Smart drug delivery system and pharmaceutical kit for dual nuclear medical cytotoxic theranostics

Abstract

To provide pharmaceutical compounds and pharmaceutical kits for dual nuclear medical / cytotoxic theranostics.SOLUTION: A smart drug delivery system for dual nuclear medical cytotoxic theranostics is provided, comprising either a first compound having a structure defined herein, or a second compound having the structure Chel-S-TV and a third compound having the structure CT-L-TV, wherein in the first, second, and third compounds, Chel is a radical of a chelating agent for complexing a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each linkers; and S1, S2, and S are each spacers.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a smart drug delivery system and a pharmaceutical kit for nuclear medicine / cytotoxicity dual theranostics.

[0002] This smart drug delivery system has the following structure: CT-L1-Chel-S1-TV; or [ka] a first compound having: a second compound having the structure Chel-S-TV or a third compound having the structure CT-L-TV; comprising In the first, second and third compounds, Chel is a radical of a chelator for complexing a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each a linker; and S1, S2 and S are each a spacer.

[0003] This medicine kit includes: a first container containing a first compound or a first carrier material containing a first compound; or a second container containing a second compound or a second carrier material containing a second compound; and a third container containing a third compound or a third carrier material containing a third compound; It consists of The first compound has the structure CT-L1-Chel-S1-TV; or [ka] having; the second compound has the structure Chel-S-TV; and The third compound has the structure CT-L-TV, In the structure, Chel is the radical of a chelator for complexation of a radioisotope; CT is the radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are linkers, respectively; S1, S2 and S are spacers, respectively. [Background technology]

[0004] Cytotoxic drugs, such as doxorubicin, have been used in chemotherapy for decades. In conventional systemic chemotherapy, cytotoxic drugs are administered intravenously, orally, or intraperitoneally at relatively high doses. Cytotoxic drugs damage not only cancer cells but also healthy tissues, especially cells with high dividing rates, causing severe side effects, some of which can be life-threatening, often forcing treatment to be discontinued.

[0005] To reduce side effects, low-dose targeted cytotoxic drugs with high binding affinity to tumor cells have been used for several years. Tumor affinity is mediated by a targeting vector linked to the cytotoxic active ingredient. Targeting vectors are generally agonists (substrates) or antagonists (inhibitors) of membrane-associated proteins that are significantly overexpressed in the envelope of tumor cells compared to healthy somatic cells. Targeting vectors include simple organic compounds, oligopeptides with natural or derivatized amino acids, and aptamers.

[0006] Furthermore, imaging nuclear medicine diagnostic methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been increasingly used in clinical treatment for about 15 years. Theranostic methods have also recently gained importance.

[0007] Cancer imaging nuclear medicine diagnosis and treatment (theranostics) complements and replaces chemotherapy.

[0008] In nuclear medicine diagnostics and theranostics, tumor cells are treated with radioactive isotopes, e.g. 68 Ga or 177Lu or irradiate it. This involves covalently binding each radioisotope ( 18 F) or coordinate bond ( 68 Ga, 99 mTc, 177 In the case of a medical isotope, the labeled precursor comprises a chelating agent as a chemical component essential for effective and stable complex formation of the radioisotope, and a biological targeting vector as a functional component that binds to target structures in tumor tissues, particularly membrane-bound proteins.

[0009] Targeting vectors with high affinity for cancer cells are equally suitable for targeted chemotherapy and nuclear medicine diagnostics and theranostics, and therefore research in these fields is complementary.

[0010] After intravenous injection into the blood circulation, the radioisotope-complexed nuclear medicine-labeled precursor accumulates on or within tumor cells. To minimize the radiation dose to healthy tissue, small amounts of radioisotopes with short half-lives of a few hours to a few days are used in diagnostic tests.

[0011] Chelating agents alter the composition and chemical properties of targeting vectors, generally significantly affecting their affinity for tumor cells. Therefore, combinations of chelating agents with at least one targeting vector are tailored through complex trial-and-error testing or what is called biochemical screening. This involves synthesizing numerous labeled precursors containing chelating agents and targeting vectors and quantifying their affinity for tumor cells. The chemical bond between the chelating agent and the targeting vector is crucial for the biological and nuclear medicine efficacy of each labeled precursor.

[0012] In addition to high affinity, the label precursor must fulfill the following additional requirements: Rapid and effective complexation or covalent binding of each radioisotope; High selectivity for tumor cells compared to healthy tissue; In vivo stability, i.e., biochemical stability in serum under physiological conditions.

[0013] prostate cancer Prostate cancer is the most common type of cancer and the third most deadly among men in developed countries. The disease exhibits slow tumor growth, and when diagnosed at an early stage, the 5-year survival rate approaches 100%. Survival rates drop dramatically only if the cancer is discovered when the tumor has metastasized. Meanwhile, treating the tumor too early or too invasively can unnecessarily impair a patient's quality of life. For example, surgical removal of the prostate can lead to incontinence and impotence. Reliable diagnosis and information regarding the stage of the disease are essential for successful treatment and a high quality of life. Aside from a physician's prostate examination, a common diagnostic tool is measuring tumor markers in the patient's blood. The most prominent marker of prostate cancer is the level of prostate-specific antigen (PSA). However, the significance of PSA levels is controversial, as patients with only slightly elevated levels often do not have prostate cancer; 15% of prostate cancer patients do not exhibit elevated PSA levels. Another target structure for diagnosing prostate tumors is prostate-specific membrane antigen (PSMA). In contrast to PSA, PSMA is not detectable in the blood. PSMA is a membrane-bound glycoprotein with enzymatic activity. Its function is to remove the C-terminal glutamic acid from N-acetyl-aspartyl-glutamic acid (NAAG) and folate-(poly)-γ-glutamic acid. While PSMA is rarely present in normal tissues, it is significantly overexpressed in prostate cancer cells, and its expression correlates closely with tumor stage. Lymph nodes and bone metastases of prostate cancer also express PSMA in approximately 40% of cases.

[0014] One strategy for molecular targeting of PSMA consists of binding antibodies against the protein structure of PSMA. A further approach is to exploit the enzyme activity of PSMA, which is well understood. The enzyme binding pocket of PSMA contains two Zn-binding sites that bind glutamic acid. 2+ The aromatic binding pocket is occupied by these two Zn2+ The protein faces the ion-bearing center. The protein can expand to accommodate binding partners (induced fit), using a pteroate group that docks within an aromatic binding pocket to bind not only NAAG but also folate. Exploiting the enzymatic affinity of PSMA allows for substrate uptake into cells (endocytosis) regardless of enzymatic cleavage of the substrate.

[0015] Therefore, PSMA inhibitors are particularly suitable as targeting vectors for imaging diagnostic and therapeutic radiopharmaceuticals or radiotracers. The radiolabeled inhibitor binds to the active site of the enzyme but is not converted there. Therefore, the bond between the inhibitor and the radiolabel is not separated. When facilitated by endocytosis, the radiolabeled inhibitor is internalized into the cell and accumulates in tumor cells.

