx-Ahx-KuE, PSMARuc2-16 (16Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-β-Ala- TXA-L-Nal-D-Lys-EuE, or PSMARuc2-17 (17Lys): DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D- Phe-D-Phe-Ahx-D-Lys-EuE, or a salt, solvate or tautomer thereof. Preferably, the conjugate compound as vehicle for the specific delivery of at least one PARP inhibitor moiety to SSTR-expressing cells and tumors: Has general formula I, wherein T targets SSTR, such as SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics,, P comprises or consists of rucaparib and o is 1. preferably having one of the following structures Ruc-SS-MMC-TOC or Ruc-SS-(PEG)4-MMC-TOC or Ruc-SS-MMC-TATE or Ruc-SS-(PEG)4-MMC-TATE or a salt, solvate or tautomer thereof. As outlined above, the present invention provides the compound or the pharmaceutical composition of the present invention for use in medicine. As outlined above, the present invention provides the compound or the pharmaceutical composition of the present invention for use in the treatment of cancer. The cancer to be treated is preferably - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8- integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor 1 (MC1R). A “PSMA-positive tumor” or “PSMA-expressing tumor” as used herein refers to a tumor that expresses PSMA as determined by standard of care clinical tests, including immunohistochemistry and a PSMA-PET or SPECT scan. A PSMA-positive tumor or cancer is preferably prostate cancer, such as castration sensitive metastatic prostate cancer (mCRPC), primary prostate cancer. “Tumors expressing the target” refers to all tumors in patients that have been tested positive for the respective target, preferably via histology or imaging. A “tumor expressing SSTR”, preferably SSTR2, as used herein refers to a tumor that expresses SSTR, preferably SSTR2, as determined by standard of care clinical tests, including immunohistochemistry of tumor tissue and nuclear medicine imaging procedures (e.g. [68Ga]Ga-DOTA-TATE PET scan). A tumor expressing SSTR, preferably SSTR2, is preferably neuroendocrine tumors (NET), gastroenteropancreatic NET (GEP-NET), small cell lung cancer, pituitary tumors, insulinomas, breast cancers and pancreatic cancers. Said tumors further include, but are not limited to: Target = GRPR: e.g. prostate cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, Target = CXCR4 (confirmed in 23 tumor types): e.g. hematological malignancy, breast cancer, colorectal cancer, esophageal cancer, renal cancer, gynecologic cancer, pancreatic cancer and liver cancer, Target = Avb6: epithelial cancers, e.g. pancreatic cancer, head and neck cancer , Target = Avb8: epithelial cancers, e.g. lung, brain, ovarian, endometrial, melanoma, breast, prostate, colon, skin, and stomach, Target = A5b1: e.g. oral squamous cell carcinoma and ovarian cancer, Target = Avb1: cancer-associated fibroblasts in various tumor types, Target = folate receptor: e.g. breast, cervical, colorectal, renal, nasopharyngeal, ovarian, and endometrial (in general epithelial cancers), Target = neurotensin-1: e.g. pancreatic, lung, breast, prostate cancers and colon cancer, Target = melanocortin-1: melanoma. For example, the cancer treatment can be several cycles of treatment, such as daily applications. Exemplary doses can be similar or lower than clinically used doses of PARPi. Preferred routes of administration are intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal. In a preferred embodiment, the use for cancer treatment is in combination with another therapy, preferably - - chemotherapy, - - hormonal therapy, such as hormonal therapy of mCRPC, - - immune-checkpoint blockade, - - DNA damage response (DDR) inhibiting agents, such as ATR/ATM inhibitors, AR targeting agents, DNA damaging agents, AKT inhibitors, - antiangiogenic agents, - tubulin inhibitors, such as MMAE (maytansine) and mertansine (DM1) or further conjugates of agents wherein the agents themselves are to toxic for systemic application (e.g. antibody-drug-conjugates), and/or - standard of care treatment. In case of chemotherapy or the use of a chemotherapeutic agent, a “chemotherapeutic agent” as used herein refers to all chemotherapeutic and cytotoxic agents comprising the clinically approved chemotherapeutic agents. In a preferred embodiment, the use for cancer treatment is in combination with external beam radiation therapy. In a preferred embodiment, the cancer treatment is in combination with endoradiotherapy, e.g. targeted radioligand therapy (RLT) or peptide receptor radiotherapy (PRRT), preferably comprising using therapeutic isotopes in RLT or PRRT agent(s), said therapeutic isotopes being selected from 47Sc, 67Cu, 67Ga, 89Sr, 90Y, 149Pm, 149Tb, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 211At, 212Bi, 212Pb or 225Ac in RLT or PRRT agents. For example, the conjugate compounds, not radiolabeled or cold-labeled (labeled with a stable isotope), can be given as single dose or treatment cycles, in combination with single or multiple cycles of endoradiotherapy (e.g. RLT or PRRT) with targeted alpha- or beta-emitting ligands. Preferably, both compounds have the same target, e.g. PSMA, SSTR2, or others. In the case of PSMA-targeted therapy, RLT could be treatment with PSMA-targeting ligands, such as [177Lu]-PSMA-617 or [177Lu]-rhPSMA, which are typically given in several cycles with intervals of six to eight weeks in between each application. In the case of SSTR2- targeted therapy, PRRT could be treatment with SSTR2-targetings ligands, such as [177Lu]- DOTA-TATE or [177Lu]-DOTA-LM3, which are typically given in several cycles with intervals of six to eight weeks in between each application. As outlined above, the present invention provides the compound or the pharmaceutical composition of the present invention for use in patient selection. Said use preferably comprises molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) with said compound or said pharmaceutical composition. “Patient selection” as used herein refers to the determination whether the patient will likely benefit from the treatment with a compound or pharmaceutical composition of the present invention. The procedure for “patient selection” will consist of administering a sub- pharmacologic dose of the radiolabeled form of the compound and confirming accumulation in tumors, preferably by PET or SPECT. Methods of treatment and patient selection As outlined above, the present invention provides a method of treatment of cancer comprising the administration of a therapeutically effective amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient. The cancer to be treated is preferably - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8- integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor 1 (MC1R). As discussed above, a “PSMA-positive tumor” or “PSMA-expressing tumor” as used herein refers to a tumor that expresses PSMA as determined by standard of care clinical tests, including immunohistochemistry and a PSMA-PET or SPECT scan. A PSMA-positive tumor or cancer is preferably prostate cancer, such as castration sensitive metastatic prostate cancer (mCRPC), primary prostate cancer. “Tumors expressing the target” refers to all tumors in patients that have been tested positive for the respective target, preferably via histology or imaging. A “tumor expressing SSTR”, preferably SSTR2, as used herein refers to a tumor that expresses SSTR, preferably SSTR2, as determined by standard of care clinical tests, including immunohistochemistry of tumor tissue and nuclear medicine imaging procedures, as discussed above. A tumor expressing SSTR, preferably SSTR2, is preferably neuroendocrine tumors (NET), gastroenteropancreatic NET (GEP-NET), small cell lung cancer, pituitary tumors, insulinomas, breast cancers and pancreatic cancers. Please see above for further exemplary tumors. For example, the cancer treatment can be several cycles of treatment, such as daily applications. Exemplary doses can be similar or lower than clinically used doses of PARPi. Preferred routes of administration are intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal. In a preferred embodiment, and as discussed above, the use for cancer treatment is in combination with another therapy, preferably - - chemotherapy, - - hormonal therapy, such as hormonal therapy of mCRPC, - - immune-checkpoint blockade, - - DNA damage response (DDR) inhibiting agents, such as ATR/ATM inhibitors, AR targeting agents, DNA damaging agents, AKT inhibitors, - antiangiogenic agents, - tubulin inhibitors, such as MMAE (maytansine) and mertansine (DM1) or further conjugates of agents wherein the agents themselves are to toxic for systemic application (e.g. antibody-drug-conjugates), and/or - standard of care treatment. In a preferred embodiment, the cancer treatment is in combination with external beam radiation therapy. In a preferred embodiment, the cancer treatment is in combination with targeted radioligand therapy (RLT) or peptide receptor radiotherapy (PRRT), preferably comprising using therapeutic isotopes in RLT or PRRT agent(s), said therapeutic isotopes being selected from 47Sc, 67Cu, 67Ga, 89Sr, 90Y, 149Pm, 149Tb, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 211At, 212Bi, 212Pb or 225Ac in RLT or PRRT agents. A “therapeutically effective amount” of a conjugate compound of the present invention refers to the amount which has to be administered to a subject in need thereof in order to achieve a desired therapeutic result or outcome. Therapeutically effective amounts and suitable administration regimen will be determined from preclinical and clinical studies designed by qualified medical personnel. For example, the conjugate compounds, not radiolabeled or cold-labelled (labelled with a stable isotope), can be given as single dose or treatment cycles, in combination with single or multiple cycles of endoradiotherapy (e.g. RLT or PRRT) with targeted alpha- or beta-emitting ligands. Preferably, both compounds have the same target, e.g. PSMA, SSTR2, or others. In the case of PSMA-targeted therapy, RLT could be treatment with PSMA-targeting ligands, such as [177Lu]-PSMA-617 or [177Lu]-rhPSMA, which are typically given in several cycles with intervals of six to eight weeks in between each application. In the case of SSTR2- targeted therapy, PRRT could be treatment with SSTR2-targetings ligands, such as [177Lu]- DOTA-TATE or [177Lu]-DOTA-LM3, which are typically given in several cycles with intervals of six to eight weeks in between each application. As outlined above, the present invention provides a method of patient selection comprising the administration of a sub-pharmacologic amount of a conjugate compound or pharmaceutical composition of the present invention to a cancer patient and performing molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Further description of preferred embodiments 1) PARP inhibitors as mono- and combination therapy agents in prostate cancer. Inhibitors of the DNA repair enzyme Poly(ADP-ribose)Polymerase 1/2 (PARP) have been approved for treatment of numerous indications in patients with breast, ovarian, pancreatic and prostate cancer, among others. Currently, 4 PARPi are FDA and/or EMA approved, namely Olaparib, Rucaparib, Talazoparib and Niraparib (Deeks 2015; Syed 2017; Hoy 2018). Olaparib and Rucaparib (Ruc), have recently been approved for the treatment of mCRPC patients (Deeks, 2015 and Syed, 2017). Patient eligibility is based on mutations in the DNA damage repair machinery, i.e. the presence of homologous recombination deficiencies (HRD). HRD in combination with pharmacological PARP inhibition leads to synthetic lethality in the absence of functional DNA repair pathways. In the TRITON2 trial (NCT02952534) that led to the accelerated FDA approval of Ruc, 44% of patients showed an objective response, including a small number of patients with complete response and 30-40% with a partial response (Abida et al., 2020). Both PARP inhibitors (PARPi) are approved as monotherapy agents in PC patients with BRCA1/2 mutations. Olaparib treatment is also approved for 12 other HRD gene alterations, including ATM and PALB2. Although up to 25% of PC patients exhibit HRD gene alterations, only around 5% have BRCA1/2 mutations, which seem to be associated with more consistent and durable responses than other HRD gene alterations. In order to extend the promising anti-tumor activity of PARPi to PC patients without HRD, the interest in creating a synthetic lethality phenotype in non-HRD/BRCA-functional patients by combining PARPi with other drugs emerged. Hence, almost in parallel to the approval of monotherapy, clinical studies were initiated to explore the potential of PARPi in combination with other PC therapies. Currently, over a dozen clinical trials are ongoing combining PARPi with temozolomide, AR-targeting, immunotherapy, irradiation and radionuclide therapy (Antonorakis et al., 2020; Nizialek et al., 2020; Pezaro 2020; Virtanen et al., 2019). Several trials include both patients with and without HRD alterations. Importantly, preclinical studies have already shown that combination therapies can be effective in tumors without an HRD phenotype, supporting the concept that synthetic lethality can be induced by drug combinations. Similar findings in the clinic would extend the benefits of PARPi combination treatment to an even larger number of PC patients and could improve survival rates. However, early clinical evidence indicates significant systemic toxicity associated with combinatorial dosing regimens, often requiring dose reductions and leading to more severe adverse events than use of either monotherapy alone (Rajan et al., 2012; Takebe et al., 2019). Strategies that improve the tolerability of combination therapy using PARPi would address an important clinical need in urologic oncology and allow continued clinical development of critically needed new therapies for PC. PSMA as a tumor-selective biomarker for PC therapy. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that has 100 to 1000-fold higher expression in PC cells compared to normal prostate epithelial cells. The vast majority of prostate cancers overexpress PSMA at the cell surface. Importantly, PSMA overexpression has been found to be even higher with increasing de-differentiation or castration-resistant disease, making it an attractive biomarker for targeted probe development (Ghosh et al., 2004). Indeed, a multitude of high-affinity, PSMA-directed small molecules have been translated into patients over the last decade. Increasingly, radiolabeled PSMA analogs (with gallium-68 (68Ga) or Fluorine-18) for positron emission tomography (PET) have been used for assessing tumor burden in patients with biochemical recurrence or advanced disease, staging of primary disease, and monitoring treatment response (Hoffmann et al., 2019; Fendler et al., 2019; Eiber et al., 2015; Fendler et al., 2016). Here, we disclose an innovative strategy that introduces selective delivery of PARP inhibitors to cells expressing tumor biomarkers (e.g. cell surface receptors). Ruc as an ideal agent for bioconjugate development and combination therapy of mCRPC. Among all FDA approved PARPi, namely Olaparib, Ruc, Veliparib and Talazoparib (Deeks 2015; Syed 2017; Hoy 2018), Ruc is the only one with an indole-based fluorochrome embedded in its structure, rendering it a potent anti-cancer drug and a biocompatible fluorophore at the same time (Kossatz et al., 2018). This allows direct imaging to track the delivery, target-engagement, distribution, and clearance of Ruc without the need of external labeling techniques (Figure 1). Thus, Ruc fluorescence can become integral in understanding and optimizing Ruc-based treatment strategies. In the present case, Ruc fluorescence allows to straightforwardly validate and monitor PSMA-dependent delivery of PARPi. PSMA-targeted radioligand therapy (RLT) for combination with Ruc. PSMA is also the target structure for PSMA-targeted 177Lu-RLT, which was recently granted breakthrough therapy designation by the FDA, after publication of the VISION trial data, which showed prolonged median overall survival (15.3 vs.11.3 months) in late stage mCRPC patients compared to standard therapy (Sartor et al., 2021). The VISION trial employed PSMA-617, a PSMA analog of particular importance because of its versatile drug design that provides 68Ga-PET and therapeutic utility with the same PSMA-targeting motif (Benesova et al., 2015; Fendler et al., 2017). Subsequently, 177Lu-PSMA-617 (“Pluvicto”) was FDA approved for treatment of metastatic castration-resistant prostate cancer on March 23rd, 2022 (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto- metastatic-castration-resistant-prostate-cancer). Other 177Lu-labelled PSMA-targeting agents are currently in phase III clinical evaluation. When used with the therapeutic, beta-emitting radionuclide, lutetium-177 (177Lu), precise systemic delivery of cytotoxic radiation to tumors is achieved (Heinzel et al., 2019; Yadav et al., 2019). Despite the immense potential of 177Lu- PSMA therapy, a significant subset of patients show a limited or no response, for reasons that are not well understood. The radiation produced by the ionizing beta particles of 177Lu result in both DNA single-strand breaks (SSB) and double-strand breaks (DSB), which are lethal if unrepaired. Therefore, the combination of RLT and PARPi can be an immensely powerful treatment to induce a synthetic lethality state, even in absence of HRD, which could benefit a much larger patient population than current PARPi treatment and lead to improved therapeutic outcomes compared