PSMA ligands for imaging and internal radiotherapy

Abstract

To provide further improved prostate-specific membrane antigen (PSMA) binders for mitigating radiation-induced side effects in PSMA-targeted radiolabeled diagnostics and therapeutics and for increasing tumor uptake of diagnostics and therapeutics.SOLUTION: The present disclosure relates to a prostate-specific membrane antigen (PSMA) binder having a specific structure that can be used for imaging and internal radiotherapy of diseases involving PSMA. Provided are compounds which bind or inhibit PSMA and furthermore carry at least one moiety which is amenable to radiolabeling.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to imaging and internal radiotherapy for diseases involving prostate-specific membrane antigen (PSMA). Compounds are provided that bind to or inhibit PSMA and have at least one moiety suitable for radiolabeling. Medical uses of such compounds are also provided.

[0002] In this specification, several documents, including patent applications and manufacturer's descriptions, are incorporated by reference. While the disclosures of these documents are not considered relevant to the patentability of the present invention, they are incorporated herein by reference in their entirety. More specifically, all relevant documents are incorporated by reference to the same extent as to indicate that each individual document is incorporated by reference specifically and individually. [Background technology]

[0003] Prostate cancer (PCa) remains the most common malignant disease in men, with a high rate of poor survival rates over the past few decades. Prostate-specific membrane antigen (PSMA) or glutamate carboxypeptidase II (GCP II) has demonstrated its suitability as an excellent target for the development of highly sensitive radiolabeling agents for internal radiotherapy and imaging of prostate cancer due to its overexpression in prostate cancer (Silver, DA et al., Prostate-specific membrane antigen expression in normal and malignant human tissues. Clinical Cancer Research, 1997.3(1):81-85). (Afshar-Oromieh, A. et al., The diagnostic value of PET / CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. European journal of nuclear medicine and molecular imaging, 2015.42(2):197-209; Benesova, M. et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. Journal of Nuclear Medicine, 2015.56(6):pp. 914-920; Robu, S. et al., Preclinical evaluation and first patient application of 99mTc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. Journal of Nuclear Medicine, 2016:jnumed. 116.178939; Weineisen, M.Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endoradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2014.55(Supplement 1): pages 1083-1083; Rowe, S. et al., PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges. Prostate cancer and prostatic diseases, 2016; Maurer, T. et al., Current us. e of PSMA-PET in prostate cancer management. Nature Reviews Urology, 2016). Prostate-specific membrane antigen (PSMA) is an extracellular hydrolase whose catalytic center contains two zinc(II) ions with a cross-linked hydroxido ligand. Although PSMA is highly upregulated in metastatic and hormone-refractory prostate cancer, its physiological expression has also been reported in the kidney, salivary glands, small intestine, brain, and, to a lesser extent, in healthy prostate tissue. In the intestine, PSMA promotes folate absorption by converting pteroylpoly-γ-glutamate to pteroylglutamate (folate). In the brain, PSMA hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate. The enzymatic function of PSMA in normal and pathological prostates has not been elucidated.

[0004] PSMA-targeting molecules typically contain a binding unit that includes a zinc-binding group (such as urea (Zhou, J. et al., NAAG peptidase inhibitors and their potential for diagnosis and therapy. Nature Reviews Drug Discovery, 2005.4(12):1015-1026), phosphinate, or phosphoramidate) linked to a P1' glutamate moiety (Machulkin, AE et al., Small-molecule PSMA ligands. Current state, SAR and perspectives. Journal of drug targeting, 2016: pp. 1-15). The binding unit ensures high affinity and specificity to PSMA and is typically further linked to an effector functional group. The effector moiety is more mobile and to some extent resistant to structural modifications. The entry tunnel into PSMA contains two distinct and significant structural properties that are important for ligand binding. The first is an arginine patch, a positively charged region on the wall of the entrance tunnel, which provides a structural explanation for the preference of negatively charged functional groups at the P1 site of PSMA. Upon binding, the concerted positional changes of the arginine side chain can lead to the opening of the S1 hydrophobic accessory pocket, a second important structure, which has been shown to accept the iodobenzyl group of several urea-based inhibitors, thus contributing to its high affinity for PSMA (Barinka, C. et al., Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization†. Journal of medicinal chemistry, 2008. 51(24):7737~7743).