[0016] Inhibitors with high affinity for PSMA (Scheme 1) generally contain a glutamic acid motif and an enzymatically non-cleavable structure. Highly effective PSMA inhibitors are 2-phosphonomethylglutaric acid or 2-phosphonomethyl-pentanedioic acid (2-PMPA), in which the glutamic acid motif is linked to a phosphonic acid group that is non-cleavable by PSMA. A further group of PSMA inhibitors, utilized in the clinically relevant radiopharmaceuticals PSMA-11 (Scheme 2) and PSMA-617 (Scheme 3), is the group of urea-based inhibitors.

[0017] It has been found advantageous to access the aromatic binding pocket of PSMA in addition to the binding pocket of the glutamic acid motif. For example, in the highly potent radiopharmaceutical PSMA-11, the L-lysine-urea-L-glutamic acid (KuE) binding motif is linked to the aromatic HBED chelator (N,N'-bis(2-hydroxy-5-(ethylene-β-carboxy)benzyl)ethylenediamine diacetate) via a hexyl linker.

[0018] In contrast, when L-lysine-urea-L-glutamic acid (KuE) is conjugated to the non-aromatic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), reduced affinity and accumulation in tumor tissue is observed. 177 Lu or 225 The use of DOTA chelators with radiopharmaceuticals bearing therapeutic radioisotopes such as Ac requires the adaptation of linkers. By specific substitution of hexyl with various aromatic structures, the highly effective radiopharmaceutical PSMA-617 was discovered as the current gold standard. [ka] [ka] [ka]

[0019] Tumor stroma Many tumors contain malignant epithelial cells surrounded by multiple non-tumorigenic cell populations, including activated fibroblasts, endothelial cells, pericytes, immunomodulatory cells, and cytokines in the extracellular matrix. These so-called stromal cells surrounding tumors play an important role in the initiation, growth, and metastasis of carcinomas. The majority of stromal cells are activated fibroblasts called cancer-associated fibroblasts (CAFs). During tumor progression, CAFs change their morphology and biological function. These changes are induced by intercellular communication between cancer cells and CAFs. CAFs then create a microenvironment that promotes cancer cell proliferation. Treatments targeting cancer cells alone have been shown to be insufficient. Effective therapies must involve the tumor microenvironment, namely CAFs. In over 90% of all human carcinomas, CAFs overexpress fibroblast activation protein (FAP). Therefore, FAPs represent a promising target for nuclear medicine diagnostics and theranostics. Similar to PSMA, FAP inhibitors (FAPIs or FAPi) are particularly suitable affine targeting vectors for FAP-labeled precursors. FAP exhibits bimodal activity, with dipeptidyl peptidase (DPP) and prolyl oligopeptidase (PREP) catalyzed by the same active site. Therefore, there are two potential types of inhibitors that inhibit the DPP and / or PREP activities of FAP. Known inhibitors of PREP activity of FAP have low selectivity for FAP. However, in cancer types where both FAP and PREP are overexpressed, PREP inhibitors may also be suitable as targeting vectors, despite their low FAP selectivity.

[0020] Scheme 4 shows a DOTA-conjugated FAP-labeled precursor in which the chelator is attached to the pharmacophore unit ((S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-aminobutyloxy)-quinoline-4-carboxamide) via the 4-aminobutoxy functionality on the quinoline. [ka]

[0021] Bone metastases Bone metastases express farnesyl pyrophosphate synthase (FPPS), an enzyme in the HMG-CoA reductase (mevalonate) pathway. Inhibition of FPPS suppresses the production of farnesyl, a molecule important for docking signaling proteins to the cell membrane. As a result, apoptosis of oncogenic bone cells is induced. FPPS is inhibited by bisphosphonates such as alendronate, pamidronate, and zoledronate. For example, the tracer BPAMD, along with the targeting vector pamidronate, is routinely used to treat bone metastases.

[0022] A particularly effective tracer for theranostics of bone metastases has been found to be zoledronate (ZOL), a hydroxybisphosphonate with a heteroaromatic N-unit. Together with chelators, NODAGA- and DOTA-conjugated zoledronate (Scheme 5) are currently the most effective radiotheranostics for bone metastases. [ka]

[0023] The prior art discloses numerous labeled precursors for cancer diagnosis and theranostics using radioisotopes.

[0024] WO2015055318A1 discloses radiotracers for the diagnosis and theranostics of prostate or epithelial cancer, such as, inter alia, the compound PSMA-617 shown in Scheme 3. DISCLOSURE OF THE INVENTION

[0025] It is an object of the present invention to provide pharmaceutical compounds and pharmaceutical kits for nuclear medicine / cytotoxicity dual theranostics.

[0026] The purpose of this is to CT-L1-Chel-S1-TV; or [ka] a first compound having: a second compound having the structure Chel-S-TV and a third compound having the structure CT-L-TV comprising; In the first, second and third compounds, Chel is a radical of a chelator for complexation of a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each a linker; S1, S2 and S are each a spacer. This is achieved through smart drug delivery systems.

[0027] The present invention further comprises: a first container containing a first compound or a first carrier material containing a first compound; or a second container containing a second compound or a second carrier material containing a second compound; and a third container containing a third compound or a third carrier material containing a third compound; Consists of; The first compound has the structure CT-L1-Chel-S1-TV; or [ka] and the second compound has the structure Chel-S-TV; and The third compound has the structure CT-L-TV; In the structure, Chel is the radical of a chelator for complexation of a radioisotope; CT is the radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each a linker; S1, S2 and S are each a spacer. A pharmaceutical kit for nuclear medicine / cytotoxic dual theranostics is provided.

[0028] The present invention further provides a structure CT-L1-Chel-S1-TV In the present invention, the compound for nuclear medicine / cytotoxic dual theranostics has the structure: Chel is a radical of a chelator for complexation of a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 is a linker; and S1 is a spacer.

[0029] The present invention further provides a structure [ka] In the structure, Chel is a radical of a chelator for complexing a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 is a linker; and S1 and S2 are spacers, respectively.