to RLT alone. This invention produces a PC-targeted PARPi that can be used, e.g. to augment the antitumor effect of 177Lu-PSMA-617, which was also recently clinically approved by the FDA for treatment of mCRPC or other therapeutic agents (e.g. chemotherapy, external beam irradiation, hormonal therapy). Furthermore, the new conjugate compounds can substantially reduce the hematotoxicity of PARP inhibitors because PSMA is not expressed by hematopoietic cells. By eliminating or reducing the side effects of systemic PARP inhibition, tumor specific delivery of PARP inhibitors can facilitate the use of this therapy in earlier stages of prostate cancer, for example in combination with hormonal therapy of castration sensitive metastatic prostate cancer (mCRPC) or in combination with external beam radiotherapy of primary prostate cancer. This appears feasible because DNA repair defects are often present already at the time of prostate cancer diagnosis. Therefore, this invention leads not only to a more effective palliative radionuclide therapy of advanced mCRPC, but can also serve for novel treatment approaches that result in long-term remissions in mCRPC and increase the likelihood of cure for high-risk localized prostate cancer. Our invention centers on the development of a selective drug delivery system for PARPi to PC cells that express the prostate specific membrane antigen (PSMA). PSMA has already proven to be an effective cellular target for delivery of radioactive cargo for imaging and therapy. We disclose herein targeted drug conjugates that deliver a PARPi, e.g. Rucaparib (Ruc), to tumors via PSMA, thereby inducing PARP inhibition preferably in PSMA+ cells. Consequently, limiting PARP inhibition to PSMA+ cells should enable safe and effective combination therapies, e.g. with radioligand therapy and other PC treatment. Our invention is also highly suitable with respect to other tumor types, wherein said tumors in particular express the following targets: somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8-integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R). In these instances, conjugates of PARPi with molecules targeting the aforementioned targets will be employed alone or in combination with other therapeutic agents for the respective disease entities. Synthesis of PSMA-Ruc conjugates and their characterization We successfully synthesized a library of 18 PSMA-Ruc conjugates and examined their potential for PSMA-mediated Ruc delivery. As shown in Figure 2 and Table 1, the chemical composition of the conjugates include - PSMA-targeting vectors based on EuK and EuE urea analogs (Robu et al., 2018; Petrov et al., 2021; Kelly et al., 2017; Hensbergen et al., 2020), - different linkers for affinity/pharmacokinetic (PK) optimization, and - different chelators (DOTAGA or multimodality chelator (MMC), leading to branched or linear conjugates, respectively, that allow direct radiolabeling for quantitative assessment of binding and biodistribution. We also synthesized conjugates with 2 Rucaparib moieties (Figure 3C). The structures of all synthesized conjugates are shown in Table 1. Incorporation of a radiometal chelator into the bioconjugates allows to employ the same methodology used during preclinical development of 68Ga/177Lu-PSMA-617 (Umbricht et al., 2017; Umbricht et al., 2018). The conjugates also contain a cleavable disulfide linker that undergoes glutathione (GSH) mediated cleavage for cytoplasmic release of Ruc in target cells.
Using the radiolabeled PSMA-Ruc conjugates, we confirmed that most conjugates exhibited binding and internalization properties that were comparable to 68Ga-PSMA-617 (Figure 3A) and could be blocked in the presence of the known PSMA inhibitor, 2-PMPA (Yao and Bacich, 2006) (Figure 3B). Labelling with non-radioactive Ga allowed further characterization of binding and revealed excellent binding affinities in the low nanomolar range (IC50: 1 to <10 nM), similar to natGa-PSMA-617 (Table 2). Table 2: Summary of ligand characterization, including cell uptake, affinity (IC50) and logD- values. In a next step, we utilized the intrinsic fluorescence of Ruc to track its intracellular delivery as part of the PSMA-Ruc conjugates and translocation to the nucleus following cleavage of the disulfide bond by GSH. We observed that free Ruc localized in the cell nucleus of PSMA- expressing and non-expressing cells non-selectively, as expected. However, the Ruc-based fluorescence signal from PSMA-Ruc conjugates had a distinctly different localization pattern indicated by detection at the cell membrane (where PSMA is localized) and in the cell nucleus (where PARP1 is localized) of PC3-PIP cells (Figure 4A). No Ruc fluorescence was observed in PSMA-negative PC3-flu cells. Flow cytometry confirmed the microscopy findings and showed that incubation with PSMA-Ruc conjugates produced fluorescence only in PSMA- expressing cells, leading to an up to 40-fold higher Ruc accumulation in PC3-PIP compared to PC3-flu cells (Figure 4B). Conjugates with 2 Ruc-moieties (10Lys-17Lys) led to a higher amount of Ruc-related fluorescence than the corresponding single-Ruc variants, indicating that we can further increase the PSMA-dependent PARPi delivery of conjugates. We determined the serum stability of PSMA-Ruc conjugates to confirm that Ruc will not be released from the conjugates in vivo before reaching PSMA-expressing tumor cells (Figure 5A). In addition, we showed that exposure to GSH indeed lead to effective release of Ruc within a 30 min incubation period by analyzing the occurrence of intact conjugate and free rucparib (Figure 5B). PSMA-Ruc conjugates induce selective cytotoxicity in vitro We tested the effect of PSMA-Ruc conjugates on prostate cancer cell lines to determine if i) they have a similar potency as free Rucaparib and ii) they can induce this cytotoxicity selectively (Figure 6). We observed that free Ruc had similar cytotoxic effects on the cell viability in both PSMA+ (LNCaP) and PSMA- (PC3) cells, resulting in cell viability of 30-50% compared to untreated cells. In contrast, PSMA-Ruc conjugates only induced cytotoxic effects in PSMA+ cells, where the cell viability was 50-60% compared to untreated cells. In PSMA- negative cells, cell viability was >80% and similar to the untreated controls. Importantly, the non-cleavable control (conjugate 13), did not show cytotoxic effects in PSMA+ cells, demonstrating the need for intracellular release of Ruc to exert cytotoxic effects. Hence, PSMA-Ruc conjugates showed PSMA-selective cytotoxicity, while free Ruc did not. Differences in potency of monotherapies potentially arise from saturation of PSMA at the high concentrations of Ruc needed to exert cytotoxic effects in monotherapy. PSMA-Ruc in combination with 177Lu-PSMA treatment in vitro. We also tested the PSMA-Ruc conjugates in combination therapy with 177Lu-PSMA RLT to explore its radiosensitization potential in comparison to Ruc. Here, we used a low concentration of Ruc (1 µM; compared to 20 µM for mono-treatment) alone and in combination with 177Lu-PSMA RLT (0.1875 MBq/well). We tested the treatment combination in two PSMA-positive (LNCaP, C42) and PSMA-negative (DU145, PC3) cell lines, to explore the PSMA-specificity of the observed effects. Figure 7 shows an example of the combination therapy effects of conjugate 15, which shows strongly synergistic cytotoxicity in a PSMA-dependent manner. Combination with free Rucaparib showed similar synergistic cytotoxic effects, but was not PSMA-dependent. We subsequently analyzed the synergistic cytotoxicity in 3 PSMA-positive (LNCaP, C42, PC3-PiP) and 2 PSMA-negative (PC3, DU145) cell lines (Figure 8). Hereby, we defined synergistic cytotoxicity as a viability lower than treatment with RLT only and lower than 50% compared to vehicle treated cells at the end of the 72h treatment period. In LNCaP cells, which have high PSMA expression and the highest degree of HRD (and should therefore be sensitive to PARP inhibition), all conjugates exhibited synergistic cytoxicity comparable or stronger than Ruc + RLT. In C42 cells, 6 conjugates exhibited synergistic cytotoxicity and in PC3-PiP cells 7 exhibited synergistic cytotoxicity. Conjugates 11, 12, 14, 15 and 18 showed synergistic cytotoxicity in all PSMA- positive cell lines, as did Ruc + RLT. In the PSMA-negative cell lines, none of the conjugates showed synergistic cytoxicity, while Ruc+RLT showed synergistic cytoxicity in PC3 cells, despite the absence of PSMA. The non-cleavable control (referred to as 13 or 13-NC) did not show synergistic cytotoxicity in any of the tested cell lines. PSMA-selective in vivo imaging using a PSMA-Ruc conjugate Based on in vitro data that identified PSMA-Ruc-11 as a promising agent for in vivo testing, we performed an imaging study with 68Ga-PSMA-Ruc-11 (Figure 9). We prepared the PC3- PIP/PC3-flu bilateral tumor model that is routinely used in proof-of-concept studies with PSMA-targeted agents (Chen et al., 2011; Banerjee et al., 2014; Harmatys et al., 2018; Ray Banerjee et al., 2016). PET/CT imaging revealed 68Ga-PSMA-Ruc-11 uptake in PSMA+ PC3-PIP tumors and no accumulation in PSMA- PC3-Flu tumors at 60 min p.i. (Figure 9A). These findings demonstrate retention of PSMA-targeting properties after payload conjugation. We also made the observation that the biodistribution profile of 68Ga-PSMA-Ruc-11 was similar to 68Ga-PSMA-617, with uptake limited to PSMA-expressing tumors and kidneys, and fundamentally different from the typical biodistribution of PARPi (e.g., 18F-Olaparib, Wilson et al.2019), which is characterized by low tumor uptake and high gut uptake. We subsequently also conducted an imaging and biodistribution study with 68Ga-PSMA-Ruc-9, 68Ga-PSMA-Ruc-16 and 68Ga-PSMA-Ruc-18 using the PC3-PIP/PC3-flu bilateral tumor model (Figure 10). Conjugates 16 and 18 showed selective uptake in PC3-PiP tumors and low uptake in PC3-Flu tumors and other organs, resulting in PiP:Flu ratios of >8 and PiP/muscle ratios >2560 min p.i. The selective accumulation of the PSMA-targeted Ruc conjugates in PSMA-expressing tumors could also be observed on PET/CT images (Figure 10B) and the full biodistribution data (Figure 10C). PSMA-Ruc conjugates with 2 Ruc moieties in combination with 177Lu-PSMA treatment in vitro We tested if conjugates containing two Ruc moieties can increase the cytotoxic effects of 177Lu-PSMA treatment (10Lys/PSMA-Ruc(2)-10, 11Lys/ PSMA-Ruc(2)-11, 12Lys/ PSMA- Ruc(2)-12, 16Lys/ PSMA-Ruc(2)-16 and 17Lys/ PSMA-Ruc(2)-17). We applied a sequential treatment scheme, where cells were first treated with [177Lu]Lu-PSMA I&T for 24 h (0.1875 MBq/well), and subsequently with the PSMA-Ruc(2)-ligand (1 µM). We tested the treatment combination in three PSMA-positive (LNCaP, C42, PC3-PiP) and PSMA-negative (DU145, PC3) cell lines (Figure 11). In the PSMA-negative cell lines, [177Lu]Lu-PSMA I&T treatment had no effect on cell viability as expected, and combination treatment with PSMA-Ruc(2)- ligands did not lead to additional cytotoxicity. Reduced viability was only observed in PC3 cells when [177Lu]Lu-PSMA I&T was combined with Rucaparib. In the PSMA-positive cell lines, PSMA-Ruc(2)-conjugate combination treatment led to decreased viability compared to [177Lu]Lu-PSMA I&T only treatment. Although the effect was moderate, it was stronger than for the combination with free Rucaparib in some instances (e.g. PSMA-Ruc(2)-12). SSTR2-targeting PARPi conjugates - rationale Neuroendocrine tumors (NETs) have an increasing incidence rate. Among NETs, well- differentiated neuroendocrine tumors are rare and the majority of patients are affected by metastasis, which complicates treatment. The somatostatin receptor type 2 (SSTR2) is often overexpressed in NETs, therefore it is already a clinically validated biomarker in most NETs. A selective delivery of PARPi e.g. rucaparib to SSTR2 expressing tumor cells via peptide-drug conjugates could trigger synthetic lethality through combination therapies only in the cancer cells, but not in healthy cells. Such an effective radiosensitizer would improve the therapeutic index of peptide receptor radionuclide therapy (PRRT) by maintaining potency with lower administered doses per cycle, and potentially extend the duration of treatment benefit. Accordingly, we used solid phase peptide synthesis to synthesize four SSTR2-targeted rucaparib conjugates (Ruc-TOC, Ruc-(PEG)4-TOC, Ruc-TATE and Ruc-(PEG)4-TATE), bearing a multimodality chelator (MMC) and a cleavable disulfide linker that undergoes GSH- mediated cleavage in the cytoplasm,. We examined the potential of the compounds for SSTR2- mediated Ruc-delivery via fluorescence microscopy in SSTR2-transfected HCT116 cell lines. Also, we tested the cytotoxic effect of the SSTR2-targeted Ruc conjugates on cell lines that endogenously express SSTR2 (e.g. H69). With the radiolabeled compounds, hydrophilicity (logD7.4) was investigated. Furthermore, we performed a first in vivo imaging study with [68Ga]Ga-Ruc-TOC and [68Ga]Ga-Ruc-(PEG)4-TATE in H69 tumor bearing mice. Ruc-SS-MMC-TOC 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4- aminobutyl)-4-(((2S,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-16-(4-hydroxybenzyl)-7-((S)- 1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19- yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(3-(3-((3-((4-(8-fluoro-1-oxo- 2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3- oxopropyl)disulfaneyl)propanamido)propanoyl)-1,4,7,10-tetraazacyclododecane-1,7- diyl)diacetic acid Ruc-SS-(PEG)4-MMC-TOC 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4- aminobutyl)-4-(((2S,3R)-1,3-dihydroxybutan-2-yl)carbamoyl)-16-(4-hydroxybenzyl)-7-((S)- 1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19- yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(1-(4-(8-fluoro-1-oxo-2,3,4,6- tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl-3,10,26-trioxo-14,17,20,23- tetraoxa-6,7-dithia-2,11,27-triazatriacontan-30-oyl)-1,4,7,10-tetraazacyclododecane-1,7- diyl)diacetic acid Ruc-SS-MMC-TATE 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4- aminobutyl)-4-(((1R,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-hydroxybenzyl)-7- ((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19- yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(3-(3-((3-((4-(8-fluoro-1-oxo- 2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)amino)-3- oxopropyl)disulfaneyl)propanamido)propanoyl)-1,4,7,10-tetraazacyclododecane-1,7- diyl)diacetic acid Ruc-SS-(PEG)4-MMC-TATE 2,2'-(4-(2-(((R)-1-(((4R,7S,10S,13R,16S,19R)-13-((1H-indol-3-yl)methyl)-10-(4- aminobutyl)-4-(((1R,2R)-1-carboxy-2-hydroxypropyl)carbamoyl)-16-(4-hydroxybenzyl)-7- ((S)-1-hydroxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-19- yl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-10-(1-(4-(8-fluoro-1-oxo-2,3,4,6- tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)phenyl)-2-methyl-3,10,26-trioxo-14,17,20,23- tetraoxa-6,7-dithia-2,11,27-triazatriacontan-30-oyl)-1,4,7,10-tetraazacyclododecane-1,7- diyl)diacetic acid In vitro experiments Fluorescence microscopy To track the intracellular rucaparib delivery and SSTR2 specificity of our SSTR2-targeted Ruc conjugates, we utilized the intrinsic fluorescence of rucaparib and performed fluorescence microscopy (see also Example 11). Ruc-TOC was internalized into HCT-116SSTR2 expressing cells, whereas it showed nearly no uptake in HCT-116 wildtype cells (Figure 13, first and second row). As a control, free Ruc (5 µM) was used and showed nuclear accumulation in both cell lines. When Ruc-TOC was co-administered with octreotide (500 µM), no Ruc signal was observed in the cells, indicating SSTR2-mediated uptake (Figure 13, last row): A similar experiment with Ruc-(PEG)4-TATE also showed SSTR2-specific uptake via fluorescence detection of Ruc (Figure 14). Viability assays (AlamarBlue) To investigate the cytotoxic effects of the Ruc conjugates, we performed viability assays with H69 cells (see also Example 11). Cells were treated for 72 h with 5 µM of either Ruc-TOC or Ruc-(PEG)4-TATE. After 72 h, cell viability was strongly reduced to 57.6 ± 27.1% (Ruc-TOC) and 18.2 ± 5 % (Ruc-(PEG)4-TATE) compared to untreated cells and cells containing 0.5% DMSO (vehicle) (Figure 15). These results suggest SSTR2-mediated delivery and cytotoxicity of Ruc-TOC and Ruc-(PEG)4-TATE, with more pronounced effects of the latter. Radioligand uptake assay To determine the SSTR2-mediated internalization, a radioactive uptake assay was performed (see Example 11). We measured the relative uptake of the compound at two different concentrations (0.6 nM or 6 nM) with and without octreotide blocking . After 1 h of incubation with [68Ga]Ga-Ruc-(PEG)4-TATE, a specific uptake of 3.95 % ± 1.76 % (6 nM ligand concentration) and 3.62 % ± 0.59 % (0.6 nM ligand concentration) was observed (Figure 16). These results reflect SSTR2-specific cell binding and internalization of [68Ga]Ga- Ruc-(PEG)4-TATE. In vivo experiments In vivo PET/MR imaging Athymic nude mice bearing subcutaneous H69 xenografts were intravenously injected with ca. 10 MBq of either [68Ga]Ga-Ruc-TOC and [68Ga]Ga-Ruc-(PEG)4-TATE and PET/MR imaging was carried out 45-60 min post injection using a Mediso nanoPET/MR scanner. Both compounds accumulated in the H69 tumors and allowed tumor visualization (Figure 17). After 60 min, we measured 2.2% ID/g of [68Ga]Ga-Ruc-TOC and 2.7% ID/g of [68Ga]Ga-Ruc- (PEG)4-TATE in the tumor. The compounds were excreted renally and showed kidney uptake of 3.7% ID/g for [68Ga]Ga-Ruc-TOC and 2.9% ID/g for [68Ga]Ga-Ruc-(PEG)4-TATE, respectively. Hence, [68Ga]Ga-Ruc-(PEG)4-TATE had a preferable tumor to kidney