[0005] Zhang et al. discovered a remote arene-binding site on prostate-specific membrane antigen (Zhang, AX et al., A remote arene-binding site on prostate-specific membrane antigen) that can utilize a bidentate binding mode. Revealed by antibody-recruiting small molecules. Journal of the American Chemical Society, 2010. 132(36): pp. 12711-12716). The so-called arene binding site is a simple structural motif formed by the side chains of Arg463, Arg511, and Trp541, and is part of the PSMA entrance lid. Binding of the distal inhibitor moiety to the arene binding site can result in a substantial increase in inhibitor affinity to PSMA due to avidity. PSMA I&T (see Figure 1) was developed with the intention of interacting with PSMA in this manner, but nevertheless, no crystal structure analysis of the available binding mode exists. According to Zhang et al., the required property is a linker unit (suberic acid in the case of PSMA I&T) that promotes the opening of the PSMA entrance lid, thereby enabling proximity of the arene binding site. The structural composition of the linker is important for tumor targeting and biological activity, as well as... It has been further shown that it has a significant effect on imaging of contrast and pharmacokinetics (Liu, T. et al., Spacer length effects on in vitro). Imaging and surface accessibility of fluorescent inhibitors of prostate-specific membrane antigen. Bioorganic & medicinal chemistry letters, 2011.21(23):7013-7016). These are properties important for both high image quality and effective targeted internal radiotherapy.

[0006] Two categories of PSMA-targeted inhibitors are currently used in clinical practice. One category consists of tracers with chelate units for complexing radionuclides, such as PSMA I&T or related compounds (Kiess, AP et al., Prostate-specific membrane antigen as a target for cancer imaging and therapy. The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section (Official publication of the Society of..., 2015.59(3):241). The other is a small molecule containing a targeting unit and an effector molecule. Depending on the radionuclide / halogen used, radiolabeled PSMA inhibitors can be used for imaging or internal radiotherapy. Among small molecule inhibitors with chelating agents for imaging, the most frequently used drugs for selective PSMA imaging are PSMA HBED-CC (Eder, M. et al., 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjugate chemistry, 2012.23(4):688~697) and PSMA-617 (Benesova, M. et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety). These include PSMA I&T (Weineisen, M. et al., Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endoradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2015. 56(6): pp. 914-920) and PSMA I&T (Weineisen, M. et al., Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endoradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2014. 55(Appendix 1): pp. 1083-1083). PSMA HBED-CC or PSMA-11 is one of the first PSMA inhibitors and is currently used for imaging because the chelating agent HBED-CC is not therapeutically applicable. However, due to the unique physical characteristics and advantages of 18F for PET imaging, such as a longer half-life and lower positron energy, which leads to higher image resolution and the possibility of large-scale production in cyclotrons, several groups are advocating for its use in PCa imaging. 18 We focused on developing fluorine-labeled urea-based inhibitors. 18 F-labeled urea-based PSMA inhibitor [ 18 [18F]DCFPyl shows promising results in the detection of primary and metastatic PCa (Rowe, SP et al., PSMA-Based [18F]DCFPyl PET / CT Is Superior to Conventional Imaging for Lesion Detection in Patients with Metastatic Prostate Cancer.Molecular Imaging and B iology, 2016: pp. 1-9), and in comparative studies, [ 68[18F] DCFPyL and [68Ga] Ga-PSMA-HBED-CC demonstrated superiority over [18F] PSMA-HBED-CC (Dietlein, M. et al., Comparison of [18F] DCFPyL and [68Ga] Ga-PSMA-HBED-CC for PSMA-PET imaging in patients with relapsed prostate cancer. Molecular Imaging and Biology, 2015. 17(4): pp. 575-584).

[0007] PSMA DKFZ 617 (Benesova, M. et al., Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. Journal of Nuclear Medicine, 2015. 56(6): pp. 914-920; Becker, A. et al., Nephro- and hepatotoxicity after radioligand therapy of metastatic castrate-resistant prostate cancer with 177Lu-PSMA-617. Journal of Nuclear Medicine, 2016. 57(Appendix 2): pp. 1430-1430; Rahbar, K. et al., Response and tolerability of a single dose of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: a multicenter retrospective analysis. Journal of Nuclear Medicine, 2016: jnumed. 116. 173757) and PSMA I&T (Weineisen, M. et al., Development and first in human evaluation of PSMA I&T - A ligand for diagnostic imaging and endoradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2014. 55(Suppl 1): 1083 - 1083 pages, Eiber, M. et al., Systemic radioligand therapy with 177Lu - PSMA I&T in patients with metastatic castration - resistant prostate cancer. Journal of Nuclear Medicine, 2016. 57(Suppl 2): 61 - 61 pages; Schottelius, M. et al., [111In] PSMA - I&T: expanding the spectrum of PSMA - I&T applications towards SPECT and radioguided surgery. EJNMMI research, 2015. 5(1): 1 page) are applied in the symptomatic treatment of prostate cancer patients in clinical settings. The range of possible radioactive metal chelation, especially 111 In, 177 Lu, 90 Y and 213 Bi, enables the chelate units DOTA and related DOTAGA to be used not only for imaging but also for therapeutic applications. 111 In]PSMA I&T has already been clinically implemented in radioguided surgery to assist surgeons during the resection of malignant tissue (Schottelius, M. et al., [111 In] PSMA-I&T: expanding the spectrum of PSMA-I&T applications towards SPECT and radioguided surgery. EJNMMI research, 2015.5(1): p. 1). Similarly, the PSMA inhibitor PSMA I&S (imaging and surgery), which has been developed and clinically tested in recent years, has shown very promising results (Robu, S. et al., Preclinical evaluation and first patient application of 99mTc-PSMA-I&S). for SPECT imaging and radioguided surgery in prostate cancer.Journal of Nuclear Medicine, 2016:jnumed.116.178939 page).