[0030] Smart drug delivery system, pharmaceutical kit and compound of the present invention CT-L1-Chel-S1-TV and [ka] Suitable embodiments of The TV is a targeting vector selected from one of structures [1] to

[18] ; [ka] [ka] Structures [1]-[8] and

[18] represent amino acid sequences; L and L1 are independently JPEG2025138647000015.jpg25161; In the structure, M1, M2, M3, M4, M5, M6, M7, M8 and M9 are amide, carboxamide, phosphinic acid, alkyl, triazole, thiourea, ethylene, maleimide radical, -(CH2)-, -(CH2CH2O)-, -CH2-CH(COOH)-NH- and -(CH2) m NH-, where m=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n1, n2, n3, n4, n5, n6, n7, n8 and n9 are independently selected from the set {0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20}; QS is the squaric acid radical [ka] and Clv is a cleavable group; S is the same as L (S=L); and / or S, S1 and S2 are independently JPEG2025138647000017.jpg18161; In the structure, O1, O2, and O3 represent amide, carboxamide, phosphinic acid, alkyl, triazole, thiourea, ethylene, maleimide radicals, -(CH2)-, -(CH2CH2O)-, -CH2-CH(COOH)-NH-, and -(CH2) q NH-, where q=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p1, p2, and p3 are independently selected from the set {0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20}; CT includes adozelesin, alestatin, anastrozole, anthramycin, bicalutamide, bizelesin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carzelesin, CC-1065, chlorambucil, cisplatin, cyclophosphamide, cytarabine (ara-C), dacarbazine (DTIC), dactinomycin, daunorubicin, dexamethasone, disulfiram, docetaxel, doxorubicin, duocarmycin A, and duocarmycin B. B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, erismodegib, etoposide (VP-16), fludarabine, fluorouracil (5-FU), flutamide, fulvestrant, gemcitabine, goserelin, idarubicin, ifosfamide, L-asparaginase, leuprolide, lomustine (CCNU), mechlorethamine (nitrogen mustard), megestrol acetate a radical of a cytotoxic compound selected from acetatr), melphalan (BCNU), menadione, mertansine, metformin, methotrexate, mirataxel, mitoxantrone, monomethylauristatin E (MMAE), motesanib, maytansinoids, napabucasin, NSC668394, NSC95397, paclitaxel, prednisone, pyrrolobenzodiazepines, pyrvinium pamoate, resveratrol, rucaparib, S2, S5, salinomycin, salidegib, shikonin, tamoxifen, temozolomide, tesetaxel, tetrazole, tretinoin, verteporfin, vinblastine, vincristine, vinorelbine, vismodegib, α-chaconine, α-solamidine, α-solanine, and α-tomatine; CT is a group of active ingredients: antimetabolites, e.g., capecitabine, cytarabine, fludarabine, fluorouracil (5-FU), gemcitabine, methotrexate; Alkylating cytostatics, such as adozelesin, bizelesin, busulfan, carzelesin, chlorambucil, cyclophosphamide, ifosfamide, lomustine (CCNU), dacarbazine (DTIC), cisplatin, carboplatin, mechlorethamine, melphalan (BCNU), temozolomide; Topoisomerase inhibitors, e.g., etoposide (VP-16); Mitotic inhibitors, such as vinblastine, vincristine, vinorelbine, docetaxel, paclitaxel, tesetaxel, mertansine, mirataxel, monomethyl auristatin E (MMAE), maytansinoids, napabucasin, and saridegib; Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, idarubicin anthramycin, salinomycin, mitoxantrone; Enzyme inhibitors, such as arrestatin, anastrozole, camptothecin, L-asparaginase, motesanib; Antiandrogens and antiestrogens, such as bicalutamide, flutamide, fulvestrant, tamoxifen, megestrol acetate; PARP inhibitors, e.g., rucaparib, olaparib, niraparib, veliparib, iniparib; Proteasome inhibitors, e.g., bortezomib; Others, such as dexamethasone, disulfiram, erismodegib, goserelin, leuprolide, menadione, metformin, NSC668394, NSC95397, prednisone, pyrrolobenzodiazepines, pyrvinium pamoate, resveratrol, S2, S5, shikonin, tetrazole, tretinoin, verteporfin, vismodegib, α-chaconine, α-solamagine, α-solanine, α-tomatine is a radical of a cytotoxic compound selected from: The cleavable group Clv is [ka] [ka] selected from the group comprising: Chelating agents Chel include H4pypa, EDTA (ethylenediaminetetraacetic acid), EDTMP (diethylenetriaminepenta(methylene-phosphonic acid)), DTPA (diethylenetriaminepentaacetic acid) and its derivatives, DOTA (dodeca-1,4,7,10-tetraaminetetraacetic acid), DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)-pentanedioic acid) and other DOTA derivatives, TRITA (trideca-1,4,7,10-tetraaminetetraacetic acid), TETA (tetradeca-1,4,8,11-tetraaminetetraacetic acid), acid) and its derivatives, NOTA (nona-1,4,7-triamine-triacetic acid) and its derivatives, such as NOTAGA (1,4,7-triazacyclononane, 1-glutaric acid, 4,7-acetic acid), TRAP (triazacyclononanephosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]), PEPA (pentadeca-1,4,7,10,13-pentaminepentaacetic acid), HEHA (hexadeca-1,4,7,10,13, 16-Hexaminepentaacetic acid) and its derivatives, HBED (hydroxybenzylethylenediamine) and its derivatives, DEDPA and its derivatives, for example, HDEDPA (1,2-[[6-(carboxylate-)pyridin-2-yl]methylamino]ethane), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives, for example, YM103, TEAP (tetraadicyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepine-N ,N,N',N'-tetraacetic acid) and derivatives, for example DATA ((6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetic acid); SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]-eicosane-1,8-diamine) and salts thereof, (NH2)2SAR (1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane) and salts and derivatives thereof, aminothiols and derivatives thereof; and / or The first, second and third carrier materials are independently selected from the group comprising water, 0.45% aqueous NaCl, 0.9% aqueous NaCl, Ringer's solution (lactated Ringer's solution), 5% dextrose solution and aqueous alcohol solution.

[0031] The smart drug delivery system and pharmaceutical kit of the present invention enable a new form of dual-targeted cancer therapy with diagnostic and therapeutic modalities (see Figure 2 and Table 1), which involves the use of low and high doses of the same active ingredient complex or two biologically and pharmacokinetically similar active ingredient complexes.

[0032] The structure of the compound or active ingredient conjugate of the present invention is shown schematically in Figures 1a to 1d, where CT represents a cytotoxic group; L and L1 each represent a cleavable linker group; Chel represents a chelating agent for labeling with a radioisotope; S represents a cleavable linker or spacer group; S1 and S2 each represent a spacer group; and TV represents a biological targeting vector.

[0033] The diagnostic and therapeutic modalities provided by the present invention are illustrated in Figure 2 by five membrane-bound receptors (i)-(v), where the designations CT, L, L1, Chel, S, S1, S2, and TV have the same meanings as explained above with respect to Figures 1a-1d. Receptors (i)-(v) shown in Figure 2, Table 1 are assigned diagnostic and therapeutic modalities (A), (B1), (B2) and (C), (D1), (D2), respectively, along with qualitative dose designations.

[0034] [Table 1]

[0035] In modalities (A), (B1), and (B2) listed in Table 1, the same active ingredient conjugate is used with (A, B2) and without (B1) a radioisotope. In modality (B1), cancer cells are exposed only to the cytotoxic active ingredient CT after endocytosis and cleavage of the linker L1, while in modality (B2), they are simultaneously exposed to the cytotoxic active ingredient CT and radiation emitted by the radioisotope.