ratio of 0.9 over [68Ga]Ga-Ruc-TOC with 0.6. We also conducted a dynamic scan for 90 min following i.v. injection of [68Ga]Ga-Ruc-(PEG)4- TATE (Figure 18). Time–activity curves of tumor, heart, kidney and muscle showed a rapid clearance from the blood pool (heart) as well as rapid background clearance (muscle) and low non-specific accumulation. Renal excretion was characterized by a sharp peak 2 min post injection and subsequent clearance over time. Importantly, the tumoral accumulation of [68Ga]Ga-Ruc-(PEG)4-TATE was higher than blood pool within 20 min and showed a continuous increase over 90 min . Taken together, We successfully synthesized SSTR2-targeting conjugates containing the PARPi Rucaparib. We showed SSTR2-dependent uptake in vitro and in vivo and have observed efficient cell killing in cells. The data indicate that both conjugates are suitable for SSTR2- dependent delivery of PARPi to tumor cells with [68Ga]Ga-Ruc-(PEG)4-TATE having higher tumor uptake and more potent cell killing compared to [68Ga]Ga-Ruc-TOC.. Note that the present technology can also be configured as described in the following items. (1) A conjugate compound comprising a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof. (2) The conjugate compound of item (1), wherein the disease-targeting moiety (T) comprises a peptide or small molecule, which internalizes upon binding to a cell surface biomarker, wherein said peptide or small molecule preferably targets the prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8-integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R). (3) The conjugate compound of item (1) or (2), wherein the disease-targeting moiety (T) comprises monomers or multimers, and/or comprises further components, such as PEG linker(s), albumin-binding domain(s), further amino acid(s), and/or peptidomimetics. (4) The conjugate compound of any one of items (1) to (3), wherein the disease-targeting moiety (T) targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), or wherein the disease-targeting moiety (T) targets SSTR, preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics. (5) The conjugate compound of any one of items (1) to (4), wherein the PARP inhibitor moiety (P) comprises or consists of rucaparib, olaparib, talazoparib, niraparib or analogs thereof, and/or comprising two or more PARP inhibitor moieties (P), such as 2 or 3. (6) The conjugate compound of any one of the preceding items, wherein the cleavable linker (X) comprises a substrate for enzyme cleavage or redox reaction, such as a substrate for prostate specific antigen (PSA), caspases or cathepsins, proteases or peptidases, or for the antioxidant glutathione. (7) The conjugate compound of any one of the preceding items, wherein the chelating agent (C) is a macrocyclic chelator or a non-cyclic chelating agent, wherein the chelating agent (C) is preferably selected from the group consisting of 1,4,7,10-tetraazacyclododecane (cyclen), 2-(7-(4-aminobutyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)pentanedioic acid (MMC), 2,2',2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (DOTAGA), 2,2',2",2"′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 2,2',2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 2-[1,4,7-triazacyclononan-1-yl-4,7-bis(tBu-ester)]-1,5-pentanedioic acid (NODAGA), 1,4,7,10-tetraazacyclo- dodecane-1,4,7,10-tetrakis[methylene(2- carboxyethyl)phosphinic acid] (DOTPI), N,N’-Di(2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid monohydrochloride (HBED), N,N’-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid (HBED-CC), 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), 3,3′,3”-(((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(hydroxyphosphoryl)) tripropanoic acid (TRAP), 3-(((4,7-bis((hydroxy(hydroxymethyl)phosphoryl)methyl)-1,4,7-triazonan-1- yl)methyl)(hydroxy)phosphoryl)propanoic acid (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), and ethylenediaminetetraacetic acid (EDTA), and derivatives thereof, and/or wherein the chelating agent (C) comprises or contains a radionuclide, wherein the radionuclide is preferably selected from 44Sc, 45Ti, 47Sc, 59Fe, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 89Sr, 90Y, 94mTc, 99mTc, 111In, 149Pm, 153Gd, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 203Pb, 211At, 212Bi, 212Pb or 225Ac. (8) The conjugate compound of any one of the preceding items, having the general formula (I) or (II) wherein T is said disease-targeting moiety, S is a functional spacer, m is 0 or 1, C is said chelating agent, n is 0 or 1, A is an anchor unit, such as lysine or cysteine, X is said cleavable linker, P is said PARP inhibitor moiety o is at least 1, preferably 1, 2 or 3, or a salt, solvate or tautomer thereof. (9) The conjugate compound of item (8), wherein the functional spacer (S) comprises at least two amino acids or amino acid derivatives, preferably non-natural amino acids, such as aminohexanoic acid (Ahx), naphthylalanine (Nal), trans-4- (aminomethyl)-cyclohexanecarboxylic acid (TXA), D-amino acids, such as D-phenylalanine, D-tyrosine, D-aspartic acid, D-lysine, β-amino acids, such as β-alanine (βA), and combinations thereof, and/or wherein the functional spacer (S) comprises polyethylenglycol (PEG), preferably (PEG)n wherein n is 1 to 24, such as n is 4. (10) The conjugate compound of item (8) or (9), wherein the functional spacer (S) comprises or consists of an amino acid sequence selected from i. TXA-L-Nal, ii. D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.1], iii. D-Lys-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.2], iv. D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.3], v. D-Lys-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.4], vi. D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.5], vii. D-Asp-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.6], viii. D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.7], ix. D-Lys-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.8], x. D-Lys-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys [SEQ ID NO.9], xi. D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.10], xii. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.11], xiii. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.12], xiv. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx, [SEQ ID NO.13], and xv. D-Lys(D-Lys)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.14]. (11) The conjugate compound of any one of the preceding items, having general formula I, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined in items 9 and 10, n is 1 and C is as defined in item 7, X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-KuE, Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, or Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, or a salt, solvate or tautomer thereof. (12) The conjugate compound of any one of items (1) to (11), having general formula II, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined in items 9 and 10, n is 1 and C is as defined in item 7, X comprises a substrate for glutathione, preferably having one of the following structures DOTAGA-D-Lys(Ruc-SS)-D-Asp-β-Ala-TXA-L-Nal-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys-EuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, or DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys- EuE, or a salt, solvate or tautomer thereof. (13) The conjugate compound of any one of the preceding items, having general formula I, wherein T targets SSTR, preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics, P comprises or consists of rucaparib and o is 1, m is 0, n is 1 and C is as defined in item 7 X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-TOC, Ruc-SS-(PEG)4-MMC-TOC, Ruc-SS-MMC-TATE, Ruc-SS-(PEG)4-MMC-TATE, or a salt, solvate or tautomer thereof. (14) A pharmaceutical composition comprising at least one conjugate compound of any one of items (1) to (13) and, optionally, pharmaceutically acceptable carrier and/or excipient(s). (15) The compound of any one of items (1) to (13) as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to, wherein said cells are preferably tumor cells, preferably, as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors, or, preferably as vehicle for the specific delivery of at least one PARP inhibitor moiety to SSTR-expressing cells and tumors. (16) The compound of any one of items (1) to (13) or the pharmaceutical composition of item (14) for use in medicine. (17). The compound of any one of items (1) to (13) or the pharmaceutical composition of item (14) for use in the treatment of cancer, wherein, preferably, the cancer is - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6 integrin, αvβ8 integrin, α5β1 integrin, αvβ1 integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor 1 (MC1R), wherein the route of administration is preferably intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal. (18) The compound or pharmaceutical composition for use according to item (16) or (17), in combination with another therapy, preferably chemotherapy, hormonal therapy, immune-checkpoint blockade, DNA damage response (DDR) inhibiting agents, antiangiogenic agents, tubulin inhibitors, and/or standard of care treatment, and/or in combination with external beam radiation therapy, or in combination with endoradiotherapy, such as targeted radioligand therapy (RLT) or peptide receptor radiotherapy (PRRT), preferably comprising using therapeutic isotopes in endoradiotherapy agent(s), said therapeutic isotopes being selected from 47Sc, 67Cu, 67Ga, 89Sr, 90Y, 149Pm, 149Tb, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 211At, 212Bi, 212Pb or 225Ac, e.g. in RLT or PRRT agents. (19) The compound of any one of items (1) to (13) or the pharmaceutical composition of item (14) for use in patient selection, preferably comprising molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) with said compound or said pharmaceutical composition. The following examples and drawings illustrate the present invention without, however, limiting the same thereto. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Characteristics of the PARP inhibitor Rucaparib (Ruc). Ruc (A) is intrinsically fluorescent, which enables intracellular drug-tracking (B) and quantification, since fluorescence intensity is correlated with the Ruc concentration (C). MFI – mean fluorescence intensity. Figure 2. Design of the PSMA-Ruc conjugates of the invention. Design of linear (A) and branched (B) PSMA-Ruc conjugates and conjugates with two Ruc moieties (C). Figure 3. Characterization of PSMA-binding properties of PSMA-Ruc conjugates in LNCaP cells. Conjugates 9-13 are branched and 14-15 are linear. Conjugate 13 is a non-cleavable control. (A) Binding and internalization after 60 min incubation with 0.4 nM 68Ga-labelled conjugates. (B) Binding specificity was determined via PMPA blocking. Displayed are mean values of three biological replicates. Figure 4. PSMA-dependent delivery of Ruc via PSMA-Ruc conjugates. (A) After incubation with conjugate 11, only PSMA+ cells showed Ruc fluorescence at the membrane and in the cell nucleus, where PARP1 is located. Free Ruc showed non-selective uptake in PSMA+ and PSMA- cells. (B) Flow cytometry confirmed the PSMA-dependency of uptake of PSMA-Ruc conjugates. PC3-PIP or PC3-flu were incubated with 0.5 µM Ruc or PSMA-Ruc conjugate for 30 min before flow cytometry. NC – non-cleavable. Figure 5. Stability of PSMA-Ruc conjugates in serum and after GSH exposure. (A) After incubation in human serum, PSMA-Ruc conjugates remain largely stable (> 80%) for 2 h and were still >74% intact after 24 hours. PSMA-Ruc-9 and PSMA-Ruc-17 were highly stable for 1-2 h in serum, which provides sufficient time to reach the target site in vivo. The non-cleavable control 13 also remained stable (2 h: 94%, 24 h: 89%). (B) Exposure to GSH lead to effective release of Ruc. After 30 min of exposure 50-90% of the detected metabolites represented free Ruc. Figure 6. Cell viability after treatment of PSMA+ and PSMA- cells with Ruc, PSMA-Ruc conjugates or controls at 20 µM for 72h. Ruc: free Rucaparib, 7-12: branched PSMA-Ruc conjugates, 13: non-cleavable control, 14- 15: linear PSMA-Ruc conjugates. All cells were pretreated with 10 mM GSH and contained 0,2% DSMO. Figure 7. Cell viability in PSMA+ and PSMA- cell lines. Cells (PSMA+: LNCaP, C42; PSMA-: DU145, PC3) were treated for 72 h with 1 µM free Ruc, 1 µM Conj.15, 0.1875 MBq RLT(177Lu-PSMA-I&T) or the combination of both. Viability was assessed via Alamar Blue assay and calculated relative to untreated control. All samples (except untreated control) contained 10 mM GSH, 0,2% DSMO. PDC-peptide drug conjugate. Figure 8. Assessment of cytotoxicity of PSMA-Ruc conjugates with one Ruc moiety per ligand. Cells (PSMA+: LNCaP, C42, PC3-PiP; PSMA-: DU145, PC3) were treated for 72 h with 1 µM free Ruc, 1 µM Conj.15, 0.1875 MBq RLT(177Lu-PSMA-I&T) or the combination of both. Viability was assessed via Alamar Blue assay and calculated relative to the vehicle control (containing 10 mM GSH and 0,2% DMSO). NC-non-cleavable control. Synergistic cytotoxicity was defined as viability lower than RLT only (dotted line) and lower than 50% (solid line). Conditions with synergistic cytoxicity are represended by dotted bars. Figure 9. Proof-of-concept of PSMA-dependent Ruc delivery in vivo. PET (A) and biodistribution (B) data show specific PSMA-targeting of 68Ga-PSMA-Ruc-11, where uptake is limited to PSMA+ tumors and kidneys (n=3 mice).68Ga-PSMA-Ruc-11 showed no organ uptake other than kidneys, in contrast to free PARPi, e.g.18F-Olaparib, which shows high liver and gut uptake (see Wilson et al. (2019)). Figure 10. In vivo imaging and biodistribution data of several PSMA-Ruc conjugates in vivo. Tumor-to-organ ratios (A), PET (B, n=2 mice/group) and biodistribution (C, n=5 mice/group) data show specific PSMA-targeting for 68Ga-PSMA-Ruc-9, 68Ga-PSMA-Ruc-16 and 68Ga- PSMA-Ruc-18 where uptake is limited to PSMA+ tumors and kidneys at 1 h post-injection. Figure 11. Cell viability analysis of sequential combination treatment of [177Lu]Lu- PSMA I&T with PSMA-Ruc(2)-ligands. Cells (PSMA+: LNCaP, C42, PC3-PiP; PSMA-: DU145, PC3) were treated for 24 h with 0.1875 MBq RLT(177Lu-PSMA-I&T) followed by 1 h with 10 mM GSH and 47 h with medium (RLT only), 1 µM free Ruc or 1 µM PSMA-Ruc(2)-conjugate. Viability was assessed via Alamar Blue assay and calculated relative to untreated control, which contained 0.2 % DMSO. Figure 12. Inhibition of parylation by PSMA-Ruc conjugates. Parylation was measured using a cell-based ELISA kit (Cell BioLabs). PC3-PiP cells were incubated with 1 µM Ruc, Ruc-SH or PSMA-Ruc(2)-16 and parylation levels of cell lysates were determined via ELISA. Figure 13. SSTR2-specific cellular uptake of Ruc-TOC. First row: HCT-116 SSTR2 cells after treatment with Ruc-TOC (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay). Second row: HCT-116 WT cells after treatment with Ruc-TOC. (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay). Last row: HCT-116 SSTR2 cells after pre-treatment with octreotide for blocking and treatment with Ruc-TOC. (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay). Figure 14. SSTR2-specific cellular uptake of Ruc-PEG-(TATE)4. First row: HCT-116 SSTR2 cells after treatment with Ruc-(PEG)4-TATE (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay). Second row: HCT-116 SSTR2 cells after pre-treatment with octreotide for blocking and treatment with Ruc-(PEG)4-TATE (left: Cy5 channel (626-644 nm), middle: DAPI channel (335-377 nm), right: overlay). Figure 15. In vitro treatment of H69 cells Analysis of the viability of H69 cells after treatment with 5 µM Ruc-TOC or 5 µM Ruc- (PEG)4-TATE compared to untreated cells (medium only) and medium containing 0.5% DMSO (similar to DMSO concentration in treatment groups). Cell viability was determined via 10% AlamarBlueTM HS incubation at 37 °C for 3h and fluorescence measurement at 570 nm. Viability values were set relative to cell viability of untreated cells (Medium only). Figure 16. SSTR2-mediated internalization of [68Ga]Ga-Ruc-(PEG)4-TATE, shown as percentage of applied activity after incubation in H69 cells at 37 °C for 1 h. Blocking was performed with octreotide (10 µM). Figure 17. PET Imaging in H69 tumor bearing mice. Maximum intensity projection (MIP) of [68Ga]Ga-Ruc-TOC, [68Ga]-Ruc-(PEG)4-TATE and the clinical imaging standard [68Ga]-DOTA-TOC 45-60 min post injection shows accumulation in the H69 tumor in addition to kidney uptake and a high signal in the bladder, due to the excretion pattern of the ligand. %IA/g = percent injected activity per gram. Figure 18. Time-activity curves of select organs of [68Ga]-Ruc-(PEG)4-TATE. A) Time-activity curves from a 90 min dynamic PET scan after injection of 10 MBq [68Ga]- Ruc-(PEG)4-TATE . B) Representative MIPs at select time points from the dynamic dataset (n=1). %IA/g = percent injected activity per gram. EXAMPLES EXAMPLE 1 Synthesis of PSMA-Ruc conjugates and their characterization General information Chemical synthesis. For the reactions performed in this work, all protected amino acid analogs and coupling reagents were purchased from Carbolution Chemicals (St. Ingbert, Germany), Iris Biotech (Marktredwitz, Germany), Alfa Aesar (Karlsruhe, Germany) or Bachem (Bubendorf, Switzerland). The 2-chlorotrityl chloride (2-CTC) resin was obtained from Carbolution Chemicals. DOTAGA-anhydride was delivered by Chematech (Dijon, France). Rucaparib was obtained from Selleckchem (Berlin, Germany), and PSMA-617 from MedChemExpress (Sollentuna, Sweden), respectively. All solvents were purchased from Sigma-Aldrich (Munich, Germany), VWR (Darmstadt, Germany), Carl Roth (Karlsruhe, Germany) or Iris Biotech, of analytical, for synthesis, peptide or HPLC grade and used without further purification. Unless otherwise noted, all other used chemicals and reagents for the performed syntheses were obtained from Sigma-Aldrich, VWR, Merck (Darmstadt, Germany), abcr (Karlsruhe, Germany) or Alfa Aesar. Solid phase syntheses were performed in 20 mL plastic syringes from B. Braun, which were equipped with a frit from Roland Vetter Laborbedarf (Ammerbuch, Germany). By drawing up the syringe, reaction or wash solutions were added to the resin. Complete mixing was accomplished on a rotating unit. The equivalents (eq.) of amino acids were referred to the theoretical loading given by the manufacturer. Column chromatography was performed using a 100-fold excess of silica gel (40-63 µm grain size, Si 60, 230-400 mesh ASTM) from Merck at 1 bar overpressure. The respective eluent ratios were described in the experimental procedures. For detection of product fractions after column chromatography, thin- layer reaction controls (TLC) were performed on aluminum foils coated with silica gel 60 F254 obtained from Merck using different mixtures of organic solvents. The respective eluent ratios were described in the experimental procedures as well. Via UV absorption at 254 nm the substances were hereby detected. Semi-preparative reversed phase high-performance liquid chromatography (RP-HPLC) was realized on the following devices: a) Waters (Milford, USA) instrument including a Waters 2545 (Binary Gradient Module), Waters SFO (System Fluidics Organizer), Waters 2996 (Photodiode Array Detector), and Waters 2767 (Sample Manager), respectively. The applied flow rate was 40 mL/min. b) Shimadzu (Shimadzu Deutschland GmbH, Neufahrn, Germany) RP-HPLC system including a CBM-20A communications bus module, SPD-M20A prominence diode array detector, LC-20AP prominence preparative liquid chromatograph (for both pumps). The applied flow rate was 20 mL/min. As eluents linear gradients of water (H2O; with 0.1% (v/v) trifluoroacetic acid (TFA), buffer A) and acetonitrile (MeCN; with 0.1% (v/v) TFA, buffer B) were applied for the purification of all compounds using a C18-column (Reprosil 100 C18, 5 μm, 150 x 30 mm, Dr. Maisch, Ammerbuch-Entringen, Germany). The UV-detection was carried out at 220, and 254 nm, respectively. All final compounds were analyzed via electrospray ionization mass spectrometry (ESI-MS) coupled to an analytical RP-HPLC system (HPLC-ESI-MS) to confirm a purity of ≥95% (λ = 220 and 254 nm). Here, the LC-MS spectra were acquired on two devices: a) UltiMate 3000 UHPLC (Dionex, Sunnyvale, USA) equipped with a LCQ Fleet mass spectrometer (ThermoFisher Scientific, Waltham, USA) and two different C18 columns (Hypersil Gold aQ 175 Å, 3 μm, 150 mm × 2.1 mm or Accucore C18, 80 Å, 2.6 μm, 50 x 2.1 mm, constant flow 0.9 mL/min) from Thermo Scientific. b) Shimadzu RP-HPLC system (DGU-20A3 prominence degasser, LC-30AD Nexera liquid chromatograph (for both pumps), SIL-30AC Nexera autosampler, CBM-20A prominence communications bus module, RF-20A prominence fluorescence detector, CTO-20AC prominence column oven, SPD-M20A prominence diode array detector) coupled to a Shimadzu liquid chromatograph mass spectrometer LCMS-2020 under usage of a FCV-20AH2 valve unit (Shimadzu). A constant flow rate of 0.75 mL/min (RP-HPLC coupled to MS) or 1 mL/min (RP-HPLC without MS) was applied. As column a C18 column from Dr. Maisch (ReproSil Gold 120, C18, 5 µm) was used. For both systems, linear gradients of H2O (0.1% (v/v) TFA or formic acid) and acetonitrile (MeCN; 0.1% (v/v) TFA or formic acid) were used for analytical purposes (respective gradients are noted in the experimental procedures). For logD measurements, cell binding, and internalization as well as biodistribution studies, a Wizard2® 2480 automatic γ-counter from PerkinElmer (Waltham, USA) was used. Cell culture. For cell culture, trypsin-EDTA (10 ×), Roswell Park Memorial Institute-1640 Medium (RPMI-1640), fetal calf serum (FCS), and phosphate buffered saline (1 ×, PBS; pH 7.4) were purchased from Gibco, ThermoFisher. Poly-L-lysine solution (0.01% in sterile water) was purchased from Merck, bovine serum albumin (BSA) from Carl Roth, and alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively. For cell studies, the following cell lines were used: prostate carcinoma cell lines LNCaP, PC3, PC3-PiP, C42, and DU145, respectively. The cell lines were purchased from American Type Culture Collection (ATCC, Manassas, USA) and from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany). All cell lines were cultured in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated FCS (v/v) (Gibco, ThermoFisher Scientific) and 1% (v/v) penicillin/streptomycin (10,000 U/mL, Gibco, ThermoFisher Scientific) in a 37 °C incubator with a 5% (g/v) CO2 atmosphere. Synthesis section and analytical data General procedures GP-1: Loading of 2-CTC resin: Solid phase peptide synthesis (SPPS) was performed according to standard Fmoc-strategy (Merrifield, 1963; Carpino and Han, 972). First, dry 2- CTC resin (1.0 eq.; 0.97 mmol/g) was mixed with a solution of the Fmoc-protected amino acid derivative (Fmoc-AA-OH; 1.2 eq.) and N,N-diisopropylethylamine (DIPEA; 2.5 eq.) in anhydrous (anhyd.) dichloromethane (DCM; 10 mL/g resin) at room temperature (RT) for 2 h under constant shaking. Next, unconjugated 2-chlorotritylchloride groups were capped by addition of methanol (MeOH; 1.0 mL/g resin) and DIPEA (0.2 mL/g resin). After shaking the resin for 15 min, the resin was filtered, and washed with DCM (3×), N,N-diisopropylethylamine (DMF; 3×), DMF/MeOH 1:1 (v/v) (1×), and MeOH (3×), respectively. Subsequent drying under vacuum overnight enabled the calculation of resin loading (n): Formula 1. Determination of resin loading n [mmol/g]. m1: mass of free resin [g]; m2: mass of loaded resin [g]; MAA: molecular weight of Fmoc-protected amino acid derivative [g/mol]; MHCl: molecular weight of HCl [36.46 g/mol]. In cases the resin loading was not determined, a resin loading of 100% was assumed. Hereby, after capping, the resin was washed with DCM (3×), and DMF (5×), respectively. GP-2: On-resin Fmoc-deprotection: The resin was treated with a solution of 20% (v/v) Piperidin in DMF (1×15 min, 1×10 min) at RT. Afterwards, the resin was washed with DMF (8×). GP-3: On-resin peptide synthesis with HATU/HOBt: A solution (0.1-0.2 M) of Fmoc-AA- OH (2.0 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU; 2.0 eq.), 1-hydroxybenzotriazole (HOBt×H2O; 2.0 eq.), and DIPEA (5.0 eq.), respectively, in DMF was stirred for 15 min at RT. The pre-activated solution was added to the resin-bound, free amine and shaken for 1 h at RT. Subsequently, the resin was filtered and washed with DMF (5×). For coupling with resin-bound secondary amines, a pre-activated solution (0.1-0.2 M) of Fmoc-AA-OH (3.5 eq.), HATU (3.5 eq.), HOBt×H2O (3.5 eq.), and DIPEA (7.0 eq.), respectively, was added to the resin. After 3 h of shaking at RT, the resin was washed with DMF (5×). GP-4: Cleavage of linear peptides from the resin: For complete cleavage, the resin was first washed with DCM (3×) and then treated with a solution of 20% (v/v) hexafluoroisopropanol in DCM (1×15 min, 2×10 min). In a next step, the solvent was evaporated under reduced pressure. GP-5: Trityl-, Pbf-, Boc-, and tBu-deprotection in solution: The starting material was dissolved in a mixture of TFA/DCM/triisopropylsilane (TIPS)/H2O/DCM (90/5/2.5/2.5, v/v/v) and stirred for 60 min at RT. The progress of the reaction was monitored by HPLC-ESI-MS. The reaction was stopped by addition of an excess of toluene. Afterwards, the volatiles were removed under reduced pressure. End products were purified via semipreparative RP-HPLC and lyophilized, resulting in TFA salts. GP-6: Coupling of TFP-esters in solution: A solution of the free amine (1.0 eq.) and DIPEA (7.0 eq.) in DMF (1.3 mM) was preincubated for 5 min at RT. Afterwards, the TFP-ester (1.5 eq.) was added, and the mixture was stirred for 16 h at RT. Finally, the crude product was purified via semipreparative RP-HPLC. GP-7: Standard amino acid coupling in solution: The corresponding acid (1.2 eq.), HOBt×H2O (1.2 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.2 eq) as well as DIPEA (5.0 eq.) were dissolved in DMF (0.12 M), and incubated for 15 min at RT. The pre-activated solution was added to the deprotected, free amine (1.0 eq.), dissolved in a small amount of DMF. After stirring the reaction solution for 16-24 h at RT, the solvent was evaporated. The hereby remaining residue was redissolved in EtOAc and extracted with saturated (sat.) ammonium chloride (NH4Cl)-, sat. NaHCO3- as well as sat. NaCl-solution (each 1×). In a next step, the organic phase was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure, respectively. In case of deprotected starting materials, the extraction was not performed. Here, after the reaction step, the volatiles were removed under reduced pressure and the product was purified via semipreparative RP-HPLC. GP-8: Reductive deprotection in solution: To a solution of the starting material in MeOH palladium on carbon (10% (w/w) Pd/C) was added. The resulting suspension was hydrated by flushing the flask with hydrogen (H2; 1 atm.) for 2-4 h. Reaction progress was monitored by analytical HPLC-ESI-MS. After removal of the catalyst via filtration over Celite®, the solvent was removed under reduced pressure. The crude product was directly used in the next reaction step without further purification. GP-9: On-resin Dde-deprotection: The orthogonal Dde-deprotection was performed by treating the resin with a solution of hydrazine hydrate (2% (v/v)) in DMF for 15 min. The step was repeated for another 15 min with fresh hydrazine solution. The reaction progress was monitored by HPLC-ESI-MS. After completion of deprotection, the resin was washed with DMF (8×). GP-10: Preparation of non-radioactive natGa-complexed PSMA-ligands: A solution of the PSMA-inhibitor (2.0 mM; 10 µL) in dimethyl sulfoxide (DMSO) and a solution of Ga(NO3)3 (2.0 mM; 10 µL) in H2O/DMSO (16% H2O (v/v)) were mixed and heated at 45 °C for 40 min under shaking. Chelate formation was analyzed via RP-HPLC and ESI-MS. The resulting 1.0 mM solution was used without further purification in in vitro experiments. Building blocks for EuK- and EuE-based PSMA ligands Rucaparib containing building blocks 3-((3-((4-(8-Fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)- (methyl)amino)-3-oxopropyl)disulfaneyl)propanoic acid (Ruc-SS-OH) (1): To a solution of rucaparib*HCl (40.0 mg, 112 µmol, 1.0 eq.) in DMF (15 mL), 3,3- dithiopropionic acid (47.0 mg, 222 µmol, 2.0 eq.) was added (GP-7). After evaporation of the solvents under reduced pressure and semipreparative RP-HPLC purification (35-60% buffer B, 15 min, buffer A and B without TFA addition), pure 1 (43.4 mg, 84.3 µmol, 76%) was obtained as yellow powder. RP-HPLC (5-95%, 10 min): tR = 7.79 min. MS (ESI, positive): m/z = 516.4 [M+H+], 1031.4 [2M+H+]. 2,3,5,6-tetrafluorophenyl3-((3-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3- cd]indol-5-yl)benzyl)(methyl)amino)-3-oxopropyl)disulfaneyl)propanoate (Ruc-SS- 1 (5.00 mg, 9.70 µmol, 1.0 eq.) in anhydr. THF (1.5 mL) was cooled to 0 °C. N,N´- Dicyclohexylcarbodiimide (2.00 mg, 9.7 µmol, 1.0 eq.) and tetrafluorophenol (3.00 mg, 19.4 µmol, 2.0 eq.) were added subsequently. The mixture was stirred at RT for 16 h. After removal of the solvents in vacuo, semipreparative RP-HPLC (20-60% buffer B, 15 min, buffer A and B without TFA addition) led to pure 2 (4.16 mg, 6.28 µmol, 64%) in form of a beige powder. RP-HPLC (5-95%, 10 min): tR = 6.77 min. MS (ESI, positive): m/z = 664.32 [M+H+], 1326.48 [2M]. 8-((4-(8-Fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)(methyl)- amino)-8-oxooctanoic acid (Ruc-Sub-OH) (3): For the preparation of 3, rucaparib*HCl (15.0 mg, 41.7 µmol, 1.0 eq.) was coupled to suberic acid (15.0 mg, 83.4 µmol, 2.0 eq.) according to GP-7. After removal of the solvents under reduced pressure and semipreparative RP-HPLC purification (35-60% buffer B, 15 min, buffer A and B without TFA addition), 3 (6.12 mg, 12.7 µmol, 30%) was obtained as yellowish powder. RP-HPLC (5-95%, 10 min): tR = 10.72 min. MS (ESI, positive): m/z = 480.3 [M+H+], 959.60 [2M+2H+]. 2,3,5,6-Tetrafluorophenyl-8-((4-(8-fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3- cd]indol-5-yl)benzyl)(methyl)amino)-8-oxooctanoate (Ruc-Sub-OTFP) (4): As described for 2, 3 (25.0 mg, 52.1 µmol, 1.0 eq.) gave 4 (14.6 mg, 23.2 µmol, 44%) after semipreparative RP-HPLC purification (20-60% buffer B, 15 min, buffer A and B without TFA addition). RP-HPLC (5-95%, 10 min): tR = 5.13 min. MS (ESI, positive): m/z = 628.5 [M+H+], 1255.8 [2M+H+]. N-(4-(8-Fluoro-1-oxo-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-5-yl)benzyl)-3-mer- capto-N-methylpropanamide (Ruc-SH) (5): Rucaparib*HCl (5.00 mg, 13.9 µmol, 1.0 eq.) and 3-mercaptopropionic acid (1.60 mg, 14.5 µmol, 1.05 eq.) were coupled according to GP-7. After evaporation of the solvents under reduced pressure and semipreparative RP-HPLC purification (35-60% buffer B, 15 min, buffer A and B without TFA addition), 5 (1.30 mg, 3.16 µmol, 22%) was obtained as yellow powder. RP-HPLC (10-95%, 15 min): tR = 12,55 min. MS (ESI, positive): m/z = 412.2 [M+H+]. The PSMA targeting motif (S)-Di-tert-butyl-2-(1Himidazole-1-carboxamido)pentanedioate (6): The synthesis of imidazole 6 was performed as previously described (Weineisen et al., 2014). Briefly, a solution of L-di-tert-butylglutamate*HCl (500 mg, 1.69 mmol, 1.0 eq.) in DCM (15.0 mL) was first treated with NEt3 (600 µL, 427 mg, 4.22 mmol, 2.5 eq.) and 4- (dimethylamino)pyridine (DMAP; 8.00 mg, 67.6 µmol, 0.04 eq.) at 0 °C. After stirring the reaction mixture for 5 min, 1,1'-carbonyldiimidazole (CDI; 328 mg, 2.02 mmol, 1.2 eq.), dissolved in DCM, was slowly added over a period of 20 min. Subsequently, the mixture was stirred for 20 h under warming to RT. The reaction was then stopped with sat. NaHCO3-solution (8.00 mL) and the organic phase was washed with H2O (2×), sat. NaCl-solution (2×), dried over Na2SO4 as well as filtrated. Evaporation of the solvents under reduced pressure led to 6 (529 mg, 1.49 mmol, 88%) as colorless oil. The crude product was directly used without further purification steps. RP-HPLC (5-95%, 8 min): tR = 2.07 min. MS (ESI, positive): m/z = 355.14 [M+2H+], 708.89 [2M+H+]. N2-(((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)carbamoyl)-N6-(1-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl)-L-lysine (K(Dde)uE(OtBu)2) (7): The synthesis of 7 was accomplished similarly to a literature procedure (Weineisen et al., 2014). 2-CTC resin (2.00 g, 1.93 mmol, 1.0 eq; resin loading: 0.97 mmol/g resin) was loaded with Fmoc-L-Lys(Dde)-OH (1.30 g, 2.32 mmol, 1.2 eq.) according to GP-1. After Fmoc-removal (GP-2), a solution of 6 (1.37 g, 3.87 mmol, 2.0 eq.) and NEt3 (700 µL, 450 mg, 4.45 mmol, 2.3 eq.) in dichloroethane (DCE; 20.0 mL), cooled to 0 °C, was added to the resin. The resin was shaken for 16 h at RT. Afterwards, the resin was washed with DCE (5×) and DMF (5×). Resin-bound 7 was used for the generation of the KuE-derived PSMA-ligands according to solid phase peptide synthesis/standard Fmoc-strategy. RP-HPLC (5-95%, 8 min): tR = 3.30 min. MS (ESI, positive): m/z = 596.11 [M+H+], 1212.65 [2M+Na+]. (S)-5-(tert-butoxy)-4-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopen- tanoic acid ((OtBu)EuE(OtBu)2) (8): The synthesis of 8 was performed similarly to the literature (Weineisen et al., 2014; Robu et al., 2018). Here, 6 (1.80 g, 5.09 mmol, 1.0 eq.) in DCE (40.0 mL) was treated with NEt3 (1.50 mL, 1.03 g, 10.1 mmol, 2.0 eq.) and H-L-Glu(Bzl)-OtBu*HCl (1.70 g, 5.09 mmol, 1.0 eq.) at 0 °C. The mixture was then stirred for 20 h at RT. After evaporation of the solvent under reduced pressure, the crude product was purified via column chromatography (EtOAc/cyclohexane/NEt3 500/500/0.8 (v/v/v)). Removal of the solvents yielded (OtBu)E(Bzl)uE(OtBu)2 (2.52 g, 4.37 mmol, 86%) as colorless oil. The reductive deprotection was subsequently performed according to GP-8, leading to 8 (1.98 g, 4.06 mmol, 93%) as colorless oil. RP-HPLC (5-95%, 10 min): tR = 9.71 min. MS (ESI, positive): m/z = 489.5 [M+H+], 977.8 [2M+H+]. N2-((S)-5-(tert-butoxy)-4-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-5-oxo- pentanoyl)-N6-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl)-L-lysine (K(Dde)- (OtBu)EuE(OtBu)2) (9): The synthesis of 9 was accomplished similarly to a literature procedure (Weineisen et al., 2014; Robu et al., 2018). In short, 2-CTC resin (2.00 g, 1.93 mmol, 1.0 eq; resin loading: 1.03 mmol/g resin) was loaded with Fmoc-D-Lys(Dde)-OH (1.30 g, 2.32 mmol, 1.2 eq.) according to GP-1. After Fmoc-removal (GP-2), the resin was treated with a solution of 8 (1.42 g, 2.90 mmol, 1.5 eq.) according to GP-3. Resin-bound 9 was used for the generation of EuE-based PSMA- ligands according to solid phase peptide synthesis/standard Fmoc-strategy. RP-HPLC (5-95%, 10 min): tR = 9.45 min. MS (ESI, positive): m/z = 781.6 [M+H+]. Generation of the composite conjugates Synthesis of EuK-based PSMA ligands General synthesis procedure. The peptide structures for the synthesis of the PSMA-targeting ligands were achieved in accordance with GP-2, GP-3, GP-4, GP-5, and GP-9, respectively, via standard solid phase peptide synthesis. As starting point, K(Dde)uE(OtBu)2 (7) was Dde- deprotected according to GP-9. The coupling of further amino acid analogues or amino acids was achieved according to GP-2 and GP-3 following Fmoc-strategy. For