[0008] [ 177 Internal radiotherapy using Lu]PSMA I&T demonstrated potential efficacy, tolerability, and high safety in patients receiving up to 4 cycles at 7.4 GBq. Dose measurements obtained for organ radiation revealed that the kidneys and salivary glands, in particular, received the second highest dose after tumor lesions. Similar radiation values ​​were observed with PSMA DKFZ 617 and [ 18 Regarding [18F]DCFPyL, it was shown (Rowe, SP et al., PSMA-Based [18F] DCFPyL PET / CT Is Superior to Conventional Imaging for Lesion Detection in Patients with Metastatic Prostate) Cancer. Molecular Imaging and Biology, 2016: pp. 1-9; Delker, A. et al., Dosimetry for 177Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer.European journal of nuclear medicine and molecular imaging, 2016.43(1):42~51 pages;Kabasakal, L. et al., Pre-therapeutic dosimetry of normal organs and tissues of 177Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer.European journal of nuclear medicine and molecular imaging imaging, 2015.42(13): pages 1976-1983; Yadav, MP et al., 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficiency, and quality of life assessment. European Journal of Nuclear Medicine and Molecular Imaging, 2016: pages 1-11). These elevated figures can be explained by the physiological expression of PSMA (Silver, DA et al., Prostate-specific membrane antigen expression in normal and malignant human tissues. Clinical Cancer Research, 1997.3(1):81-85) and the renal excretion of radiolabeled compounds. While the renal and hematological toxicity that occasionally occurs after administration is usually reversible, there is a natural concern regarding chronic toxicity, particularly in patients with long-term overall survival rates, such as PCa patients. Therefore, a suitable concept is needed to reduce unwanted radiation while simultaneously increasing tumor uptake. [Overview of the project] [Problems that the invention aims to solve]

[0009] In view of the above, the underlying technical problem of the present invention lies in the supply of means and methods for mitigating the radioactive side effects of PSMA-targeted radiolabeled diagnostics and therapies. Further technical challenges lie in the supply of means and methods for increasing tumor uptake in such diagnostics and therapies. More generally, technical challenges lie in the supply of improved PSMA conjugates. [Means for solving the problem]

[0010] The technical challenges are addressed by the subject matter outlined in the attached claims, and further details are provided below. The details will be explained. In particular, the present invention provides, in a first embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] (In the formula, m is an integer between 2 and 6, preferably between 2 and 4, more preferably 2; n is an integer between 2 and 6, preferably between 2 and 4, more preferably 2 or 4; R 1L is CH2, NH or O, preferably NH; R 2L is C or P(OH), preferably C; R 3L is CH2, NH or O, preferably NH; X 1 The bond is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds, and is preferably an amide bond; L 1This is a divalent linking group having a structure selected from oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea), preferably having a structure selected from oligoamide and oligo(ester-amide). The linking group may have an EDS group; X 2 The bond is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds, and is preferably an amide bond; R 2 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH; R 3 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH; r is 0 or 1, preferably 1; p is either 0 or 1; q is either 0 or 1; Preferably, p+q=1; R 4 The group is selected from aryl groups and EDS groups; X 3 These include amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, amine bonds, and formula

[0013] [ka]

[0014] Selected from the groups, in the formula, the bond marked with a carbonyl group is X 3 to R M It attaches to X, and other marked bonds are X 3 Attach it to the remainder of the compound of formula (I); Preferably an amide bond; R M This is a labeling group containing a chelate group which optionally contains a chelated non-radioactive or radioactive cation; Furthermore, in the formula, the EDS group is present at least once in the compound of formula (I), (E-1A), (E-1B), (E-2A), and (E-2B):

[0015] [ka]

[0016] Having a structure selected from, During the ceremony,

[0017] [ka]

[0018] This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); s is 1, 2, or 3, preferably 1 or 2, more preferably 1; t is 1, 2, or 3, preferably 1 or 2, more preferably 2; R 5A Independently, for each occurrence when s>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 5A and The bond with the phenyl ring is s R5A This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 5B Independently, for each occurrence where s>1, the substituent is one that has a lone pair of electrons on an atom directly attached to the phenyl ring represented by formula (E-1B), and the substituent is preferably selected from -OH and -NH2, more preferably -NH2, R 5B The bond between the phenyl ring and the s R 5B This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 6A Independently, for each occurrence when t>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 6A The bond between the phenyl ring and the t R 6A This indicates that the group substitutes t hydrogen atoms at any position on the phenyl ring; and R 6B Independently, for each occurrence when t>1, the substituent has a lone pair of electrons on an atom directly attached to the phenyl ring represented by formula (E-1B), and the substituent is preferably selected from -OH and -NH2, more preferably -OH, R 6B The bond between the phenyl ring and the t R 6B (This represents the substitution of t hydrogen atoms at any position on the phenyl ring.)