[0036] In the case of modality (D2), two similar active ingredient complexes are used with radioisotope (iv) and without radioisotope (v).

[0037] The targeting vector TV used in accordance with the present invention has high binding affinity to membrane-bound receptors, such as proteins overexpressed on the envelopes of tumor cells in various cancers, such as prostate-specific membrane antigen (PSMA), fibroblast activation protein (FAP), or farnesyl pyrophosphate synthase (FPPS).

[0038] The spacers S, S1, S2 link the chelator Chel to the targeting vector TV and at the same time function as chemical modulators that compensate for the impairment of the binding affinity of the targeting vector TV caused by the spacer and the chelator Chel due to, for example, steric hindrance.

[0039] Similarly, linkers L and L1, as well as an optional spacer S identical to L, connect the chelator Chel to the cytotoxic active ingredient CT or the targeting vector TV, modulating their pharmacokinetic properties. Many cytotoxic active ingredients are hydrophobic and poorly soluble in serum. The pronounced lipophobicity of the cytotoxic active ingredient CT can be effectively compensated for, inter alia, with the aid of polyethylene glycol (PEG)-containing linkers L, L1. This approach is known in the state of the art as "PEGylation."

[0040] The linkers L and L1 further comprise a Clv group which, after uptake into tumor cells (endocytosis), is cleaved by enzymes or molecules present in late endosomes or lysosomes, such as glutathione (γ-L-glutamyl-L-cysteinylglycine, abbreviated as GSH), to release the cytotoxic active ingredient CT.

[0041] The linkers L, L1 are crucial for the pharmacokinetic properties and embody the central starting point of the present invention, which is based on one identical or two biologically similar active ingredient complexes for dual nuclear medicine and cytotoxic dual therapy, allowing a direct translation from diagnosis to therapy.

[0042] The present invention further provides a pharmaceutical kit for simultaneous targeted nuclear medicine / cytotoxic cancer therapy using the modalities (B2) and (D2) elucidated above. First, a radioisotope suitable for molecular imaging by PET or SPECT is used to confirm whether the targeting vector of the smart drug delivery system binds to a molecular target expressed in sufficient amounts by the patient's tumor tissue. For example, a smart drug delivery system using a PSMA inhibitor as the targeting vector must be used in prostate cancer patients and show sufficiently high and selective accumulation in the primary tumor, lymphatic system, visceral organs, or bone metastases. In this case, the smart drug delivery system (SDDS) serves as a pre-treatment diagnostic agent, indicating the suitability of treatment for each patient. Because the same SDDS is involved, identical pharmacokinetic and pharmacodynamic properties are guaranteed. Here, the patient's response level can be predicted with high accuracy. A known SDDS contains only a cytostatic drug bound to the targeting vector. Therefore, when using a known SDDS, suitability for the patient does not need to be confirmed before treatment begins. At best, target expression in patients is determined by a PET radiotracer other than SDDS, but the PET signal measured by the other PET tracer does not represent the binding and pharmacokinetics of SDDS, the latter of which is crucial for efficacy and systemic barrier penetration and dose determination.This is especially true for metastatic prostate cancer, where 11.8% of affected patients have mutations in DNA repair genes (CC Pritchard, J. Mateo, MF Walsh, N. De Sarkar, W. Abida, H. Beltran, A. Garofalo, R. Gulati, S. Carreira, R. Eeles, O. Elemento, MA Rubin et al.; Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer; N Engl J Med 2016; 375:443-453; doi: 10.1056 / NEJMoa1603144; C. Kratochwil, FL Giesel, C.-P. Heussel, D. Kazdal, V. Endris, C. Nientiedt, F. Bruchertseifer, M. Kippenberger, H. Rathke, J. Leichsenring, M. Hohenfellner, A. Morgenstern, U. Haberkorn, S. Duensing, and A. Stenzinger; Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair-Associated Genes; doi: 10.2967 / jnumed.119.234559). The compounds of the present invention determine whether treatment is appropriate for a patient in terms of both target expression and pharmacokinetic profile at the pretreatment stage. In particular, when combined with a radiosensitizing PARPi such as the above-mentioned rucaparib, an effective treatment approach is established. There has been a great deal of research into the combination of rucaparib with radiation therapy.

[0043] Depending on the indication, treatment can be performed with or without radiolabeling of smart drug delivery systems, i.e., by purely cytotoxic or nuclear medicine / cytotoxic means. In the latter case, due to the high local radiation dose, reactive free radicals (reactive oxygen species: ROS) are formed, which inactivate ABC transporter channels (ATP-binding cassette: ABC), such as P-gp or Ptch1, which are important for cancer cell resistance (multidrug resistance: MDR), and inhibit the exocytosis of cytotoxic compounds (CT) from cancer cells.

[0044] Cytotoxic compound CT (cell growth inhibition) The state of the art discloses a large number of cytotoxic active ingredients for cancer treatment.

[0045] For example, rucaparib and some of its derivatives inhibit the enzyme PARP (poly-ADP-ribose polymerase), which is involved in the repair of DNA single-strand breaks (SSBs). The effect of PARP inhibitors is based on synthetically induced lethality. In healthy cells with intact DNA, PARP inhibition does not lead to cell death because double-strand breaks (DSBs) resulting from SSBs are repaired by homologous recombination (HR). In contrast, in HR-deficient cells, PARP inhibition leads to cell death because DSBs accumulate in the cell and recruit apoptotic molecules. Two genes, BRCA1 and BRCA2 (breast cancer genes), are critically involved in HR. Mutations in these genes lead to DNA repair failure and increase the risk of tumorigenesis.

[0046] 20-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) have mutations in HR genes, including BRCA1 / 2. These patients would benefit from treatment with PARP inhibitors, which have high tumor specificity. It is also possible to induce BRCA deficiency pharmacologically. The active ingredient, enzalutamide, an inhibitor of the androgen receptor signaling pathway, can cause downregulation of BRCA genes. After enzalutamide administration, even patients without BRCA mutations can benefit from the selective tumor toxicity of rucaparib. Therefore, the patient population for PARP therapy could be expanded.

[0047] Docetaxel and paclitaxel belong to the taxane class, which inhibits the depolymerization of microtubules and inhibits mitosis (cell division).

[0048] Temozolomide is a pharmaceutically compatible active ingredient (prodrug) that, after metabolism and spontaneous hydrolytic cleavage, releases methylhydrazine (CH3(NH)NH2), which methylates DNA bases and induces apoptosis.

[0049] Monomethyl-auristatin E (MMAE) is an active anti-neoplastic agent that interrupts the cell cycle by inhibiting tubulin polymerization, thus leading to apoptosis.

[0050] Table 2 shows cytostatic agents that may be used in accordance with the present invention.