DOTAGA coupling, the Fmoc-deprotected resin was treated with a solution of DOTAGA anhydride (4.0 eq.) and DIPEA (10 eq.) in DMSO (0.07 mM) for 48 h. Subsequently, the PSMA ligand was cleaved from the resin according to GP-4. After global deprotection of the acid labile protection groups, performed after GP-5, the ligands were purified via semipreparative RP-HPLC. Finally, the Ruc-derivative was coupled under basic conditions according to GP-6 and the product was obtained after RP-HPLC purification. The peptide sequence was synthesized according to the general synthesis procedure. The following amino acid analogues were coupled to 7 (100 mg resin, 96.9 µmol, 1.0 eq.): N-Fmoc- 3-(2-naphthyl)-L-alanin (Fmoc-L-Nal-OH), and trans-4-(Fmoc-aminome-thyl)- cyclohexanecarboxylic acid (Fmoc-TXA), respectively. After semipreparative RP-HPLC purification (20-60%, buffer B, 15 min), 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was coupled according to GP-6. Via semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition), 10 (1.41 mg, 1.22 µmol, 60%) was yielded as beige powder. RP-HPLC (10-95%, 15 min): tR = 11.64 min. MS (ESI, positive): m/z = 1154.5 [M+2H+], 577.6 [M/2]. RUC-SS-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (Ruc-SS-dyff-Ahx-KuE) (PSMARuc-8) 11 was synthesized as 10 by coupling Fmoc-6-Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-D-Asp(OtBu)-OH to 7 (100 mg resin, 96.9 µmol, 1.0 eq.). After semipreparative RP-HPLC purification (20-60%, buffer B, 15 min), 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was coupled according to GP-6. Semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition), yielded 11 (2.11 mg, 1.40 µmol, 69%) as beige solid. RP-HPLC (10-95%, 15 min): tR = 11.32 min. MS (ESI, positive): m/z = 1503.6 [M+2H+], 752.3 [M/2]. DOTAGA-D-Lys(Ruc-SS)-D-Asp-β-Ala-TXA-L-Nal-KuE (DOTAGA-k(Ruc-SS)-d-βA- TXA-Nal-KuE) (PSMARuc-9) (12): As already described for 10, the following amino acid sequence was coupled to 7 (100 mg resin, 96.9 µmol, 1.0 eq.): Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc-β-Ala-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively. After semipreparative RP- HPLC purification (20-60%, buffer B, 15 min), 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was coupled according to GP-6. Semipreparative RP-HPLC purification (15-50%, buffer B, 15 min, buffer A and B without TFA addition) resulted in 12 (1.89 mg, 0.98 µmol, 48%) as white solid. RP-HPLC (10-95%, 15 min): tR = 9.81 min. MS (ESI, positive): m/z = 1926.7 [M+2H+], 964.0 [M/2]. DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA-k(Ruc-SS)- dyff-Ahx-KuE) (PSMARuc-10) (13): The synthesis of 13 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Lys(Boc)-OH, and DOTAGA-anhydride, respectively. The crude product was purified via semipreparative RP-HPLC (20-60%, buffer B, 15 min), and 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was coupled according to GP-6. Semipreparative RP-HPLC purification (15-50%, buffer B, 15 min, buffer A and B without TFA addition), yielded 13 (1.04 mg, 0.49 µmol, 24%) as white solid. RP-HPLC (10-95%, 15 min): tR = 9.90 min. MS (ESI, positive): m/z = 1045.6 [M/2]. DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA-k(Ruc-SS)- dyf-Nal-Ahx-KuE) (PSMARuc-11) (14): The synthesis of 14 was accomplished in similarity to 10, using Fmoc-6-Ahx- OH, Fmoc-L- Nal-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Lys(Boc)-OH, and DOTAGA-anhydride, as amino acid analogues. After coupling of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) according to GP-6, and semipreparative RP-HPLC purification (15-50%, buffer B, 15 min, buffer A and B without TFA addition), 14 (2.67 mg, 1.24 µmol, 62%) was aquired as white solid. RP-HPLC (10-95%, 15 min): tR = 10.57 min. MS (ESI, positive): m/z = 1070.7 [M/2]. DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (DOTAGA-k(Ruc- SS)-dyff-Ahx-Ahx-KuE) (PSMARuc-12) (15): The synthesis of 15 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-6- Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)- OH, Fmoc-D-Lys(Boc)-OH, and DOTAGA-anhydride. After coupling of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) in accordance with GP-6, and semipreparative RP-HPLC purification (20- 60%, buffer B, 15 min, buffer A and B without TFA addition), 15 (0.91 mg, 0.41 µmol, 20%) was obtained as beige solid. RP-HPLC (10-95%, 15 min): tR = 9.88 min. MS (ESI, positive): m/z = 1102.2 [M/2]. DOTAGA-D-Lys(Ruc-Sub)-D-Asp-β-Ala-TXA-L-Nal-KuE (DOTAGA-k(Ruc-Sub)-d-βA- TXA-Nal-KuE) (PSMARuc-13) (16): In similarity to 12, 16 was synthesized through coupling of 4 (1.89 mg, 3.01 µmol, 1.5 eq.) instead of 2. After semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition), 16 (3.00 mg, 1.58 µmol, 78%) was acquired as a white solid. RP-HPLC (10-95%, 15 min): tR = 9.72 min. MS (ESI, positive): m/z = 1890.7 [M+2H+], 946.0 [M/2]. Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-KuE (Ruc-SS-MMC-dd-βA-TXA-Nal- KuE) (PSMARuc-14) (17): The synthesis of 17 was accomplished in similarity to 10, using Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc-β-Ala-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, and MMC(OtBu)3- NH(Boc), respectively. After semipreparative RP-HPLC (20-50%, buffer B, 15 min), conjugation of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) in accordance with GP-6, and semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition), 17 (2.11 mg, 1.47 µmol, 1.5%) was acquired as beige powder. RP-HPLC (10-95%, 15 min): tR = 9.65 min. MS (ESI, positive): m/z = 1925.6 [M+1H+], 964.0 [M/2]. Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (Ruc-SS-MMC-ddyff- Ahx-Ahx-KuE) (PSMARuc-15) (18): The synthesis was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-6-Ahx-OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc- D-Asp(OtBu)-OH, and MMC(OtBu)3-NH(Boc), respectively. The crude product was purified via semipreparative RP-HPLC (20-50%, buffer B, 15 min). After conjugation of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) in accordance with GP-6, and semipreparative RP-HPLC purification (20- 60%, buffer B, 15 min, buffer A and B without TFA addition), 18 (1.09 mg, 0.49 µmol, 24%) was acquired as beige powder. RP-HPLC (10-95%, 15 min): tR = 9.69 min. MS (ESI, positive): m/z = 1102.2 [M/2]. DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE (DOTAGA- k(k(Ruc-SS)2)-ddyff-Ahx-KuE) (PSMARuc-10Lys2) (19): The synthesis of 19 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Asp(OtBu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively. The crude product was purified via semipreparative RP-HPLC (20-50%, buffer B, 15 min). Then, 2 (4.00 mg, 6.03 µmol, 3.0 eq.) was coupled according to GP-6. After semipreparative RP-HPLC purification (20-50%, buffer B, 15 min, buffer A and B without TFA addition), 19 (1.23 mg, 0.43 µmol, 21%) was acquired as beige solid. RP-HPLC (10-95%, 15 min): tR = 10.76 min. MS (ESI, positive): m/z = 1416.2 [M/2]. DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA-k(k(Ruc-SS)2)-ddyf-Nal-Ahx-KuE) (PSMARuc-11Lys2) (20): The synthesis of 20 was accomplished in similarity to 10, using Fmoc-6-Ahx-OH, Fmoc-L-Nal- OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)- OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively. The crude product was purified via semipreparative RP-HPLC (20-50%, buffer B, 15 min). After conjugation of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) in accordance with GP-6, and semipreparative RP-HPLC purification (20-50%, buffer B, 15 min, buffer A and B without TFA addition), 20 (1.12 mg, 0.38 µmol, 19%) was acquired as beige solid. RP-HPLC (10-95%, 15 min): tR = 10.82 min. MS (ESI, positive): m/z = 1441.0 [M/2]. DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE (DOTAGA-k(k(Ruc-SS)2)-ddyff-Ahx-Ahx-KuE) (PSMARuc-12Lys2) (21):
The synthesis was accomplished in accordance with 10, using Fmoc-6-Ahx-OH, Fmoc-6-Ahx- OH, Fmoc-D-Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DOTAGA- anhydride, respectively. After conjugation of 2 (2.00 mg, 3.01 µmol, 1.5 eq.) in accordance with GP-6, and semipreparative RP-HPLC purification (20-50%, buffer B, 15 min, buffer A and B without TFA addition), 21 (1.67 mg, 0.56 µmol, 28%) was acquired as beige solid. RP-HPLC (10-95%, 15 min): tR = 11.01 min. MS (ESI, positive): m/z = 1472.5 [M/2], 982.0 [M/3]. DOTAGA-D-Lys(D-Lys(Ruc-Sub)2)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE (DOTAGA-k(k(Ruc-Sub)2)-ddyf-Nal-Ahx-KuE) (PSMARucSub-11Lys2) (22): As already described for 10, the following amino acid sequence was coupled to 7 (100 mg resin, 96.9 µmol, 1.0 eq.): Fmoc-6-Ahx-OH, Fmoc-L-Nal-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)- OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D- Lys(Boc)-OH, and DOTAGA-anhydride, respectively. After semipreparative RP-HPLC purification (20-60%, buffer B, 15 min), and coupling of 4 (3.78 mg, 6.03 µmol, 3.0 eq.) according to GP-6, 22 (0.96 mg, 0.34 µmol, 17%) was obtained as beige powder after semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition). RP-HPLC (10-95%, 15 min): tR = 10.64 min. MS (ESI, positive): m/z = 1405.0 [M/2], 937.0 [M/3]. Synthesis of EuE-based PSMA ligands General synthesis procedure. The peptide structures for the synthesis of the PSMA-targeting ligands were achieved according to GP-2, GP-3, GP-4, GP-5, and GP-9, respectively, via standard solid phase peptide synthesis. First, K(Dde)-(OtBu)EuE(OtBu)2 (9) was Dde- deprotected according to GP-9. The coupling of further amino acid analogues or amino acids was achieved according to GP-2 and GP-3 following Fmoc-strategy. For DOTAGA coupling, the Fmoc-deprotected resin was treated with a solution of DOTAGA anhydride (4.0 eq.) and DIPEA (10 eq.) in DMSO (0.07 mM) for 48 h. Afterwards, the PSMA ligand was cleaved from the resin according to GP-4 and globally deprotected according to GP-5. The crude ligands were purified via semipreparative RP-HPLC. After coupling of the Ruc-derivative according to GP-6, the final product was acquired after semipreparative RP-HPLC purification. DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE (DOTAGA- k(Ruc-Sub)-dd-βA-TXA-Nal-k-EuE) (PSMARuc-16) (23): The peptide sequence of 23 was synthesized according to the general synthesis procedure of this chapter. The following amino acid analogues were coupled to 9 (100 mg resin, 103 µmol, 1.0 eq.): Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc-β-Ala-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Asp(OtBu)-OH, Fmoc-D-Lys(Boc)-OH, and DBCO-acid, respectively.2 (2.00 mg, 3.01 µmol, 1.5 eq.) was then coupled according to GP-6. Via semipreparative RP-HPLC purification (20- 60%, buffer B, 15 min, buffer A and B without TFA addition), 23 (3.74 mg, 1.72 µmol, 85%) was yielded as white solid. RP-HPLC (10-95%, 15 min): tR = 9.63 min. MS (ESI, positive): m/z = 1086.1 [M/2]. DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys-EuE (DOTAGA-k(Ruc-SS)-ddyff-Ahx-k-EuE) (PSMARuc-17) (24): The synthesis of 24 was accomplished in similarity to 23, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Asp(OtBu)-OH, Fmoc-D-Lys(Boc)-OH, and DOTAGA-anhydride, respectively. The crude product was purified via semipreparative RP-HPLC (5-30%, buffer B, 15 min). 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was then coupled according to GP-6. After semipreparative RP-HPLC purification (20-60%, buffer B, 15 min, buffer A and B without TFA addition), 24 (1.48 mg, 0.63 µmol, 31%) was acquired as beige powder. RP-HPLC (10-95%, 15 min): tR = 9.79 min. MS (ESI, positive): m/z = 1167.7 [M/2]. Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE (Ruc-SS-MMC-dd-βA-TXA- Nal-k-EuE) (PSMARuc-18) (25): The synthesis was accomplished in similarity to 23, using Fmoc-L-Nal-OH, Fmoc-TXA, Fmoc- β-Ala-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, and MMC(OtBu)3-NH(Boc), respectively. The crude product was purified via semipreparative RP-HPLC (5-30%, buffer B, 15 min). Then, 2 (2.00 mg, 3.01 µmol, 1.5 eq.) was coupled according to GP-6. Via semipreparative RP-HPLC purification (20-50%, buffer B, 15 min, buffer A and B without TFA addition), 25 (0.91 mg, 0.39 µmol, 19%) was acquired as white powder. RP-HPLC (10-95%, 15 min): tR = 9.50 min. MS (ESI, positive): m/z = 1028.6 [M/2]. DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE (DOTAGA- k(k(Ruc-SS)2)-dd-βA-TXA-Nal-k-EuE) (PSMARuc-16-Lys2) (26): The synthesis of the title compound was accomplished in similarity to 23, using Fmoc-L-Nal- OH, Fmoc-TXA, Fmoc-β-Ala-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DBCO-acid, respectively. The crude product was purified via semipreparative RP-HPLC (5-30%, buffer B, 15 min). According to GP-6, 2 (4.00 mg, 6.03 µmol, 3.0 eq.) was coupled. After semipreparative RP-HPLC purification (20- 50%, buffer B, 15 min, buffer A and B without TFA addition), 26 (1.89 mg, 0.67 µmol, 33%) was acquired as beige solid. RP-HPLC (10-95%, 15 min): tR = 10.55 min. MS (ESI, positive): m/z = 1398.9 [M/2], 933.0 [M/3]. DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys-EuE (DOTAGA-k(k(Ruc-SS)2)-ddyff-Ahx-k-EuE) (PSMARuc-17-Lys2) (27): The synthesis of 24 was accomplished in similarity to 23, using Fmoc-6-Ahx-OH, Fmoc-D- Phe-OH, Fmoc-D-Phe-OH, Fmoc-D-Tyr(OtBu)-OH, Fmoc-D-Asp(OtBu)-OH, Fmoc-D- Asp(OtBu)-OH, Fmoc-D-Lys(Alloc)-OH, Boc-D-Lys(Boc)-OH, and DBCO-acid, respectively. The crude product was purified via semipreparative RP-HPLC (5-30%, buffer B, 15 min). According to GP-6, 2 (4.00 mg, 6.03 µmol, 3.0 eq.) was coupled. After semi-preparative RP- HPLC purifi- cation (20-60%, buffer B, 15 min, buffer A and B without TFA addition), 27 (1.29 mg, 0.43 µmol, 21%) was acquired as beige solid. RP-HPLC (10-95%, 15 min): tR = 10.64 min. MS (ESI, positive): m/z = 1480.5 [M/2]. natGa-labeled PSMA ligands The labeling with Ga(NO3)3 was conducted as described under GP-10. Hereby, the resulting 1.0 mM solution was directly used in in vitro experiments. 68Ga-labeled PSMA ligands The PSMA-targeting compounds were radiolabeled according to the literature (Weineisen et al., 2014; Notni et al., 2011) using a fully automated synthesis module (GallElut+ from Scintomics GmbH, Germany). The following reaction steps were controlled by a computer program from Scintomics (Scintomics Control Center). In a first step, the 68Ge/68Ga-generator with SnO2 matrix (iTHEMBA labs, South Africa) was eluted with 0.1 M aq. HCl. Hereby, a fraction of 1.25 mL containing ca.80% of the entire activity (ca. 300 MBq) was transferred to a mixture of the PSMA ligand (10 nmol) in aq. HEPES solution (2.7 M, pH 2; 75 µL). The radioactive mixture was heated to 95 °C, then passed through a previously with EtOH (5 mL) and H2O (10 mL) purged SPE cartridge (Waters SepPak® C8 light, sorbent amount 50 mg). Afterwards, the cartridge was purged with H2O (10 mL) and air (10 mL). Into a round bottom flask, the radiolabeled product was finally eluted with EtOH/H2O (1:1 (v/v)) and the cartridge was purged with PBS (1 mL; pH 7.4) and H2O (1 mL), respectively. After evaporation of EtOH under reduced pressure, the tracer was used without further purification in in vitro and in vivo experiments. Radiochemical purity was controlled using Radio-TLC (1.0 M sodium citrate buffer and 0.06 M NH4OAc/MeOH buffer (1/1 ; v/v)). EXAMPLE 2 Ruc fluorescence correlates with Ruc concentration To analyze Ruc fluorescence in cells, 500.000 cells/well were seeded into a 96 well plate and incubated with increasing amounts of Ruc for 30 min at 37°C. Untreated control and the 7- AAD single stain control were incubated with Medium (RPMI, 10%FCS, 1%PS) only. Afterwards cells were put on ice, washed twice with PBS, resuspended in FACS Buffer (5%FCS in PBS) and transferred into the flow cytometry tubes (obtained from VWR Catalog Number 734-0001). Prior to flow cytometry cells were incubated with eBioscience™ 7-AAD Viability Staining Solution (obtained from Thermo Fisher Scientific Catalog Number 00- 6993-50) according to manufacturer’s instructions. Flow Cytometry was performed using a FACS Canto II cytometer (BD Bioscience). Data was analyzed with the FlowJoTM software version 10.6.2 (BD Bioscience). EXAMPLE 3 PSMA-Ruc conjugates show PSMA-specific internalization and high affinity to PSMA-expressing cells To determine ligand internalization, LNCaP cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in 5% BSA (w/v)/RPMI medium (100 µL/well) and incubated for 30 min at 37 °C. Afterwards, solutions (25 µL/well) of either 5% BSA (w/v)/RPMI medium or of 2-PMPA (final concentration: 10 µM) in 5% BSA (w/v)/RPMI medium for blockade were added. Then, a solution of the 68Ga-labeled PSMA-ligand (25 µL/well; 0.4 nM final concentration; AM = 26-30 MBq/nmol) was added to all wells, and the cells were incubated for 5, 15, 30, and 60 min, respectively, at 37 °C. Hereby, each time point was performed in triplicates and each experiment was repeated three times. The internalization process was terminated by placing the plate for 5 min on ice. The free radioligand was obtained by centrifugation of the plate at 600 g for 3 min and removal of the supernatant. Each well was then washed with ice-cold PBS and the fractions of the first two steps were combined. For removal of cell-bound PSMA-ligand, the cells were treated in a next step with ice-cold 2-PMPA-solution (10 µM in PBS; 150 µL/well; 15 min on ice), centrifuged (600 g, 3 min), and washed with ice-cold PBS (150 µL/well). The fractions were again combined. For the analysis of internalized radioligand, the fractions of a 1.0 N NaOH (150 µL/well; 10 min on ice) treatment as well as a concomitant washing step with 1.0 N NaOH (150 µL/well) were pooled. Free, surface