[0019] The introduction of EDS substituents, such as those described above, in which the aromatic ring has one or more substituents with high electron density selected from electron-withdrawing substituents and substituents with lone pairs of electrons, brings about several unexpected benefits. These benefits include increased affinity, improved internal translocation, increased tumor cell retention, decreased nonspecific binding, reduced renal accumulation, and increased tumor uptake.

[0020] In particular, the reduction in nonspecific uptake in organs other than the prostate leads to a reduction in unwanted radiation exposure and decreases radiation-induced side effects. To illustrate these advantages, we refer to the properties of particularly preferred compounds, referred to herein as PSMA-71 and PSMA-66, which will be discussed in more detail later.

[0021] especially,[ 177 Compared to Lu]PSMA I&T, nanomolar affinity (5.3±2.0nM vs. 7.9±2.4nM) and significantly improved internal migration (206.8±1.7% vs. 75.5±1.6%) were observed. 177 Lu]PSMA-71 demonstrates superiority. In vivo distribution data is [ 177 Lu]PSMA-71, [ 177 Compared to Lu]PSMA I&T, it showed significantly higher tumor uptake (14.29±0.89 vs. 4.06±1.12%ID / g, respectively), while renal accumulation was similar (32.36±2.49 vs. 34.66±17.20%ID / g, respectively).

[0022] Similarly, decreased nanomolar affinity (3.8±0.3nM vs. 7.9±2.4nM), significantly improved internal transfer (297.8±2.0% vs. 75.5±1.6%), increased in vitro tumor cell retention (90.1±3.5% vs. 62.8±0.4%, 60-minute incubation) accompanied by decreased in vivo nonspecific binding, reduced renal accumulation (117.5±6.9% ID / g vs. 128.9±10.7% ID / g), and more than twofold increase in tumor uptake (10.0±0.4% vs. 4.7±1.0% ID / g) were observed, [ 177 In a direct comparison with [Lu]PSMA I&T[ 177 Lu]PSMA-66 demonstrates superiority.

[0023] As noted above, salts of the compounds of the present invention, including the compound of formula (I), (and their preferred embodiments) are also suitable for use in the context of the present invention. These salts are understood to be generally pharmaceutically acceptable salt forms of these compounds, which may be formed by the protonation of atoms having lone pairs of electrons that are easily protonated, such as amino groups with inorganic or organic acids, or salts of carboxylic acid groups with physiologically acceptable cations, as is well known in the art. An example of a base addition salt is, for example, sodium This includes alkali metal salts such as potassium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, diethanolamine salt, or ethylenediamine salt; aralkylamine salts such as N,N-dibenzylethylenediamine salt and benetamine salt; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; and basic amino acid salts such as arginine salt or lysine salt. Exemplary acid addition salts include, for example, mineral salts such as hydrochloride, hydrochloride, hydroiodide, sulfate, nitrate, phosphate (e.g., phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, or perchlorate; organic salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate, or ascorbate; sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-phenylsulfonate, or camphorsulfonate; and acidic amino acid salts such as aspartate or glutamate.

[0024] Further examples of pharmaceutically acceptable salts include, but are not limited to, acetates, adipines, alginates, ascorbicates, aspartates, benzenesulfons, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, calcium edetates, camphorates, camphor sulfons, cansilates, carbonates, chlorides, citrates, clavulanates, cyclopentanepropionates, diglucons, dihydrochlorides, dodecyl sulfates, and erythrocytes. Detolate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptone, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptaneate, hexanoate, hexylresorcinate, hydravamin, hydrochloride, iodide Hydrogenates, 2-hydroxyethanesulfonates, hydroxynaphthoates, iodide salts, isothionates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malons, mandelates, mesylates, methanesulfons, methylsulfates, mucinates, 2-naphthalenesulfons, napsylates, nicotinates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), This includes palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate, etc. (See, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, pp. 1-19 (1977)).

[0025] Throughout this specification, unless otherwise specified, the term “compound” is understood to include solvates, polymorphs, prodrugs, codrugs, cocrystals, tautomers, racemates, enantiomers or diastereomers, or mixtures thereof.

[0026] When the compound of the present invention is provided in crystalline form, the structure may contain solvent molecules. The solvent is typically a pharmaceutically acceptable solvent, including, among other things, water (hydrate) or organic solvents. Examples of possible solvates include ethanes and isopropanolates.

[0027] The term "codrug" refers to two or more therapeutic compounds linked together by covalent chemical bonds. A detailed definition can be found, for example, in N. Das et al., European Journal of Pharmaceutical Sciences, 41, 2010, 571-588.