[0051] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19]

[0052] Chelating agent Chel for radioisotope labeling The chelating agent Chel binds the active ingredient complex of the present invention to 44 Sc, 47 Sc, 55 Co, 62 Cu, 64Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 89 Zr, 86 Y, 90 Y, 89 Zr, 90 Nb, 99m Tc, 111 In, 135 Sm, 159 Gd, 149 Tb, 160 Tb, 161 Tb, 165 Er, 166 Dy, 166 Ho, 175 Yb, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 213 Bi, 225 Ac and 232 The present invention is intended for labeling with a radioisotope selected from the group consisting of Th. The state of the art discloses a number of chelating agents for complexing the above radioisotopes. Scheme 6 shows examples of chelating agents that can be used in accordance with the present invention. [ka] [ka] [ka]

[0053] In nuclear medicine diagnostics (modalities (A), (C)) and simultaneous nuclear medicine / cytotoxic theranostics (modalities (B2), (D2)), radioisotopes, in particular 68 Ga and 177 According to the present invention, Lu is used. 68 Ga and also 177 The chelating agent DOTA, which has good properties for complexing Lu, is preferred. 177For complexation of Lu, the chelating agent H2pypa is preferably used. The synthesis of H4pypa is shown in Scheme 7. [ka]

[0054] Amide Coupling In the present invention, functional groups such as chelator Chel, cytotoxic compound CT, targeting vector TV, linker L, L1, and spacer S, S1, S2 are preferably linked by amide coupling reaction. In medicinal chemistry, amide coupling is the most commonly used reaction to form protein backbone. A general example of amide coupling is shown in Scheme 8. [ka]

[0055] The amide coupling strategy offers a straightforward route for the synthesis of novel compounds, as the set of readily available carboxylic acid and amine derivatives is virtually limitless. Those skilled in the art are aware of numerous reagents and protocols for amide coupling. The most commonly used amide coupling strategy is based on the condensation of a carboxylic acid with an amine. For this purpose, the carboxylic acid is generally activated. Prior to activation, the remaining functional groups are protected. This reaction can be carried out in two ways: in a single reaction medium (single pot), which involves the direct conversion of the activated carboxylic acid, or in two steps, which involves the isolation of the activated, "trapped" carboxylic acid and its reaction with an amine.

[0056] Here, carboxylic acids react with coupling agents to form reactive intermediates, which can be reacted with amines in isolated form or directly. Numerous reagents are available for carboxylic acid activation, including acid halides (chlorides, fluorides), azides, anhydrides, or carbodiimides. Furthermore, the reactive intermediates formed can be esters, such as pentafluorophenyl or hydroxysuccinimide esters. Intermediates formed from acyl chlorides or azides are highly reactive. However, harsh reaction conditions and high reactivity often pose a barrier when using sensitive substrates or amino acids. In contrast, amide coupling strategies utilizing carbodiimides such as DCC (dicyclohexylcarbodiimide) or DIC (diisopropylcarbodiimide) offer a broader range of applications. Additives are often used to improve reaction efficiency, especially in solid-phase synthesis. Aminium salts are highly efficient peptide coupling reagents with short reaction times and minimal racemization. With some additives, such as HOBt, it is impossible to completely prevent racemization. Amino reagents are used in equimolar amounts to the carboxylic acid to prevent excessive reaction with the free amines of the peptide. Phosphonium salts react with carboxylic acid salts, but this generally requires two equivalents of a base, such as DIEA. A key advantage of phosphonium salts over iminium reagents is that the phosphonium does not react with the free amino groups of the amine component. This allows coupling at the appropriate molar ratio of acid to amine, which helps prevent intramolecular cyclization of linear peptides and the overuse of expensive amine components.

[0057] A comprehensive overview of amide coupling reaction strategies and reagents can be found in the following reviews: Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?; DG Brown, J. Bostroem; J. Med. Chem. 2016, 59, 4443-4458; Peptide Coupling Reagents, More than a Letter Soup; A. El-Faham, F. Albericio; Chem. Rev. 2011, 111, 6557-6602; Rethinking amide bond synthesis; VR Pattabiraman, JW Bode; Nature, Vol. 480 (2011) 22 / 29; Amide bond formation: beyond the myth of coupling reagents; E. Valeur, M. Bradley; Chem. Soc. Rev., 2009, 38, 606-631.

[0058] Many chelators used according to the present invention, such as DOTA in particular, have one or more carboxy or amide groups and can therefore be attached in a straightforward manner to the linkers L, L1 and / or spacers S, S1, S2 using one of the amide coupling strategies known in the art.

[0059] The cleavable group Clv present in the linkers L and L1 ensures tumor-specific release of the cytotoxic active ingredient CT and is stable in the systemic circulation, i.e., in plasma. After uptake into cancer cells (endocytosis), the cleavable group Clv is cleaved, releasing the cytotoxic active ingredient CT.

[0060] Some examples of cleavable groups Clv are shown below.

[0061] Scheme 9 shows cleavable groups or linkers of the p-aminobenzoic acid-valine-citrulline type that are cleaved, in particular, by intracellular proteases of the cathepsin family. Cathepsin proteases are overexpressed in prostate tumor cells. [ka]

[0062] Scheme 10 shows a cleavable group or linker of the p-aminobenzoic acid-glutamic acid-valine-citrulline type that is also cleaved by cathepsins and is notable for its increased stability in mouse serum, which is highly advantageous for preclinical studies. [ka]

[0063] Scheme 11 shows a cleavable hydrazine group / linker that is hydrolyzed in acidic media (pH<6.2), as is present in tumor tissue. [ka]

[0064] The disulfide group / linker shown in Scheme 12 is cleaved by lysosomal glutathione (GSH: γ-L-glutamyl-L-cysteinylglycine) in a disulfide exchange reaction. [ka]

[0065] Terms used in the context of the present invention have the meanings as explained below.

[0066] Theranostics: Diagnosis and treatment of cancer using nuclear medicine agents.

[0067] Tracer: A synthetically prepared radioactively labeled substance that is used in extremely small amounts and is transformed in the body without affecting metabolism.

[0068] Label precursor: A compound containing a chelator or functional group for labeling with a radioisotope.

[0069] Pharmaceutical Kit: A single-item or multi-item pharmaceutical dosage form optionally comprising one or more containers containing one or more active ingredients optionally present, dissolved, suspended or emulsified in one or more carrier materials.

[0070] Containers: glass, metal, or plastic vials, septum vials, injection vials, or ampoules for clinical use.

[0071] Carrier substance: A liquid or solid substance that serves as a pharmaceutical carrier for an active drug ingredient and generally has no pharmaceutical activity.

[0072] Smart Drug Delivery System (SDDS): A chemical compound comprising a cytotoxic active ingredient, a cleavable linker for releasing the cytotoxic active ingredient, and a targeting vector for accumulation in tumor tissue, and optionally a further linker or spacer and a chelator for labeling with a radioisotope.

[0073] Chelating agent residue: A chelating agent as part of a chemical compound, particularly as part of an SDDS compound.

[0074] Target: A biological target structure in an organism, especially a (membrane-bound) receptor, protein, or antibody, to which a targeting vector binds.