bound, and internalized activity, respectively, was measured in a γ-counter. For IC50 value determination, LNCaP cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in 1% BSA (w/v)/HBSS (Hank’s balanced salt solution, ThermoFisher Scientific; 100 µL/well) and incubated for 15 min on ice. In the meantime, dilution series of the compounds were prepared in 1% BSA (w/v)/HBSS in a separate 96 U- bottom deep well plate ranging from 12 µM to 153.6 pM in 1:5 dilution steps. Next, solutions (25 µL/well) of either 1% BSA (w/v)/HBSS (control) or of the respective dilution series were transferred to the LNCaP cells containing plate. Hereby, each concentration was pipetted in triplicates and each experiment was repeated three times. Subsequently, [68Ga]-PSMA-617 (25 µL/well; 0.4 nM final concentration; AM = 26-30 MBq/nmol) in 1% BSA (w/v)/HBSS was added to all wells and the plate was incubated for 60 min on ice. Afterwards, the experiment was terminated by centrifugation at 600 g for 3 min and removal of the supernatant. The cells were then washed with ice-cold HBSS (150 µL/well), centrifuged (600 g, 3 min), and the supernatant as well as the washing fraction were combined, representing the amount of free, unbound radioligand. Bound radioligand was obtained by lysis of the cells with 1.0 N NaOH (150 µL/well; 10 min on ice). Afterwards, the plate was washed a second time with 1.0 N NaOH (150 µL/well). Hereby, the washing step was combined with the NaOH fraction. The quantification of bound and free radioligand was finally accomplished via measuring the samples in a γ-counter. Lipophilicity of the conjugates was determine after radiolabeling with 68Ga. The PSMA ligand (0.80 MBq) was dissolved in PBS (500 µL/pH 7.4) in a reaction vial (1.5 mL; n = 10). Afterwards, n-octanol was added (500 µL) and the mixture was rigorously vortexed for 3 min. Subsequent centrifugation (Biofuge 15, Heraus Sepatech, Osterode, Germany) at 13,000 rpm for 5 min led to a phase separation. After measuring 100 µL of each phase in a γ-counter, the distribution coefficient (logD(O/PBS)) was calculated with Microsoft Excel. EXAMPLE 4 PSMA-Ruc conjugates show PSMA-dependent uptake of Ruc Microscopy + flow For microscopic analysis, black clear-bottom 96 well cell culture plates with cover-glass bottom (µ plate 96 well black; ibidi) were coated with poly-L-lysine (0.01% (w/v) in sterile water). Cells were seeded at a density of 20-40,000 cells/well and cultured for 24 h at 37 °C. Subsequently, the PSMA ligands (1 µM; 100 µL/well) were directly added with or without blocking and ligand treatment was accomplished for 5, 60 or 180 min at 37 °C, while in case of GSH preincubation, GSH-OEt (10 mM; 100 µL/well) was applied for 1 h at 37 °C prior to ligand treatment. For the latter case, the PSMA ligands (1 µM, 100 µL/well) were added after removal of the GSH containing medium and the incubation time was 60 min at 37 °C. Afterwards, cells were washed with PBS (2×) and fixed with 4% (w/v) PFA in PBS for 8 min at RT (pH 7.4, 100 µL/well). CellMaskTM Green Plasma Membrane Stain was used to stain the cell membrane, whereas for cell nuclei DRAQ5TM was used. Before imaging, cells were washed with PBS (3×) and mounted in PBS (150 µL/well). Finally, cells were imaged using an EVOS M7000 microscope (Thermo Fisher Scientific). For flow cytometry analysis of Ruc-fluorescence in cells after incubation with PSMA-Ruc conjugates, 500.000 cells/well were seeded into a 96 well plate and incubated with a PSMA- Ruc conjugate for 30 min at 37°C. Untreated controls and the 7-AAD single stain control were incubated with Medium (RPMI, 10%FCS, 1%PS) only. Afterwards cells were put on ice, washed twice with PBS, resuspended in FACS Buffer (5%FCS in PBS) and transferred into the flow cytometry tubes (obtained from VWR Catalog Number 734-0001). Prior to flow cytometry cells were incubated with eBioscience™ 7-AAD Viability Staining Solution (obtained from Thermo Fisher Scientific Catalog Number 00-6993-50) according to manufacturer’s instructions. Flow Cytometry was performed using a FACS Canto II cytometer (BD Bioscience). Data was analyzed with the FlowJoTM software version 10.6.2 (BD Bioscience). EXAMPLE 5 Serum stability and GSH-dependent Ruc release of PSMA-Ruc conjugates For serum stability analysis, 13.5 µL human serum were mixed with 1.5 µL of an aqueous solution of the test compound (200 µM final concentration) and incubated at 37 °C for 0.5, 1, 2, and 24 h, respectively. Afterwards, 25.0 µL MeCN were added, the suspension was centrifuged (14,000 rpm, 30 min, 4 °C), the supernatant was recovered, and finally analyzed by HPLC-ESI-MS using a linear elution gradient from 10 to 95% (v/v) MeCN/0.1% (v/v) TFA in water/0.1% (v/v) TFA for 15 min. For the analysis of GSH cleavage capability, we added GSH-OEt in PBS (10 mM, 15 µL) to the PSMA ligands (160 µM, 0.5 µL) and incubated for 5, 15, and 30 min, respectively, at 37 °C in reaction vials (1.5 mL). Afterwards, the samples were diluted with MeCN (30 µL) and analyzed by HPLC-ESI-MS using a linear elution gradient from 10 to 95% (v/v) MeCN/0.1% (v/v) TFA in water/0.1% (v/v) TFA for 15 min. EXAMPLE 6 PSMA-Ruc conjugates induce selective cytotoxicity in vitro Black, clear-bottom 96 well culture plates were coated with poly-L-lysine. Afterwards, the plates were washed with PBS (1 × 100 µL), cells were seeded (2000 cells/well for PC3, 10000 cells/well for LNCaP), and cultured for 24 h (PC3) or 48 h (LNCaP) at 37 °C. The culture medium was removed, and new culture medium containing 10 mM GSH-OEt was added and incubated for 1 h at 37 °C. After removal of the GSH-OEt medium, new culture medium containing the PSMA-Ruc conjugates was added. After 72 h of incubation at 37 °C, cells were treated with Alamar Blue for visualization of cell viability. Results are shown in Figure 6. The graph displays the mean and standard deviation of biological replicates. Each data points represents one biological replicate. EXAMPLE 7 PSMA-Ruc in combination with 177Lu-PSMA treatment in vitro Black, clear-bottom 96 well culture plates were coated with poly-L-lysine. Afterwards, the plates were washed with PBS (1 × 100 µL), cells were seeded (2000 cells/well for PC3, 10000 cells/well for LNCaP), and cultured for 24 h to 48 h at 37 °C. The culture medium was removed and fresh medium containing 10 mM GSH-OEt (for PSMA-Ruc-conjugate treatment; treatment for 1 h at 37 °C), 0.1875 MBq RLT (177Lu-PSMA-I&T; treatment for 72 h) or rucaparib (0.1 - 1 µM) or both was added. After a total incubation time of 72 h, the cell viability was tested by use of Alamar Blue. The graphs display the mean and standard deviation of at least 3 biological replicates. Results are shown in Figures 7 to 9. EXAMPLE 8 PSMA-selective in vivo imaging using a PSMA-Ruc conjugate Radiolabeling. Generator-produced 68GaCl3 (t1⁄2 = 68 min) was purchased from the MD Anderson radiopharmacy (Houston, TX) and converted to 68Ga as previously described (Zhernosekov et al., 2007). PSMA-617, PSMA-Ruc-9, PSMA-Ruc-16 and PSMA-Ruc-18 (15 nmol each) were dissolved in 0.2 M sodium acetate buffer (pH 4.2; 100 µL), mixed with 68Ga (155-296 MBq; 100-150 µL), radiolabeled for 15 min at 95°C and purified using an activated Sep-Pak Light C18 (Waters) cartridge. In vivo experiment. Athymic nude mice were subcutaneously injected with 4×106 PC3-PIP (PSMA+) and 3×106 PC3-Flu (PSMA-) cells to produce a bilateral tumor model. Conjugate 11: Mice were injected with 7.4 MBq of 68Ga-PSMA-Ruc-11 or 68Ga-PSMA-617 (positive control) via the tail vein and PET/CT imaging was performed 1 hour post-injection. At the completion of the imaging study, mice were euthanized and organs were resected, weight, and analyzed by gamma counting to determine tracer biodistribution. Data are ported as percentage of injected activity per gram of tissue (%IA/g). Results are shown in Figure 9. Conjugates 9, 16 and 18: 10 days after xenografting when tumor size reached ∼5- to 10-mm maximum diameter, mice (n=5/conjugate) were injected with 2 nmol of 68Ga-PSMA-Ruc-9 (0.5±0.1 MBq), 68Ga-PSMA-Ruc-16 (7.4±0.7 MBq), 68Ga-PSMA-Ruc-18 (15.2±5.1 MBq) or 68Ga-PSMA-617 (8.0±0.6 MBq; positive control) via the tail vein and PET/CT imaging (n=2/conjugate) was performed 1 hour post-injection, except for 68Ga-PSMA-Ruc-9 due to low specific activity. At the completion of the imaging study, mice were euthanized and organs were resected, weighted, and analyzed by gamma counting to determine tracer biodistribution. Biodistribution data are reported as percentage of injected dose per gram of tissue (%ID/g). Results are shown in Figure 10. EXAMPLE 9 PSMA-Ruc conjugates with 2 Ruc moieties in combination with 177Lu- PSMA treatment in vitro Black, clear-bottom 96 well culture plates were coated with poly-L-lysine. Afterwards, the plates were washed with PBS (1 × 100 µL), cells were seeded and cultured for 24 h at 37 °C. Seeding cell density was adapted to the cell line (C42: 1000 cells/well; DU145: 1500 cells/well; LNCaP: 5000 cells/well PC3 and PC3-PIP: 500 cells/well). Treatment consisted of 24 h treatment with 0.1875 MBq [177Lu]Lu-PSMA I&T. Then, the culture medium containing the radioligand was removed and 10 mM GSH-OEt was added for 1 h, subsequently GSH was removed and either medium (monotreatment control), 1 µM Rucaparib or 1 µM of a PSMA- Ruc(2)-ligand (combination treatment) was added and incubated for 47 h. After a total incubation time of 72 h, the cell viability was tested by use of Alamar Blue. The graphs display the mean and standard deviation of at least 3 biological replicates. Results are shown in Figure 11. EXAMPLE 10 Parylation efficacy of the cleavage product Ruc-SH To investigate whether the cleavage product of the PSMA-Ruc-conjugates, Ruc-SH, is able to inhibit PARP1 as efficiently as Rucaparib, we quantified cellular PAR levels after treatment with either 1 µM Ruc, 1 µM Ruc-SH or an exemplary PSMA-targeted Ruc (1 µM PSMA- Ruc(2)-16). We used a commercial cell-based ELISA parylation assay according to the manufacturer’s instructions (Cell BioLabs) using PC3-PiP cell lysates. The Parylation assay showed efficient suppression of intracellular PAR levels upon Rucaparib treatment to 8% of the untreated control. Ruc-SH also decreased PAR levels to 26% of the untreated control. The ligand PSMA-Ruc(2)-16 was also able to inhibit PARylation down to 36% of the untreated control. Hence, we observed efficient parylation inhibition by the cleavage product Ruc-SH and the exemplary ligand PSMA-Ruc(2)-16, from which Ruc-SH is released upon gluthatione cleavage. Parylation was measured using a cell-based ELISA kit (Cell BioLabs). PC3-PiP cells were incubated with 1 µM Rucaparib, Ruc-SH or PSMA-Ruc(2)-16 and parylation levels of cell lysates were determined via ELISA. Results are shown in Figure 12. EXAMPLE 11 Synthesis of SSTR2-Ruc conjugates and their characterization General information Chemical synthesis. For the reactions performed in this work, all protected amino acid analogs and coupling reagents were purchased from Carbolution Chemicals (St. Ingbert, Germany), Iris Biotech (Marktredwitz, Germany), Merck (Munich, Germany) or Biozol (Eching, Germany). The H-L-Thr(tBu)-ol-2CT resin and the H-L-Thr(tBu)-2CT resin were obtained from Iris Biotech (Marktredwitz, Germany). Rucaparib was obtained from MedChemExpress (Sollentuna, Sweden). All solvents were purchased from Merck (Munich, Germany), VWR (Darmstadt, Germany), Carl Roth (Karlsruhe, Germany) or Iris Biotech (Marktredwitz, Germany), of analytical, for synthesis, peptide or HPLC grade and used without further purification. Unless otherwise noted, all other used chemicals and reagents for the performed syntheses were obtained from VWR, Merck (Darmstadt, Germany), abcr (Karlsruhe, Germany) or Alfa Aesar. Twenty mL-reactors for solid-phase peptide synthesis were bought from Carl Roth (Karlsruhe, Germany). By drawing up the syringe, reaction or wash solutions were added to the resin. Complete mixing was accomplished on a rotating unit. The equivalents (eq.) of amino acids were referred to the loading given by the manufacturer. Semi-preparative reversed phase high-performance liquid chromatography (RP-HPLC) was performed on the following device: Shimadzu (Shimadzu Deutschland GmbH, Neufahrn, Germany) RP-HPLC system including a CBM-20A communications bus module, SPD-M20A prominence diode array detector, LC- 20AP prominence preparative liquid chromatograph (for both pumps). The applied flow rate were 5 mL/min or 20 mL/min. As eluents, linear gradients of water (H2O; with 0.1% (v/v) trifluoroacetic acid (TFA), buffer A) and acetonitrile (MeCN; with 0.1% (v/v) TFA, buffer B) were applied for the purification of all compounds using a C18-column (Reprosil 100 C18, 5 μm, 150 x 30 mm, Dr. Maisch, Ammerbuch-Entringen, Germany). The UV-detection was carried out at 220 and 254 nm, respectively. All final compounds were analyzed via electrospray ionization mass spectrometry (ESI-MS) coupled to an analytical RP-HPLC system (HPLC-ESI-MS) to confirm a purity of ≥95% (λ = 214, 230 and 254 nm). Here, the LC-MS spectra were acquired on the following device: ISQ EM Vanquish mass spectrometer (ThermoFisher Scientific, Waltham, USA) with a C18 column (ReproSil-Pur 120 C18-AQ, 5 μm, 150 x 4 mm, Dr. Maisch, Ammerbuch-Entringen, Germany). Linear gradients of H2O (0.1% (v/v) TFA or formic acid) and acetonitrile (MeCN; 0.1% (v/v) TFA or formic acid) were used for analytical purposes (respective gradients are noted in the experimental procedures). For quantification of radioactive samples, a 2480 Wizard2® gamma counter from PerkinElmer Inc. (Waltham, Massachusetts, USA) was used. Cell culture. For cell culture, trypsin-EDTA (10 ×), Roswell Park Memorial Institute-1640 Medium (RPMI-1640), fetal calf serum (FCS), and phosphate buffered saline (1 ×, PBS; pH 7.4) were purchased from Gibco, ThermoFisher. Poly-L-lysine solution (0.01% in sterile water) was purchased from Merck, bovine serum albumin (BSA) from Carl Roth, and alamarBlue HS cell viability reagent from ThermoFisher Scientific, respectively. For cell studies, the following cell lines were used: HCT116-WT and HCT116-SSTR2, respectively. All cell lines were cultured in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated FCS (v/v) (Gibco, ThermoFisher Scientific) and 1% (v/v) penicillin/streptomycin (10,000 U/mL, Gibco, ThermoFisher Scientific) in a 37 °C incubator with a 5% (g/v) CO2 atmosphere. For the HCT116-SSTR2 cell line, 0.1% Zeocin was added. Synthesis section and analytical data General procedures GP-1: On-resin Fmoc-deprotection: The dry resin was swollen in DMF (15 min) before use and then treated with a solution of 20% (v/v) Piperidin in DMF (1×5 min, 1×15 min) at RT. Afterwards, the resin was washed with DMF (6×5 mL). GP-2: On-resin peptide synthesis with TBTU/HOBt: A solution of Fmoc-AA-OH (1.5 eq.), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.5 eq.), 1-hydroxybenzotriazole (HOBt×H2O; 1.5 eq.), and DIPEA (4.5 eq.), respectively, in DMF was stirred for 15 min at RT. The pre-activated solution was added to the resin-bound, free amine and shaken for 1.5 h at RT. Subsequently, the resin was filtered and washed with DMF (6×5 mL) and either further reacted or treated with DCM (3 × 2 min) and dried in vacuo. GP-3: On-resin peptide synthesis (L-Cys, D-Cys) The resin (1.00 eq.) was swollen in DMF for 30 min before use and the amino acid to be conjugated (Fmoc-L-Cys(Acm)-OH or Fmoc-D-Cys(Acm)-OH) (2.00 eq.) was pre-activated with DIC (4.00 eq.), Oxyma pure (2.00 eq.) and DIPEA (0.80 eq.) in DMF for 2 min. The dissolved amino acid, now present as active ester, was added to the resin for reaction. After 2.0 h reaction time the completeness of the reaction was checked by a test cleavage (cleavage of a small amount) followed by RP-HPLC and ESI-MS. Finally, the resin was washed with DMF (6×5 mL) and either further reacted or treated with DCM (3×2 min) and dried in vacuo. GP-4: Cyclisation of the peptide by disulphide bridging using thallium(III)trifluoroacetate: The dry resin (1.00 eq.) was swollen in DMF for 30 min (rt) before use. Thallium trifluoroacetate (2.00 eq.) was weighed into a Falcon tube and dissolved in DMF (38.5 ml/1 g Tl salt). After adding glycerol (4.00 eq.), the mixture was added to the resin for 45 minutes, allowing the reaction to proceed at room temperature. After this time, the solution was discarded and the process repeated. Afterwards, the resin was washed with DMF until the solution appears clear. GP-5: On-resin conjugation of the chelating unit: The resin (1.00 eq.) was swollen in DMF (rt) for 30 min before use. The coupling reagents HATU (2.00 eq.) and HOAt (2.00 eq.) were weighed together with the multimodal chelating agent (MMC) (2.00 eq.) and mixed with 5.00 mL DMF. Finally, DIPEA (4.00 eq.) was added. After a pre-activation time of 10 min, the solution was added to the peptide-coupled resin and the obtained suspension was shaken in the reactor for 3 h. GP-6: Coupling of Ruc-SS-COOH on resin: A solution of Ruc-SS-COOH (1.5 eq.), 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU; 1.5 eq.), 1-hydroxybenzotriazole (HOBt×H2O; 1.5 eq.), and DIPEA (4.0 eq.), respectively, in DMF was stirred for 15 min at rt. The pre-activated solution was added to the resin-bound, free amine and shaken for 1.5 h at rt. Subsequently, the resin was filtered and washed with DMF (6×5 mL) and either further reacted or treated with DCM (3×2 min) and dried in vacuo. GP-7: Cleavage of the peptides from the resin with additional deprotection of acid labile protecting groups: For complete cleavage, the resin was first washed with DCM (3X) and then treated with 5 mL of a solution of trifluoroacetic acid, triisopropylsilane, H2O and DCM (v/v/v; 92.5/2.5/2.5/2.5). After 45 min, the solution was eluted into a round bottom flask and another 5 mL of the solution were added to the resin. After 45 min, the solution was added to the flask and the resulting solution was concentrated under a stream of air. After dissolving the residue in MeOH and precipitation in diethyl ether, the liquid was decanted and the remaining solid was dried. Removal of remaining tBu protecting groups after peptide cleavage from the resin was carried out dissolving the crude product in TFA and stirring it until complete cleavage could be proven via HPLC-MS. After removing TFA under a stream of nitrogen, the crude unprotected product was obtained. GP-8: Purification via preparative HPLC: The crude deprotected product was dissolved in 1.0 mL of acetonitrile/water (v/v = 1/1) and filtered through a filter (VWR, Darmstadt, Germany, pore size 0.45 μm). From this, an aliquot of 100 – 1000 μL was injected into the HPLC system and the peaks that occur were collected in individual fractions so that the product can subsequently be identified by mass spectrometry. The product fractions were combined and the solvent was then concentrated in vacuo. The remaining product was mixed with tBuOH, frozen (−80 °C) and then lyophilised overnight. GP-9: Radiolabeling: 68Ga-labeling: The SSTR2-targeting compounds were radiolabeled according to the literature (Weineisen et al., 2014; Notni et al., 2011) using a fully automated synthesis module (GallElut+ from Scintomics GmbH, Germany). The following reaction steps were controlled by a computer program from Scintomics (Scintomics Control Center). In a first step, the 68Ge/68Ga-generator with SnO2 matrix (iTHEMBA labs, South Africa) was eluted with 0.1 M aq. HCl. Hereby, a fraction of 1.25 mL containing ca.80% of the entire activity (ca. 300 MBq) was transferred to a mixture of the ligand (10 nmol) in aq. HEPES solution (2.7 M, pH 2; 100 µL). The radioactive mixture was heated to 95 °C, then passed through a SPE cartridge (Waters SepPak® C18 light, sorbent amount 50 mg) into a round bottom flask. The radiolabeled product was finally eluted with EtOH/H2O (1:1 (v/v)) and the cartridge was purged with PBS (1 mL; pH 7.4) and H2O (1 mL), respectively. After evaporation of EtOH under reduced pressure, the tracer was used without further purification in in vitro and in vivo experiments. Radiochemical purity was controlled using Radio-TLC (1.0 M sodium citrate buffer). 