[0028] The term "cocrystal" refers to a multicomponent crystal in which all components are solid under ambient conditions when they are in their pure form. These components coexist as stoichiometric or non-stoichiometric ratios of a target molecule or ion (i.e., the compound of the present invention) and one or more neutral molecular cocrystal-forming agents. A detailed discussion can be found, for example, in Ning Shan et al., Drug Discovery Today, 13(9 / 10), 2008, 440-446 and DJ Good et al., Cryst.Growth Des., 9(5), 2009, 2252-2264.

[0029] The compounds of the present invention can also be provided in the form of prodrugs, that is, compounds that are metabolized in vivo to active metabolites. Preferred prodrugs are, for example, esters. Specific examples of preferred groups are shown, in particular, in paragraphs

[0082] to

[0118] under the heading "Prodrugs and Protecting Groups" in US 2007 / 0072831.

[0030] It is understood that all possible charge states are encompassed insofar as the compounds of the present invention exhibit pH-dependent charge states. In this regard, the preferred pH range is 0 to 14.

[0031] It is understood that the compounds according to the present invention are provided in an electrically neutral form, insofar as they retain a net charge. This is achieved by one or more counterions, the preferred counterions being defined above in relation to the term "salt".

[0032] In equation (I), m is an integer between 2 and 6. Preferably, m is between 2 and 4, more preferably 2. 1L R is CH2, NH or O, preferably NH. 2L R is C or P(OH), preferably C. 3L is CH2, NH or O, preferably NH. Thus, compounds of formula (I) or salts thereof are also preferred, where m is 2 and R 1L NH is R 2L C is C, and R 3L It is NH.

[0033] n is an integer between 2 and 6, preferably between 2 and 4, more preferably 2 or 4, and most preferably 2. Thus, compounds of formula (I) or salts thereof are particularly preferred, where m is 2, n is 2 or 4, and R 1L NH is R 2L C is C, and R 3L is NH. Most preferably, it is a compound of formula (I) or a salt thereof, where m is 2, n is 2, and R 1L NH is R 2L C is C, and R 3L It is NH.

[0034] X in equation (I) 1The following are selected from amide bonds (i.e., -C(O)-NH-), ether bonds (i.e., -O-), thioether bonds (i.e., -S-), ester bonds (i.e., -C(O)-O-), thioester bonds (i.e., -C(S)-O- or -C(O)-S-), urea crosslinks (i.e., -NH-C(O)-NH-), and amine bonds (i.e., -NH-). 1 Preferably, it is an amide bond.

[0035] Furthermore, in formula (I), it is even more preferable that n is 2 and X 1 However, the amide bond -C The carbon atom of (O)-NH- forms the group-(CH2) n - is an amide bond attached to X 1 However, the carbon atom of the amide bond -C(O)-NH- is the group -(CH2) n - is either an amide bond attached to -. Preferably, n is 2 and X 1 However, the carbon atom of the amide bond -C(O)-NH- is the group -(CH2) n - is an amide bond attached to the object.

[0036] Thus, particularly preferred are compounds of formula (I) and salts thereof, where m is 2, n is 2, and R 1L NH is R 2L C is R 3L NH and X 1 The carbon atom in the amide bond -C(O)-NH- is the group -(CH2) n - This is an amide bond attached to the object.

[0037] L in equation (I) 1This is a divalent linking group having an oligoamide structure in which the linking group may have an EDS group, preferably a structure selected from oligoamide and oligo(ester-amide), more preferably a structure selected from oligoamide and oligo(ester-amide), and more preferably a divalent linking group having an oligoamide structure in which the linking group may have an EDS group.

[0038] L 1 In the definitions of oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea), the term "oligo" in these terms is understood to refer to a group in which 2 to 20, more preferably 2 to 10 subunits are linked by the type of bond specified in the same term. As will be understood by those skilled in the art, when two different types of bonding are indicated in parentheses, both types of bonding are present in the group concerned (for example, in "oligo(ester-amide)", ester and amide bonds are present).

[0039] More preferably, L 1The oligoamide has a structure selected from oligo(ester-amide) which contains a total of 1 to 5, more preferably 1 to 3, and most preferably 1 or 2 amide bonds in its main chain, and oligo(ester-amide) which contains a total of 2 to 5, more preferably 2 to 3, and most preferably 2 amide and ester bonds in its main chain. In a particularly preferred embodiment, L 1 This represents a divalent linking group having an oligoamide structure containing one or two amide bonds in its main chain.