[0075] Targeting vector: A chemical group or residue that acts as a ligand, agonist, antagonist or inhibitor for a target and has high binding affinity for that target.

[0076] Radiopharmaceutical: A radiolabeled compound or labeled precursor complexed with a radioisotope for nuclear medicine diagnostics and theranostics.

[0077] Linker: A structural unit, group or radical comprising a biologically cleavable subgroup or subunit through which a targeting vector, a cytotoxic active agent or a chelating agent is attached to a further structural unit.

[0078] Cleavable group: A structural unit, group, or residue that is cleaved by an enzyme or molecule present in the cytoplasm, endosome, or lysosome.

[0079] Spacer: A structural unit that acts as a spacer between a targeting vector and a chelating agent, counteracting the steric hindrance of the targeting vector by the chelating agent. In a particularly suitable embodiment of the present invention, the spacer comprises a cleavable group and is designed as a linker.

[0080] Active ingredient conjugate: A compound comprising a cytotoxic active ingredient, a targeting vector and a cleavable linker.

[0081] Dual active ingredient complex: a compound comprising a cytotoxic active ingredient, a targeting vector, a chelating agent, a linker and a spacer. [Brief explanation of the drawings]

[0082] [Figure 1a] [Figure 1b] [Figure 1c] [Figure 1d] [Figure 2] [Figure 3] [Figure 4] [Figure 5] [Figure 6] [Figure 7a] [Figure 7b] [Figure 8] [Figure 9] [Figure 10a] [Figure 10b] [Figure 11a] [Figure 11b] [Example]

[0083] Example 1: Dual active ingredient complex Schemes 13-22 show examples of inventive dual active ingredient complexes according to FIG. 1a, comprising a targeting vector, a chelating agent for labeling with a radioisotope and a cytotoxic active ingredient. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0084] Example 2: Dual active ingredient complex according to Figure 1b Schemes 23, 24, 25 and 26 show examples of inventive dual active ingredient conjugates according to FIG. 1b, comprising a targeting vector, a chelator for labeling with a radioisotope, a cleavable linker and a cytotoxic active ingredient. [ka] [ka] [ka] [ka]

[0085] Example 3: Active ingredient complex according to Figure 1d Schemes 27, 28, 29 and 30 show examples of inventive active ingredient conjugates according to Figure 1d, comprising a targeting vector, a cleavable linker and a cytotoxic active ingredient. [ka] [ka] [ka] [ka]

[0086] Example 4: Synthetic Strategy for PSMA Labeled Precursors In the synthesis of the active ingredient conjugates of the present invention, squaric acid diesters are preferably used. In this way, a large number of active ingredient conjugates, sometimes highly complex, can be prepared by a simple reaction. Squaric acid diesters are notable for their selective reaction with amines, such that no protecting groups are required for coupling of chelators, linkers, spacers, and targeting vectors. Furthermore, the coupling reaction can be controlled by pH.

[0087] First, a PSMA targeting vector is synthesized (see Scheme 31a), purified, and then reacted with a squaric acid diester in aqueous medium at pH 7 to obtain a precursor for conjugation with a chelator (see Scheme 32). Alternatively, coupling can be performed in organic medium using triethylamine as the base. [ka]

[0088] A targeting vector synthesized for PSMA by known methods is, for example, the PSMA inhibitor L-lysine-urea-L-glutamate (KuE) (see Scheme 31b). This involves reacting polymer-resin-bound and tert-butyloxycarbonyl-protected (tert-butyl-protected) lysine with di-tert-butyl-protected glutamic acid. After the protected glutamic acid is activated with triphosgene and coupled to the solid-phase-bound lysine, L-lysine-urea-L-glutamic acid (KuE) is removed with TFA, simultaneously completely deprotecting it. The product can then be separated from the free lysine by semi-preparative HPLC in 71% yield. [ka]

[0089] The PSMA inhibitor KuE (1) can then be conjugated to the labeled precursor using diethyl squarate as a coupling reagent (see Scheme 32). The conjugation of KuE (1) with the squaric acid diester is carried out in 0.5 M phosphate buffer at pH 7. After the addition of the two reactants, the pH must be readjusted with sodium hydroxide solution (1 M) due to the insufficient buffering capacity of the phosphate buffer. At pH 7, the single amidation of the acid proceeds at room temperature in a short reaction time. KuE-QS (2) is obtained in an overall yield of 16% after HPLC purification. [ka]

[0090] The KuE squaric acid monoester thus obtained can be stored and used as a building block for further synthesis.

[0091] Example 5: Solid-Phase-Based Synthesis of KuE Units and PSMA-617 Linkers The conjugation of the glutamic acid-urea-lysine binding motif KuE to the aromatic linker unit was achieved by solid-phase peptide synthesis as described by Benesova et al. (Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors; J Med Chem, 2016, 59, 1761-1775). The synthesis reported by Benesova et al. was slightly modified (see Scheme 33). [ka] [ka] [ka] [ka]

[0092] Example 6: Synthesis of a Couplable DOTAGA Chelator and Its Coupling to a PSMA-617 Target Vector-Linker Unit The synthesis begins with commercially available DO2A(tBu)-GABz, which is functionalized at the secondary amine with a Boc-protected amino group (see Scheme 34), allowing for the later introduction of a cytostatic linker unit. [ka] The benzyl protecting group on the glutaric acid side chain of DOTAGA(COOtBu)3(NHBoc)-GABz4 is reductively removed to allow coupling to a PSMA targeting vector via a linker.

[0093] The linker-PSMA conjugate is then attached to the chelator 6 by amide coupling. [ka]

[0094] The coupling of chelator 6 to the KuE binding linker is depicted in Scheme 35. The protected PSMA617 derivative 7 obtained by amide coupling is deprotected with trifluoroacetic acid (TFA) and cleaved from the solid phase. The overall yield of the two-step synthesis after HPLC purification is 6%.

[0095] Example 7: Synthesis of invention compound MMAE.ValCit.QS.617.KuE [ka]

[0096] The synthesis of compound MMAE.ValCit.QS.617.KuE begins with commercially available MMAE.ValCit, which is coupled to diethyl squarate in phosphate buffer (0.5 M) supplemented with DMSO at pH 7 (see Scheme 36). The MMAE.ValCit.QS unit and the 617.KuE-linker-target vector unit are then coupled in ethanol supplemented with 2% triethylamine, based on a solid phase. After HPLC purification, the synthesis yield was 43%.

[0097] Example 8: Radiolabeling For radiolabeling of PSMA-labeled precursors, 68 Ga was eluted from the ITG Ge / Ga generator with 0.05 M HCl and processed through a cation exchange column with aqueous ethanol elution. Depending on the chelator, radiolabeling was performed at pH values ​​between 3.5 and 5.5 and temperatures between 25 °C and 95 °C. To confirm the kinetic parameters of this reaction, the reaction progress was monitored by HPLC and IPTC.