177Lu-labeling: To 300 μL of a buffer solution (ammonium acetate, 0.25 M, pH = 5.0) 4 μL of the respective peptide solution (10−3 M in DMSO) and approximately 100 MBq of [177Lu]LuCl3 were added and the solution was heated to 95 °C for 30 min. Synthesis results and logD7.4 Each ligand was successfully synthesized by Fmoc-based SPPS with subsequent purification by RP-HPLC resulting in total yields of 2.1 – 3.2%. (Quality controls can be found in the appendix, Fig. 7 following). 68Ga-labeling of all compounds was performed using the automated synthesis module, resulting in molar activities of 6.5 - 16.4 MBq/nmol. All labeled ligands were used without further purification. The 68Ga-labeled ligands displayed a logD7.4 value in the range between −2.58 ± 0.04 and −2.10 ± 0.19. Ruc-SS-MMC-TOC RP-HPLC analytic (10→90% H2O/MeCN + 0.1% FA in 15 min): tR = 7.7 min MS (ESI, positive): m/z = 967.35 [M+2H]2+. [68Ga]Ga-Ruc-SS-MMC-TOC: RP-HPLC analytic (10→90% H2O/MeCN + 0.1% FA in 10 min): tR = 7.16 min logD7.4 = -2.23 ± 0.09 (n=8) Ruc-SS-(PEG)4-MMC-TOC
RP-HPLC analytic (10→90% MeCN in 15 min): tR = 7.25 min MS (ESI, positive): m/z = 1090.24 [M+2H]2+. [68Ga]Ga-Ruc-SS-(PEG)4-MMC-TOC: RP-HPLC analytic (10→90% H2O/MeCN + 0.1% FA in 15 min): tR = 6.36 min logD7.4 = -2.58 ± 0.04 (n=6) Ruc-SS-MMC-TATE RP-HPLC analytic (10→90% H2O/MeCN + 0.1% FA in 15 min): tR = 7.2 min MS (ESI, positive): m/z = 973.51 [M+2H]2+, 1946.56 [M+H]+. Ruc-SS-(PEG)4-MMC-TATE
RP-HPLC analytic (10→90% H2O/MeCN + 0.1% TFA in 15 min): tR = 8.1 min MS (ESI, positive): m/z = 1097.34 [M+2H]2+. [68Ga]Ga-Ruc-SS-(PEG)4-MMC-TATE: RP-HPLC analytic (10→90% H2O/MeCN + 0.1% FA in 10 min): tR = 6.45 min logD7.4 = -2.10 ± 0.19 (n=6) In vitro and in vivo characterization n-Octanol-PBS distribution coefficient (logD7.4) Approximately 0.5-1 MBq of the labeled tracer was added to 1 mL of a 1/1 mixture (v/v) of phosphate-buffered saline (PBS, pH = 7.4) and n-octanol in an Eppendorf tube (1.5 mL). After vortexing for 3 min at rt, the tubes (n = 8) were centrifuged at 9000 rpm for 5 min (Biofuge 13, Heraeus Sepatech, Osterode, Germany) and 200 μL aliquots of each of the two phases were measured separately in a γ-counter (PerkinElmer, Waltham, United States). Determination of cellular uptake via fluorescence microscopy 30,000 HCT116-SSTR2 cells/well or 30,000 HCT116-WT cells/well for control were seeded in 8-well ibidi® slide chambers 24 h prior to incubation with the conjugate of interest or rucaparib (both 5 µM) for 1 h at 37°C. Cells were then washed with PBS (2 × 3 min, 1 × 10 min) and fixated with 4 % PFA in PBS for 10 min at rt, then Draq5 nucleus stain was added as recommended by the manufacturer (ThermoFisher) for 5 min at 37 °C and was subsequently removed. PBS was filled into the wells for microscopy. Viability assays 2,000 cells/well were seeded into black clear-bottom 96 well cell culture plates 24 h prior to the experiment. The culture medium was removed and new culture medium containing the Ruc conjugate of interest was added to a final concentration of 5 µM. Ruc conjugates were diluted from a 1 mM stock solution in DMSO, hence all treatment wells contained 0.5% DMSO. After 72 h of incubation at 37 °C, cells were treated for 3 h with 10 % Alamar Blue HS for visualization of cell viability. Afterwards, fluorescence measurement at 570 nm was performed with a Tecan (Männedorf, Switzerland) Plate Reader. Data evaluation was performed using Microsoft Excel and GraphPad Prism 9 software. PET/MR imaging Animal experiments were performed in accordance with current animal welfare regulations in Germany. Athymic nude mice were xenografted with H69 tumors in their right flank. Animals were injected with 6-10 MBq of either [68Ga]Ga-Ruc-TOC or [68Ga]Ga-Ruc-(PEG)4-TATE. PET/MR imaging was performed with a Nano Scan PET/MRI 3T (Mediso, Budapest, Hungary). Static measurements were performed 45 min p.i. for 15 min. A dynamic scan was performed for 90 min upon tracer injection. As software for image reconstruction Nucline™ (Mediso, Budapest, Hungary) was used. Radioligand uptake assay H69 cells were seeded in a 96 V-bottom well plate at a density of 100,000 cells/well in medium (120 µL/well). Afterwards, solutions (15 µL/well) of either RPMI medium or of octreotide (final concentration: 10 µM) in DMSO for blockade were added. Then, a solution of the 68Ga- labeled SSTR2-ligand (15 µL/well; 6 nM or 0.6 nM final concentration) was added to all wells, and the cells were incubated for 60 min at 37 °C. Each time point was performed in triplicates. The internalization process was terminated by placing the plate on ice for 1 min. The free radioligand was obtained by centrifugation of the plate at 600 g for 3 min and removal of the supernatant. Each well was then washed with ice-cold PBS, centrifuged again and the fractions of the first two steps were combined. Internalised activity was determined by incubating the cells in 150 μl NaOH (1 M) for at least 15 min at rt and combining with the fraction from a subsequent washing step with 150 μl NaOH (1 M). Free and internalized activity, respectively, was measured in a γ-counter. Data evaluation was performed using Microsoft Excel. For graph plotting, GraphPad Prism 9 software was utilized. The features disclosed in the foregoing description, in the claims and/or in the accompanying drawings may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. REFERENCES Abida, W., Patnaik, A., Campbell, D., Shapiro, J., Bryce, A.H., McDermott, R., Sautois, B., Vogelzang, N.J., Bambury, R.M., Voog, E., Zhang, J., Piulats, J.M., Ryan, C.J., Merseburger, A.S., Daugaard, G., Heidenreich, A., Fizazi, K., Higano, C.S., Krieger, L.E., Sternberg, C.N., Watkins, S.P., Despain, D., Simmons, A.D., Loehr, A., Dowson, M., Golsorkhi, T., Chowdhury, S., and investigators, T. "Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration." J Clin Oncol 38, no.32 (2020): 3763-72. Antonarakis, E.S., Gomella, L.G., and Petrylak, D.P. "When and How to Use PARP Inhibitors in Prostate Cancer: A Systematic Review of the Literature with an Update on On- Going Trials." Eur Urol Oncol 3, no.5 (2020): 594-611. Banerjee, S.R., Pullambhatla, M., Foss, C.A., Nimmagadda, S., Ferdani, R., Anderson, C.J., Mease, R.C., and Pomper, M.G. "⁶⁴Cu-labeled inhibitors of prostate-specific membrane antigen for PET imaging of prostate cancer." J Med Chem 57, no.6 (2014): 2657-69. Benesova, M., Schafer, M., Bauder-Wust, U., Afshar-Oromieh, A., Kratochwil, C., Mier, W., Haberkorn, U., Kopka, K., and Eder, M. "Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer." J Nucl Med 56, no.6 (2015): 914-20. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., and Jemal, A. "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries." CA Cancer J Clin 68, no.6 (2018): 394-424. Carpino, L. A.; Han, G. Y., 9-Fluorenylmethoxycarbonyl amino-protecting group. The Journal of Organic Chemistry 1972, 37 (22), 3404-3409. Chen, Y., Pullambhatla, M., Foss, C.A., Byun, Y., Nimmagadda, S., Senthamizhchelvan, S., Sgouros, G., Mease, R.C., and Pomper, M.G. "2-(3-{1-Carboxy-5-[(6- [18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer." Clinical cancer research : an official journal of the American Association for Cancer Research 17, no.24 (2011): 7645-53. Deeks, E.D. "Olaparib: first global approval." Drugs 75, no.2 (2015): 231-40. Eiber, M., Maurer, T., Souvatzoglou, M., Beer, A.J., Ruffani, A., Haller, B., Graner, F.P., Kubler, H., Haberkorn, U., Eisenhut, M., Wester, H.J., Gschwend, J.E., and Schwaiger, M. "Evaluation of Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy." J Nucl Med 56, no.5 (2015): 668-74. Fendler, W.P., Schmidt, D.F., Wenter, V., Thierfelder, K.M., Zach, C., Stief, C., Bartenstein, P., Kirchner, T., Gildehaus, F.J., Gratzke, C., and Faber, C. "68Ga-PSMA PET/CT Detects the Location and Extent of Primary Prostate Cancer." J Nucl Med 57, no. 11 (2016): 1720-25. Fendler, W.P., Rahbar, K., Herrmann, K., Kratochwil, C., and Eiber, M. "(177)Lu- PSMA Radioligand Therapy for Prostate Cancer." J Nucl Med 58, no.8 (2017): 1196-200. Fendler, W.P., Calais, J., Eiber, M., Flavell, R.R., Mishoe, A., Feng, F.Y., Nguyen, H.G., Reiter, R.E., Rettig, M.B., Okamoto, S., Emmett, L., Zacho, H.D., Ilhan, H., Wetter, A., Rischpler, C., Schoder, H., Burger, I.A., Gartmann, J., Smith, R., Small, E.J., Slavik, R., Carroll, P.R., Herrmann, K., Czernin, J., and Hope, T.A. "Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial." JAMA Oncol (2019). Ghosh, A., and Heston, W.D. "Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer." J Cell Biochem 91, no.3 (2004): 528-39. Gillessen, S., Omlin, A., Attard, G., de Bono, J.S., Efstathiou, E., Fizazi, K., Halabi, S., Nelson, P.S., Sartor, O., Smith, M.R., Soule, H.R., Akaza, H., Beer, T.M., Beltran, H., Chinnaiyan, A.M., Daugaard, G., Davis, I.D., De Santis, M., Drake, C.G., Eeles, R.A., Fanti, S., Gleave, M.E., Heidenreich, A., Hussain, M., James, N.D., Lecouvet, F.E., Logothetis, C.J., Mastris, K., Nilsson, S., Oh, W.K., Olmos, D., Padhani, A.R., Parker, C., Rubin, M.A., Schalken, J.A., Scher, H.I., Sella, A., Shore, N.D., Small, E.J., Sternberg, C.N., Suzuki, H., Sweeney, C.J., Tannock, I.F., and Tombal, B. "Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015." Ann Oncol 26, no.8 (2015): 1589-604. Harmatys, K.M., Overchuk, M., Chen, J., Ding, L., Chen, Y., Pomper, M.G., and Zheng, G. "Tuning Pharmacokinetics to Improve Tumor Accumulation of a Prostate-Specific Membrane Antigen-Targeted Phototheranostic Agent." Bioconjug Chem 29, no. 11 (2018): 3746-56. Heinzel, A., Boghos, D., Mottaghy, F.M., Gaertner, F., Essler, M., von Mallek, D., and Ahmadzadehfar, H. "(68)Ga-PSMA PET/CT for monitoring response to (177)Lu-PSMA-617 radioligand therapy in patients with metastatic castration-resistant prostate cancer." Eur J Nucl Med Mol Imaging 46, no.5 (2019): 1054-62. Hensbergen, A.W., Buckle, T., van Willigen, D.M., Schottelius, M., Welling, M.M., van der Wijk, F.A., Maurer, T., van der Poel, H.G., van der Pluijm, G., van Weerden, W.M., Wester, H.-J., and van Leeuwen, F.W.B. "Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye–Protein Interaction." Journal of Nuclear Medicine 61, no.2 (2020): 234-41. Hoffmann, M.A., Wieler, H.J., Baues, C., Kuntz, N.J., Richardsen, I., and Schreckenberger, M. "The Impact of 68Ga-PSMA PET/CT and PET/MRI on the Management of Prostate Cancer." Urology (2019). Hoy, S.M. "Talazoparib: First Global Approval." Drugs 78, no.18 (2018): 1939-46. Kelly, J.M., Amor-Coarasa, A., Nikolopoulou, A., Kim, D., Williams, C., Vallabhajosula, S., and Babich, J.W. "Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics: Stability and complexation kinetics of 68Ga3+, 111In3+, 177Lu3+ and 225Ac3+." Nuclear Medicine and Biology 55 (2017): 38-46. Kossatz, S., Carney, B., Farley, C., Weber, W.A., Drain, C.M., and Reiner, T. "Direct Imaging of Drug Distribution and Target Engagement of the PARP Inhibitor Rucaparib." J Nucl Med 59, no.8 (2018): 1316-20. Merrifield, R. B., Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide. Journal of the American Chemical Society 1963, 85 (14), 2149-2154. Nizialek, E., and Antonarakis, E.S. "PARP Inhibitors in Metastatic Prostate Cancer: Evidence to Date." Cancer Manag Res 12 (2020): 8105-14. Notni, J.; Šimeček, J.; Hermann, P.; Wester, H.-J., TRAP, a Powerful and Versatile Framework for Gallium-68 Radiopharmaceuticals. Chemistry – A European Journal 2011, 17 (52), 14718-14722. Pezaro, C. "PARP inhibitor combinations in prostate cancer." Ther Adv Med Oncol 12 (2020): 1758835919897537. Petrov, S.A., Zyk, N.Y., Machulkin, A.E., Beloglazkina, E.K., and Majouga, A.G. "PSMA-targeted low-molecular double conjugates for diagnostics and therapy." Eur J Med Chem 225 (2021): 113752. Rajan, A., Carter, C.A., Kelly, R.J., Gutierrez, M., Kummar, S., Szabo, E., Yancey, M.A., Ji, J., Mannargudi, B., Woo, S., Spencer, S., Figg, W.D., and Giaccone, G. "A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors." Clin Cancer Res 18, no.8 (2012): 2344-51. Ray Banerjee, S., Chen, Z., Pullambhatla, M., Lisok, A., Chen, J., Mease, R.C., and Pomper, M.G. "Preclinical Comparative Study of 68Ga-Labeled DOTA, NOTA, and HBED- CC Chelated Radiotracers for Targeting PSMA." Bioconjug Chem 27, no.6 (2016): 1447-55. Robu, S., Schmidt, A., Eiber, M., Schottelius, M., Günther, T., Hooshyar Yousefi, B., Schwaiger, M., and Wester, H.-J. "Synthesis and preclinical evaluation of novel 18F-labeled Glu-urea-Glu-based PSMA inhibitors for prostate cancer imaging: a comparison with 18F- DCFPyl and 18F-PSMA-1007." EJNMMI research 8, no.1 (2018): 30. Sartor, O., de Bono, J., Chi, K.N., Fizazi, K., Herrmann, K., Rahbar, K., Tagawa, S.T., Nordquist, L.T., Vaishampayan, N., El-Haddad, G., Park, C.H., Beer, T.M., Armour, A., Perez- Contreras, W.J., DeSilvio, M., Kpamegan, E., Gericke, G., Messmann, R.A., Morris, M.J., Krause, B.J., and Investigators, V. "Lutetium-177-PSMA-617 for Metastatic Castration- Resistant Prostate Cancer." N Engl J Med (2021). Syed, Y.Y. "Rucaparib: First Global Approval." Drugs 77, no.5 (2017): 585-92. Takebe, N., Quinn, M., Gupta, G., and Chen, A.P. "PARP Inhibition to Enhance Response to Chemotherapy." In Targeting Cell Survival Pathways to Enhance Response to Chemotherapy, 231-57: Elsevier, 2019. Umbricht, C.A., Benešová, M., Schmid, R.M., Türler, A., Schibli, R., van der Meulen, N.P., and Müller, C. "44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA- 617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617." EJNMMI research 7, no.1 (2017): 9. Umbricht, C.A., Benešová, M., Schibli, R., and Müller, C. "Preclinical Development of Novel PSMA-Targeting Radioligands: Modulation of Albumin-Binding Properties To Improve Prostate Cancer Therapy." Molecular Pharmaceutics 15, no.6 (2018): 2297-306. Virtanen, V., Paunu, K., Ahlskog, J.K., Varnai, R., Sipeky, C., and Sundvall, M. "PARP Inhibitors in Prostate Cancer-The Preclinical Rationale and Current Clinical Development." Genes (Basel) 10, no.8 (2019). Weineisen, M.; Simecek, J.; Schottelius, M.; Schwaiger, M.; Wester, H. J., Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. Ejnmmi Res 2014, 4 (1), 63. Wilson, T. C., Xavier, M. A., Knight, J., Verhoog, S., Torres, J. B., Mosley, M., Hopkins, S. L., Wallington, S., Allen, P. D., Kersemans, V., Hueting, R., Smart, S., Gouverneur, V., & Cornelissen, B. (2019). PET imaging of PARP expression using 18F- olaparib. Journal of Nuclear Medicine, 60(4), 504–510. Yadav, M.P., Ballal, S., Sahoo, R.K., Dwivedi, S.N., and Bal, C. "Radioligand Therapy With (177)Lu-PSMA for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis." AJR Am J Roentgenol (2019): 1-11. Yao, V., and Bacich, D.J. "Prostate specific membrane antigen (PSMA) expression gives prostate cancer cells a growth advantage in a physiologically relevant folate environment in vitro." The Prostate 66, no.8 (2006): 867-75. Zhernosekov, Filosofov, D. V., Baum, R. P., Aschoff, P., Bihl, H., Razbash, A. A., Jahn, M., Jennewein, M., & Rosch, F. (2007). Processing of Generator-Produced 68Ga for Medical Application. The Journal of Nuclear Medicine (1978), 48(10), 1741–1748. https://doi.org/10.2967/jnumed.107.040378