[0040] Furthermore, L 1 This refers to an EDS group as defined herein (i.e., a group having a high electron density substituent or "high electron density substituent"), i.e., L 1 It can have EDS groups covalently attached to it. Preferably, any EDS group is a divalent linking group L 1 It is attached to the main chain as a substituent, L 1 These are oligoamides, oligoethers, oligothioethers, oligoesters, oligothioesters, oligoureas, oligo(ether-amides), oligo(thioether-amides), oligo(ester-amides), oligo(thioester-amides), oligo(urea-amides), oligo(ether-thioethers) Structures selected from oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea), preferably structures selected from oligoamide and oligo(ester-amide), and most preferably, the main chain being X in the compound of formula (I). 1 and X 2 It has an oligoamide structure that extends between it and L. 1 Applying a further preferred definition of L 1has a structure selected from an oligoamide containing a total of 1 to 5, more preferably a total of 1 to 3, and most preferably a total of 1 or 2 amide bonds in its main chain, and an oligo(ester - amide) containing a total of 2 to 5, more preferably a total of 2 to 3, and most preferably a total of 2 amide and ester bonds in its main chain. In a particularly preferred embodiment, L 1 represents a divalent linking group having an oligoamide structure containing 1 or 2 amide bonds in its main chain.

[0041] According to the above, L 1 can have one or more, for example 2 or 3, EDS groups. However, preferably, L 1 has no EDS group, or L 1 has one EDS group, and more preferably, L 1 has one EDS group.

[0042] L 1 When L (including the more preferred case where EDS has one EDS group) has an EDS group, preferably, the EDS group has a structure selected from (E - 1A), (E - 2A), and (E - 2B). More preferably, the EDS group has a structure selected from (E - 2A) and (E - 2B), and most preferably, the EDS group has structure (E - 2A).

[0043] As will be understood by those skilled in the art, the accommodation that L 1 can have an EDS group serves as information about the possible positions of this group in the compounds according to the present invention. The fact that L 1 can have an EDS group does not impose restrictions on the presence of other groups that can be present as alternative or additional substituents on the main chain of, for example, L 1 . For example, preferably, the linking group L 1 independently contains one or more, for example 2, groups selected from -OH, -OCH₃, -COOH, -COOCH₃, -NH₂, and -NHC(NH)NH₂ attached as substituents to its main chain. More preferably, the linking group L 1contains one or more, for example two, groups -COOH attached as substituents to its main chain.

[0044] In formula (I), X 2 is selected from an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge and an amine bond, preferably an amide bond. More preferably, the nitrogen atom of the amide bond -C(O)-NH- is attached to L 1 is attached.

[0045] Thus, and preferably, X 1 and X 2 are both amide bonds, particularly amide bonds arranged in the preferred direction further defined above. In accordance with the above, preferably, the moiety -X 2 -L 1 -X 1 - in formula (I) is: *-C(O)-NH-R 7 -NH-C(O)-R 8 -C(O)-NH- (L-1), *-C(O)-NH-R 9A -NH-C(O)-R 10A -C(O)-NH-R 11A -NH-C(O)- (L-2A), and *-C(O)-NH-R 9B -C(O)-NH-R 10B -C(O)-NH-R 11B -NH-C(O)- (L-2B) having a structure selected from (wherein the amide bond marked with * is attached to the carbon atom having R in formula (I) [[ID=5q]] 2 and R 7 、R 8 、R 9A 、R 9B 、R 11A and R 11BEach of the alkanediyl groups is independently selected from optionally substituted C2-C10 alkanediyl groups, preferably optionally substituted linear C2-C10 alkanediyl groups, and each of the alkanediyl groups is independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and EDS groups. They may be substituted with one or more substituents selected from, and R 10A and R 10B The C2-C10 alkanediyl group is selected from optionally substituted C2-C10 alkanediyl groups, preferably optionally substituted linear C2-C10 alkanediyl groups, and optionally substituted C6-C10 arenediyl groups, preferably phenylene groups, and each alkanediyl and arenediyl group may be independently substituted with one or more substituents selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2, and EDS groups. 10A Preferably, it is a C2-C10 alkanediyl substituted with the optional substitutions defined above, more preferably a linear C2-C10 alkanediyl substituted with the optional substitutions. 10B This is preferably a C6-C10 arenediyl substituted with any of the options defined above, more preferably a phenylene group, such as a para-phenylene group).

[0046] In the base of formulas (L-1), (L-2A), and (L-2B), preferably, R 7 Any substituent above is -COOH, R 8 Any substituent of is an EDS group, R 9A and R 9B Any substituent above is -COOH, R 10A Any substituent above is an EDS group, and R 11A and R 11B Any substituent above is -COOH.

[0047] Preferably, each of the groups of formula (L-1) and (L-2A) has at least one substituent, preferably R, as described above. 8 and R10A The molecule has an EDS group as a substituent. In this context, preferably, the EDS group has a structure selected from (E-1A), (E-2A), and (E-2B). More preferably, the EDS group has a structure selected from (E-2A) and (E-2B), and most preferably, the EDS group has structure (E-2A).

[0048] Furthermore, preferably, R in formula (L-1) 7 and R 8 The total number of carbon atoms in the molecule is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituent, and R of formula (L-2A) 9A , R 10A and R 11A The total number of carbon atoms in the molecule is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituent, and R of formula (L-2B) 9B , R 10B and R 11B The total number of carbon atoms in the molecule is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituents.