[0098] Example 9: Squaric Acid as a Complexing Agent For clinical use, it is crucial that complexation proceeds efficiently at low temperatures. Squaric acid complexes free metals, thereby protecting the chelator moiety from nonspecific coordination. This effect is observed in the radiolabeling of TRAP.QS at various temperatures. TRAP quantitatively complexes at room temperature. In contrast, under the same conditions, the measured RCY value for TRAP.QS is only 50%. Increasing the temperature increases the labeling yield of TRAP.QS to quantitative values. This demonstrates the impact of squaric acid on complexation. This effect, shown in Scheme 37, allows the chelating agent AAZTA.QS to form stable complexes of highly coordinated metals, such as zirconium. [ka]

[0099] In suitable embodiments of the pharmaceutical kit of the present invention, the first, second and / or third compounds comprise one or more squaric acid groups QS. The use of squaric diesters can greatly simplify the coupling reaction.

[0100] Example 10a: Squaric Acid as an Affinity Promoter Furthermore, the inventors unexpectedly found that incorporating a squaric acid group (QS) improves the pharmacological properties and enhances the binding affinity of PSMA-specific targeting vectors. The inventors predict that the increased binding affinity is due to the ionic interaction between the squaric acid group (QS) and ARG463. To test this hypothesis, docking studies were performed. Figures 3 and 4 show the favorable positioning based on the docking studies. ARG463 is located within what is called the arginine patch of PSMA. A further putative mechanism of action is based on hydrogen bonding to Trp541, which enhances the affinity for the arene-binding pocket of PSMA.

[0101] The squaric acid group interacts with Arg463 in the arginine-rich region (dark region) and with Trp541 in the arene-binding pocket. The light-colored dotted lines represent distances in Å. The zinc ion present in the active binding pocket is shown as a sphere. Structural data are based on the structure of PSMA complexed with PSMA1007 (PDB 5O5T) determined by X-ray diffraction.

[0102] Figure 5 shows the putative binding mode of AAZTA.QS.KuE in the PSMA binding pocket. The AAZTA chelator protrudes from the PSMA pocket. The QS linker interacts with the hydrophobic portion of the binding pocket. The binding motif is located in the pharmacophore portion of the pocket and is complexed by two zinc ions. Figure 6 shows the putative binding mode of DATA.QS.EuE. The EuE binding motif results in an elongation of the linker, associated with a spatial shift of the QS linker, disrupting electrostatic interactions with amino acids within the binding pocket. Subsequent in vitro assays confirmed the results of this docking analysis.

[0103] Example 10b: Squaric Acid as an Excretion Regulator Scheme 38 shows an example of a targeting vector for PSMA and an active ingredient conjugate or label precursor having a squaric acid group attached to the targeting vector. [ka]

[0104] Conjugation of squaric acid (QS) to the PSMA tracer reduces accumulation in the kidney and the associated masking or obstruction of PET signal from the adjacent prostate, thereby significantly improving the sensitivity and reliability of PET imaging of prostate cancer. Figures 7A and 7b show 68 Ga]Ga.DOTA.QS.PSMA(A),[ 68 Ga]Ga-PSMA-11(B) and [ 68μPET images (60 min pi) of [Ga]Ga-PSMA-617(C) are shown, as well as standard uptake values ​​(SUV) of tumor tissue, kidney, and liver.

[0105] Scheme 39 shows further QS derivatives that were tested in vivo in tumor-bearing animals. [ka]

[0106] DATA.QS.KuE 68 The IgG was labeled with Ga and tested in vivo in LNCaP tumor-bearing Balb / c mice. 68 The organ accumulation (biodistribution) of [Ga]-DATA.QS.KuE is shown. The selectivity of binding was determined by competitive co-injection of the PSMA inhibitor PMPA. For comparison, Figure 9 shows the [Ga]-DATA.QS.KuE accumulation in organs (biodistribution). 68 4 shows the biodistribution of Ga]-PSMA-11.

[0107] Figures 10a and 10b show the [ 68 Ga]-PSMA-11 and [ 68 Figure 1 shows the maximum intensity predictions from the μPET study using [Ga]-DATA, QS, and KuE, respectively.

[0108] Figures 11a and 11b show the 68 Ga]-PSMA-11 and [ 68 Figure 1 shows the time-activity curve of [Ga]-DATA.QS.KuE, which exhibits significantly lower kidney exposure / dose compared to PSMA11 at approximately the same tumor enrichment. 68 Not Ga 177 In the case of treatment with highly ionizing radionuclides such as Lu, DATA.QS.KuE allows a decisive reduction in nephrotoxicity.

[0109] Example 11a: Evaluation of in vitro PSMA binding affinity of selected compounds and compound components Cellular assays were used to determine the affinity of the target vector-linker units QS.KuE, QS.K.EuE, and KuE with lipophilic linkers (similar to PSMA-617), as well as the affinity of the substructures NH2.DOTGA.617.KuE and NH2-DOTGA.QS.KuE. Additionally, the PSMA affinity of the structure MMAE.ValCit.QS.617.KuE (see Scheme 30) was determined in this study.

[0110] For the assay, LNCaP cells were pipetted into multiwell plates (Merck Millipore Multiscreen™). Each compound to be analyzed was added to a defined volume or concentration of a known K d Reference compounds with values 68 The antibodies were mixed with Ga[Ga]PSMA-10 and incubated with LNCaP cells in wells for 45 minutes. After repeated washing, cell binding activity was determined. The resulting inhibition curves were used to calculate the IC values ​​reported in Table 1. 50 value and K i values ​​were calculated.

[0111] [Table 3]

[0112] To determine nonspecific binding, all compounds were further mixed with an excess of the PSMA inhibitor 2-PMPA (2(phosphonomethyl)-pentanoic acid) and subjected to the same LNCaP assay as above.

[0113] Both the TV linker unit and the chelator-TV linker unit have affinity for PSMA similar to that of the reference compound PSMA-617. Thus, the use of QS as a linker unit results in an affinity comparable to that of the peptide PSMA-617. Neither conjugation with the DOTAGA chelator nor its labeling with the radionuclides gallium-68 and lutetium-177 results in a loss of affinity.

[0114] Using the binding unit EuE rather than KuE significantly reduces PSMA affinity, a result that confirms the findings of docking studies regarding the unfavorable orientation of the EuE derivative in the PSMA binding pocket.

[0115] Binding of the sterically bulky cytostatic drug MMAE to the ValCit linker and the TV linker unit QS.617.KuE leads to a clear decrease in affinity.

[0116] Example 7b: Determination of the cytotoxicity of the dimeric compound MMAE.ValCit.QS.617.KuE in vitro In the CellTiter Blue assay, LNCaP cells were incubated with test substances for 72 hours, and then the IC 50 Table 4 shows the IC of the preferred compound MMAE.ValCit.QS.617.KuE according to the present invention (Scheme 30) compared to the pure active ingredient MMAE. 50 Indicates the value.