Claims

Claims 1. A conjugate compound comprising a disease-targeting moiety (T), at least one PARP inhibitor moiety (P), a cleavable linker (X) connecting the PARP inhibitor moiety (P) to the conjugate compound, and optionally, a chelating agent (C), or a salt, solvate or tautomer thereof. 2. The conjugate compound of claim 1, wherein the disease-targeting moiety (T) comprises a peptide or small molecule, which internalizes upon binding to a cell surface biomarker, wherein said peptide or small molecule preferably targets the prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR subtypes 2, 3, and 5), gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6-integrin, αvβ8-integrin, α5β1-integrin, αvβ1-integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and/or melanocortin receptor 1 (MC1R). 3. The conjugate compound of claim 1 or 2, wherein the disease-targeting moiety (T) comprises monomers or multimers, and/or comprises further components, such as PEG linker(s), albumin-binding domain(s), further amino acid(s), and/or peptidomimetics. 4. The conjugate compound of any one of claims 1 to 3, wherein the disease-targeting moiety (T) targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), or wherein the disease-targeting moiety (T) targets SSTR, preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics. 5. The conjugate compound of any one of claims 1 to 4, wherein the PARP inhibitor moiety (P) comprises or consists of rucaparib, olaparib, talazoparib, niraparib or analogs thereof, and/or comprising two or more PARP inhibitor moieties (P), such as 2 or 3. 6. The conjugate compound of any one of the preceding claims, wherein the cleavable linker (X) comprises a substrate for enzyme cleavage or redox reaction, such as a substrate for prostate specific antigen (PSA), caspases or cathepsins, proteases or peptidases, or for the antioxidant glutathione. 7. The conjugate compound of any one of the preceding claims, wherein the chelating agent (C) is a macrocyclic chelator or a non-cyclic chelating agent, wherein the chelating agent (C) is preferably selected from the group consisting of 1,4,7,10-tetraazacyclododecane (cyclen), 2-(7-(4-aminobutyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1- yl)pentanedioic acid (MMC), 2,2',2”-(10-(2,6-dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane- 1,4,7-triyl)triacetic acid (DOTAGA), 2,2',2",2"′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), 2,2',2”-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA), 2-[1,4,7-triazacyclononan-1-yl-4,7-bis(tBu-ester)]-1,5-pentanedioic acid (NODAGA), 1,4,7,10-tetraazacyclo- dodecane-1,4,7,10-tetrakis[methylene(2- carboxyethyl)phosphinic acid] (DOTPI), N,N’-Di(2-hydroxybenzyl)ethylenediamine-N,N’-diacetic acid monohydrochloride (HBED), N,N’-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N’-diacetic acid (HBED-CC), 2,2',2”,2”’-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetamide (DOTAM), 3,3′,3”-(((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(hydroxyphosphoryl)) tripropanoic acid (TRAP), 3-(((4,7-bis((hydroxy(hydroxymethyl)phosphoryl)methyl)-1,4,7-triazonan-1- yl)methyl)(hydroxy)phosphoryl)propanoic acid (NOPO), 3,6,9,15-Tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), and ethylenediaminetetraacetic acid (EDTA), and derivatives thereof, and/or wherein the chelating agent (C) comprises or contains a radionuclide, wherein the radionuclide is preferably selected from 44Sc, 45Ti, 47Sc, 59Fe, 60Cu, 61Cu, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 89Sr, 90Y, 94mTc, 99mTc, 111In, 149Pm, 153Gd, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 203Pb, 211At, 212Bi, 212Pb or 225Ac. 8. The conjugate compound of any one of the preceding claims, having the general formula (I) or (II) wherein T is said disease-targeting moiety, S is a functional spacer, m is 0 or 1, C is said chelating agent, n is 0 or 1, A is an anchor unit, such as lysine or cysteine, X is said cleavable linker, P is said PARP inhibitor moiety o is at least 1, preferably 1, 2 or 3, or a salt, solvate or tautomer thereof. 9. The conjugate compound of claim 8, wherein the functional spacer (S) comprises at least two amino acids or amino acid derivatives, preferably non-natural amino acids, such as aminohexanoic acid (Ahx), naphthylalanine (Nal), trans-4- (aminomethyl)-cyclohexanecarboxylic acid (TXA), D-amino acids, such as D-phenylalanine, D-tyrosine, D-aspartic acid, D-lysine, β-amino acids, such as β-alanine (βA), and combinations thereof, and/or wherein the functional spacer (S) comprises polyethylenglycol (PEG), preferably (PEG)n wherein n is 1 to 24, such as n is 4. 10. The conjugate compound of claim 8 or 9, wherein the functional spacer (S) comprises or consists of an amino acid sequence selected from i. TXA-L-Nal, ii. D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.1], iii. D-Lys-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.2], iv. D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.3], v. D-Lys-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.4], vi. D-Lys-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.5], vii. D-Asp-D-Asp-β-Ala-TXA-L-Nal [SEQ ID NO.6], viii. D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx [SEQ ID NO.7], ix. D-Lys-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.8], x. D-Lys-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys [SEQ ID NO.9], xi. D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.10], xii. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx [SEQ ID NO.11], xiii. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx [SEQ ID NO.12], xiv. D-Lys(D-Lys)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx, [SEQ ID NO.13], and xv. D-Lys(D-Lys)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys [SEQ ID NO.14]. 11. The conjugate compound of any one of the preceding claims, having general formula I, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined in claims 9 and 10, n is 1 and C is as defined in claim 7, X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-KuE, Ruc-SS-MMC-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, or Ruc-SS-MMC-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, or a salt, solvate or tautomer thereof. 12. The conjugate compound of any one of claims 1 to 11, having general formula II, wherein T targets PSMA and preferably comprises Glu-urea-Glu (EuE), Glu-urea-Lys (EuK) and/or other urea-based peptides or peptidomimetics, such as Lys-urea-aminoadipic acid (Lys-urea-Aad), P comprises or consists of rucaparib and o is 1 or 2, m is 1 and S is as defined in claims 9 and 10, n is 1 and C is as defined in claim 7, X comprises a substrate for glutathione, preferably having one of the following structures DOTAGA-D-Lys(Ruc-SS)-D-Asp-β-Ala-TXA-L-Nal-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, DOTAGA-D-Lys(Ruc-SS)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys-EuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-L-Nal-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-Ahx-KuE, DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-β-Ala-TXA-L-Nal-D-Lys-EuE, or DOTAGA-D-Lys(D-Lys(Ruc-SS)2)-D-Asp-D-Asp-D-Tyr-D-Phe-D-Phe-Ahx-D-Lys- EuE, or a salt, solvate or tautomer thereof. 13. The conjugate compound of any one of the preceding claims, having general formula I, wherein T targets SSTR, preferably SSTR2, and preferably comprises TOC or TATE and/or other octreotide peptides or peptidomimetics, P comprises or consists of rucaparib and o is 1, m is 0, n is 1 and C is as defined in claim 7 X comprises a substrate for glutathione, preferably having one of the following structures Ruc-SS-MMC-TOC, Ruc-SS-(PEG)4-MMC-TOC, Ruc-SS-MMC-TATE, Ruc-SS-(PEG)4-MMC-TATE, or a salt, solvate or tautomer thereof. 14. A pharmaceutical composition comprising at least one conjugate compound of any one of claims 1 to 13 and, optionally, pharmaceutically acceptable carrier and/or excipient(s). 15. The compound of any one of claims 1 to 13 as vehicle for the specific delivery of at least one PARP inhibitor moiety to cells expressing the target the disease-targeting moiety (T) recognizes or binds to, wherein said cells are preferably tumor cells, preferably, as vehicle for the specific delivery of at least one PARP inhibitor moiety to PSMA-positive cells and tumors, or to NAALADaseL- or mGluR8-positive cells and tumors, or, preferably as vehicle for the specific delivery of at least one PARP inhibitor moiety to SSTR-expressing cells and tumors. 16. The compound of any one of claims 1 to 13 or the pharmaceutical composition of claim 14 for use in medicine. 17. The compound of any one of claims 1 to 13 or the pharmaceutical composition of claim 14 for use in the treatment of cancer, wherein, preferably, the cancer is - a PSMA-positive tumor, such as prostate cancer, wherein the prostate cancer can be metastatic prostate cancer and/or biochemically recurrent prostate cancer, glioma, lung cancer, - a tumor expressing the target, wherein the target is the somatostatin receptor (SSTR subtypes 2, 3, and 5), preferably SSTR2, - tumors expressing the target, wherein the target is selected from gastrin-releasing peptide receptor (GRPR), C-X-C motif chemokine receptor 4 (CXCR4), αvβ6 integrin, αvβ8 integrin, α5β1 integrin, αvβ1 integrin, folate receptor (FR), neurotensin receptor 1 (NTSR1), and melanocortin receptor 1 (MC1R), wherein the route of administration is preferably intravenous, intraperitoneal, oral, nasal, as solution or spray, more preferably intravenous or intraperitoneal. 18. The compound or pharmaceutical composition for use according to claim 16 or 17, in combination with another therapy, preferably chemotherapy, hormonal therapy, immune-checkpoint blockade, DNA damage response (DDR) inhibiting agents, antiangiogenic agents, tubulin inhibitors, and/or standard of care treatment, and/or in combination with external beam radiation therapy, or in combination with endoradiotherapy, such as targeted radioligand therapy (RLT) or peptide receptor radiotherapy (PRRT), preferably comprising using therapeutic isotopes in endoradiotherapy agent(s), said therapeutic isotopes being selected from 47Sc, 67Cu, 67Ga, 89Sr, 90Y, 149Pm, 149Tb, 153Sm, 161Tb, 166Ho, 177Lu, 186Re, 188Re, 211At, 212Bi, 212Pb or 225Ac, e.g. in RLT or PRRT agents. 19. The compound of any one of claims 1 to 13 or the pharmaceutical composition of claim 14 for use in patient selection, preferably comprising molecular imaging, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) with said compound or said pharmaceutical composition.
EP23837651.1A 2022-12-22 2023-12-21 Conjugate compounds and their use in cancer treatment and diagnosis Pending EP4637826A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22216113.5A EP4389150A1 (en) 2022-12-22 2022-12-22 Conjugate compounds and their use in cancer treatment and diagnosis
PCT/EP2023/087422 WO2024133780A1 (en) 2022-12-22 2023-12-21 Conjugate compounds and their use in cancer treatment and diagnosis

Publications (1)

Publication Number Publication Date
EP4637826A1 true EP4637826A1 (en) 2025-10-29

Family

ID=84569074

Family Applications (2)

Application Number Title Priority Date Filing Date
EP22216113.5A Ceased EP4389150A1 (en) 2022-12-22 2022-12-22 Conjugate compounds and their use in cancer treatment and diagnosis
EP23837651.1A Pending EP4637826A1 (en) 2022-12-22 2023-12-21 Conjugate compounds and their use in cancer treatment and diagnosis

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP22216113.5A Ceased EP4389150A1 (en) 2022-12-22 2022-12-22 Conjugate compounds and their use in cancer treatment and diagnosis

Country Status (3)

Country Link
EP (2) EP4389150A1 (en)
AU (1) AU2023409587A1 (en)
WO (1) WO2024133780A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025029946A1 (en) 2023-07-31 2025-02-06 Curium Us Llc [177lu] lutetium-psma i&t composition and dosimetry, kit, method of making, and method of using thereof
CN120324628B (en) * 2025-04-16 2026-01-30 上海生物制品研究所有限责任公司 Folic acid conjugates, their preparation methods and applications
CN121135816A (en) * 2025-08-12 2025-12-16 广东省人民医院 A radionuclide-labeled targeted PET probe, its preparation method and application

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102019135564B4 (en) * 2019-12-20 2022-05-19 Johannes-Gutenberg-Universität Mainz Connection for smart drug delivery and pharmaceutical kit for dual nuclear medicine-cytotoxic theranostics
TW202317205A (en) * 2021-06-29 2023-05-01 美國公爵大學 Radiolabeled parp inhibitor conjugates for cancer treatment

Also Published As

Publication number Publication date
AU2023409587A1 (en) 2025-05-01
WO2024133780A1 (en) 2024-06-27
EP4389150A1 (en) 2024-06-26

Similar Documents

Publication Publication Date Title
EP4389150A1 (en) Conjugate compounds and their use in cancer treatment and diagnosis
ES2795923T3 (en) Neurotensin receptor ligands
EP3131585B1 (en) Multidentate bifunctional chelating agents for radionuclide complexation in diagnostics and therapy
JP2025521237A (en) Trifunctional compounds and uses thereof
WO2019065774A1 (en) Radioactive drug
Ferro-Flores et al. Third generation radiopharmaceuticals for imaging and targeted therapy
Singh et al. Dimerization of a phage-display selected peptide for imaging of αvβ6-integrin: two approaches to the multivalent effect
CA3171753A1 (en) Stable formulations for radionuclide complexes
KR20240099330A (en) Gastric inhibitory peptide receptor ligand
US12485191B2 (en) Radiopharmaceuticals and methods of use thereof
JP7787083B2 (en) Cyclic peptides and their conjugates for addressing alpha-V-beta-6-integrin in vivo - Patent Application 20070122997
Hirata et al. Synthesis and evaluation of a multifunctional probe with a high affinity for prostate-specific membrane antigen (PSMA) and bone
SG11202113333SA (en) Compounds and methods of use
IL312107A (en) CD73 compounds
JP6410339B2 (en) Radionuclide labeled octreotide derivatives
EP4321526A1 (en) Peptide ligand targeting carbonic anhydrase ix, peptide construct comprising same, and uses thereof
CN114845742A (en) Modified GRPR antagonist peptides for cancer imaging and treatment
RU2808636C1 (en) METHOD OF OBTAINING PSMA-TARGET COMPOUND COMPLEX BASED ON UREA 177Lu-PS-161 AND COMPLEX
EP4610269A1 (en) Urokinase plasminogen activator surface receptor (upar) ligands for diagnostic or therapeutic use
Wirtz Development of biomarkers for molecular imaging and endoradiotherapy of prostate cancer
Braz Mitochondria-Targeted 111In-Radiocomplexes for Auger Therapy of Prostate Cancer
Figueiredo Dual-Targeted99mTc-radioconjugates for Prostate Cancer Theranostics
WO2024223742A1 (en) Gastric inhibitory peptide receptor ligands with bio-distribution modifier
WO2026027415A1 (en) Cxcr4 ligand suitable for radiopharmaceutical applications and method for preparation thereof
IL312106A (en) Combined therapy of RADIONUCLIDE COMPLEX

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20250717

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC ME MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)