[0049] The above n and X 1 From the information provided regarding the preferred meaning of -X in formula (I), even more preferably, 2 -L 1 -X 1 -However, when n is 4, it has structure (L-1), and -X in formula (I) 2 -L 1 -X 1 - However, it is understood that when n is 2, it has structure (L-2A) or (L-2B).

[0050] In accordance with the above definition, even more preferably, the part -X in formula (I) 2 -L 1 -X 1 -teeth: *-C(O)-NH-CH(COOH)-R 12 -NH-C(O)-R 13 -C(O)-NH- (L-3), *-C(O)-NH-CH(COOH)-R 14 -NH-C(O)-R 15 -C(O)-NH-R 16 -CH(COOH)-NH-C(O)- (L-4), and *-C(O)-NH-CH(COOH)-R 17 -C(O)-NH-R 18 -C(O)-NH-R 19 -CH(COOH)-NH-C(O)- (L-5) Having a structure selected from (In the formula, the combination marked with * is R in formula (I) 2 It is attached to a carbon atom having, R 12 and R 14 These are independently selected from linear C2-C6 alkanediyl molecules, preferably from linear C3-C6 alkanediyl molecules. R 13 These are linear C2-C10 alkanediyl molecules, preferably linear C4-C8 alkanediyl molecules. R 15 and R 16 These are independently selected from linear C2-C6 alkanediyl molecules, preferably from linear C2-C4 alkanediyl molecules. Furthermore, R 13 and R 15 Each of these may have one EDS group as a substituent, preferably R 13 and R 15 Each of them has one EDS group as a substituent, R 17 This is a linear C2-C6 alkanediyl, preferably a linear C2-C4 alkanediyl. R 18 is a phenylene group, for example, a para-phenylene group, and R 19 (These are linear C2-C6 alkanediyl molecules, preferably linear C2-C4 alkanediyl molecules.)

[0051] In this context, preferably, R 13 and R 15The EDS group, which may be attached to the material, has a structure selected from (E-1A), (E-2A), and (E-2B). More preferably, the EDS group has a structure selected from (E-2A) and (E-2B), and most preferably, the EDS group has structure (E-2A).

[0052] Furthermore, preferably, R in formula (L-3) 12 and R 13 The total number of carbon atoms in the group is 6 to 16, more preferably 6 to 14, excluding the carbon atoms contained in the EDS group as substituents, and R in formula (L-4) 14 , R 15 and R 16 The total number of carbon atoms in the molecule is 6 to 16, more preferably 6 to 14, excluding the carbon atoms contained in the EDS group as substituents.

[0053] The above n and X 1 From the information provided regarding the preferred meaning of -X in formula (I), it is particularly preferred that 2 -L 1 -X 1 -However, when n is 4, it has structure (L-3), and -X in formula (I) 2 -L 1 -X 1 - However, it is understood that when n is 2, it has structure (L-4) or (L-5).

[0054] Specifically, preferably, in formula (I), n is 2, and part -X 2 -L 1 -X 1 - has the following structure: *-C(O)-NH-CH(COOH)-(CH2)4-NH-C(O)-CH(EDS)-CH2-C(O)-NH-(CH2)3-CH(COOH)-NH-C(O)- (L-6) *-C(O)-NH-CH(COOH)-(CH2)2-C(O)-NH-Ph-C(O)-NH-(CH2)3-CH(COOH)-NH-C(O)- (L-7) It has one of the (In the formula, the combination marked with * is R in formula (I)2 It is attached to a carbon atom having a p-phenylene group, where EDS is an EDS group as defined herein, including in its preferred embodiment, and Ph is a p-phenylene group.

[0055] In this context as well, preferably, the EDS group has a structure selected from (E-1A), (E-2A), and (E-2B). More preferably, the EDS group has a structure selected from (E-2A) and (E-2B), and most preferably, the EDS group has structure (E-2A).

[0056] In formula (I), R 2 This is an optionally substituted aryl group or an optionally substituted aralkyl group, preferably an optionally substituted aralkyl group. To be understood, as used herein, the term “aralkyl group” refers to an alkyl group in which a hydrogen atom is substituted with an aryl group as a substituent. Preferably, an aralkyl group is a group in which one aryl group is bonded to an alkanediyl group. 2 The aryl or aralkyl group represented by may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH. The aryl portion is preferably selected from naphthyl groups such as phenyl and 2-naphthyl. The alkanediyl portion of the aralkyl group is preferably a C1-C4 alkanediyl group, more preferably a -CH2- group. Thus, R 2 More preferably, it is selected from optionally substituted -CH2-phenyl and optionally substituted -CH2-naphthyl, and particularly optionally substituted -CH2-(2-naphthyl). The optionally substituted -CH2-(2-naphthyl) is R 2 This is a particularly favorable option.

[0057] The aryl portion of the optionally substituted aryl group and the optionally substituted aralkyl group may be substituted with one or more substituents selected from halogens, preferably I and -OH, including in these preferred embodiments. Thus, one or more substituents, for example, two or three, can be present, selected from halogens, preferably I and -OH. However, preferably, R 2 This is a non-substitution.