[0117] [Table 4]

[0118] The compound of the present invention, MMAE.ValCitQS.617.KuE, exhibits somewhat less cytotoxicity in vitro than the pure active ingredient MMAE, but is nevertheless in the lower nanomolar range.

Claims

1. structure CT-L1-CheI-S1-TV; or 【Chemical 1】 and In the structure, Che1 is the radical of a chelator for complexation of a radioisotope; CT is the radical of a cytotoxic compound; TV is a biological targeting vector; L1 is a linker; S1 and S2 are each spacers. Compounds for nuclear medicine / cytotoxic dual theranostics.

2. structure CT-L1-CheI-S1-TV; or 【Chemistry 2】 or a first compound of claim 1 having the formula: a second compound having the structure Chel-S-TV and a third compound having the structure CT-L-TV comprising In the first, second and third compounds, Chel is a radical of a chelator for complexation of a radioisotope; CT is a radical of a cytotoxic compound; TV is a biological targeting vector; L1 and L are each a linker; S1, S2 and S are each a spacer. Smart drug delivery system for nuclear medicine / cytotoxicity dual theranostics.

3. a first container containing a first compound or a first carrier material containing a first compound; or a second container containing a second compound or a second carrier material containing a second compound; and a third container containing a third compound or a third carrier material containing a third compound; Consists of; The first compound has the structure CT-L1-CheI-S1-TV; or 【Chemistry 3】 having the second compound has the structure Chel-S-TV; and The third compound has the structure CT-L-TV, wherein: Chel is the radical of a chelator for complexation of the radioisotope; CT is a radical of a cytotoxic compound; TV is a targeting vector selected from one of structures [1] to [18]; 【Chemistry 4-1】 【Chemistry 4-2】 Structures [1]-[8] and [18] represent amino acid sequences; L and L1 are independently 【change】 having a structure selected from: In the structure, M1, M2, M3, M4, M5, M6, M7, M8, and M9 are amides, carboxamides, phosphinic acids, alkyls, triazoles, thioureas, ethylenes, maleimide radicals, -(CH ２ ) -, -(CH ２ CH ２ O) -, -CH ２ -CH(COOH)-NH- and -(CH ２ ) ｍ NH—, where m=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n1, n2, n3, n4, n5, n6, n7, n8, and n9 are independently selected from the set {0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20}; Clv is a cleavable group; QS is the squaric acid radical 【Chemistry 5】 and S is the same as L (S=L); and / or S, S1 and S2 are independently 【change】 having a structure selected from: In the structure, O1, O2, and O3 are amides, carboxamides, phosphinic acids, alkyls, triazoles, thioureas, ethylenes, maleimide radicals, -(CH ２ ) -, -(CH ２ CH ２ O) -, -CH ２ -CH(COOH)-NH- and -(CH ２ ) ｑ NH—, where q=1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p1, p2 and p3 are independently selected from the set {0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20}; A pharmaceutical kit for nuclear medicine / cytotoxic dual theranostics according to claim 1 or 2.

4. CT is performed using adazelesin, alestatin, anastrozole, anthramycin, bicalutamide, bizelesin, bortezomib, busulfan, camptothecin, capecitabine, carboplatin, carzelesin, CC-1065, chlorambucil, cisplatin, cyclophosphamide, cytarabine (ara-C), dacarbazine (DTIC), dactinomycin, daunorubicin, dexamethasone, disulfiram, docetaxel, docetaxel, Xorubicin, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, erismodegib, etoposide (VP-16), fludarabine, fluorouracil (5-FU), flutamide, fulvestrant, gemcitabine, goserelin, idarubicin, ifosfamide, L-asparaginase, leuprolide , lomustine (CCNU), mechlorethamine (nitrogen mustard), megestrol acetate, melphalan (BCNU), menadione, mertansine, metformin, methotrexate, mirataxel, mitoxantrone, monomethyl auristatin E (MMAE), motesanib, maytansinoids, napabucasin, NSC668394, NSC95397, paclitaxel, prednisone, pyrrolobenzodiazepines, pamophen The radiopharmaceutical kit according to claim 3, wherein the radioactive ion is a radical of a cytotoxic compound selected from pyrvinium acetate, resveratrol, rucaparib, S2, S5, salinomycin, salidegib, shikonin, tamoxifen, temozolomide, tesetaxel, tetrazole, tretinoin, verteporfin, vinblastine, vincristine, vinorelbine, vismodegib, α-chaconine, α-solamargine, α-solanine, and α-tomatine.

5. The cleavable group Clv is 【Chemistry 6-1】 【Chemistry 6-2】 5. The radiopharmaceutical kit of claim 3 or 4, selected from the group comprising:

6. The chelating agent Chel is H ４ PYPA, EDTA (ethylenediaminetetraacetic acid), EDTMP (diethylenetriaminepenta(methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetic acid) and its derivatives, DOTA (dodeca-1,4,7,10-tetraaminetetraacetic acid), DOTAGA (2-(1,4,7,10-tetraazacyclododecane-4,7,10)-pentanedioic acid) and other DOTA derivatives, TRITA (trideca-1,4,7,10-tetraaminetetraacetic acid), TETA (tetradeca-1,4,8,11-tetraaminetetraacetic acid) and its derivatives, NOTA (nona-1,4,7-triaminetriacetic acid) and its derivatives, e.g. For example, NOTAGA (1,4,7-triazacyclononane, 1-glutaric acid, 4,7-acetic acid), TRAP (triazacyclononanephosphinic acid), NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)-phosphinic acid]-7-[methylene(2-carboxyethyl)-phosphinic acid]), PEPA (pentadeca-1,4,7,10,13-pentaaminepentaacetic acid), HEHA (hexadeca-1,4,7,10,13,16-hexaaminepentaacetic acid) and derivatives thereof, HBED (hydroxybenzylethylenediamine) and derivatives thereof, DEDPA and derivatives thereof, e.g., H ２ DEDPA (1,2-[[6-(carboxylate-)pyridin-2-yl]methylamino]ethane), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives, for example, YM103, TEAP (tetraazacyclodecane phosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-1,4-diazepine-N,N,N',N'-tetraacetic acid) and derivatives, for example, DATA ((6-pentanoic acid)-6-(amino)methyl-1,4-diazepine triacetic acid); SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) and its salts, (NH ２ ) ２ The radiopharmaceutical kit according to any one of claims 3 to 5, wherein the radiopharmaceutical is selected from the group comprising SAR (1,8-diamino-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane) and salts and derivatives thereof, aminothiol and derivatives thereof.

7. The radiopharmaceutical kit according to any one of claims 3 to 6, wherein the space S is the same as the space L (S=L).

8. 8. The radiopharmaceutical kit of any one of claims 3 to 7, wherein the first, second, and third carrier materials are independently selected from the group comprising water, 0.45% aqueous NaCl, 0.9% aqueous NaCl, Ringer's solution (lactated Ringer's solution), 5% aqueous dextrose, and aqueous alcohol.

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