[0058] From the above perspective, R 2 Most preferably, the naphthyl group is unsubstituted -CH2-(naphthyl), and the naphthyl group is R 2 It is understood that the most preferred group is a 2-naphthyl group in order to provide -CH2-(2-naphthyl).

[0059] In formula (I), R 3 R is an optionally substituted aryl group or an optionally substituted aralkyl group, preferably an optionally substituted aralkyl group. The aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH. The aryl portion of the aryl and aralkyl group is preferably selected from phenyl and naphthyl such as 2-naphthyl. More preferably, the aryl portion of the aryl and aralkyl is phenyl. The alkanediyl portion of the aralkyl group is preferably a C1-C4 alkanediyl group, more preferably a -CH2- group. Thus, R 3 is more preferably an optionally substituted -CH2-phenyl.

[0060] The aryl portion of the optionally substituted aryl group and the optionally substituted aralkyl group may be substituted with one or more substituents selected from halogens, preferably I and -OH, including in these preferred embodiments. Thus, one or more substituents, for example, two or three, can be present, selected from halogens, preferably I and -OH. Preferably, R 3It is substituted with one substituent that is -OH, or a combination of one substituent -OH and one substituent -I.

[0061] Thus, particularly preferably, R 3 This is a -CH2-phenyl compound substituted on the phenyl ring with one substituent, which is -OH, or a combination of one substituent -OH and one substituent -I, most preferably the substituent -OH is located at the para position of the phenyl ring relative to the -CH2- group.

[0062] In accordance with the above definition, preferably, in formula (I), R 2 is, formula

[0063] [ka]

[0064] It is the basis of R 3 is, formula

[0065] [ka]

[0066] The basis of (In the formula,

[0067] [ka]

[0068] R 2 and R 3 These marks indicate the bonds that will be attached to the remainder of the compound in formula (I). More preferably, R 2 and R 3 It is a combination of R 2 is an expression

[0069] [ka]

[0070] It is the basis of R 3 is, formula

[0071] [ka]

[0072] The basis of (In the formula,

[0073] [ka]

[0074] These are, respectively, R 2 and R 3 (This is a mark indicating the bond that attaches to the rest of the compound.) In formula (I), r can be 0 or 1, preferably r is 1.

[0075] Furthermore, as explained above, p is 0 or 1, and q is 0 or 1, preferably p+q=1. More preferably, p is 0 and q is 1. R in equation (I) 4 R is selected from an aryl group and an EDS group. The aryl is preferably selected from naphthyl groups such as phenyl and 2-naphthyl. Thus, 4 The group is more preferably selected from phenyl, naphthyl such as 2-naphthyl, and an EDS group. 4 The most preferred group is an EDS group.

[0076] R 4 When is an EDS group, preferably the EDS group has a structure selected from (E-1A), (E-2A), and (E-1B). X 3 These include amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, amine bonds, and formula

[0077] [ka]

[0078] Selected from (wherein the formula, the bond marked with a carbonyl group is X 3 to R M It attaches to X, and other marked bonds are X 3 (It attaches to the rest of the molecule.) Preferably, X 3 is an amide bond and formula

[0079] [ka]

[0080] Selected from the groups (wherein the formula, the bond marked with a carbonyl group is X 3 to R M It attaches to X, and other marked bonds are X 3 (It attaches to the rest of the molecule.) In a more preferred embodiment, X 3 The carbon atom is R M It is an amide bond -C(O)-NH- attached to it.

[0081] R M This is a labeling group containing a chelating group that optionally contains a chelated non-radioactive or radioactive cation. As will be understood by those skilled in the art, R M The above definition, which includes a chelating group, is R M This includes cases where is a chelating group, and in these cases, the chelating group is typically X 3 It is directly coupled with, And, R M However, when combined with a chelating group, it can include cases that involve, for example, a further linker portion, in which case the chelating group acts through this further linker portion to X 3 It can be indirectly linked to this.

[0082] R MThe chelating groups provided are suitable for forming chelates with radioactive or non-radioactive cations. Suitable chelating groups for a variety of cations are well known in the art and can be used in the context of the present invention.

[0083] Chelate groups containing optionally chelated non-radioactive or radioactive cations are preferably, (i) A macrocyclic ring structure comprising two or more, preferably three or more, ring atoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, and (ii) an acyclic, open-chain chelate structure having 8 to 20 main chain atoms, two or more, preferably three or more, heteroatoms selected from oxygen, sulfur, and nitrogen atoms. Selected from chelate groups containing at least one of the following.

[0084] Exemplary chelating group, therefore exemplary group R MAlso, bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradeca-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl]-N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazabicyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazabicyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphate) (DPDP) , diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol (ethyleneglykol)-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate ( HP-DOA3), 6-Hydradinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-Triazacyclononane-1-succinate-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy(carbooxy))-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononane triacetic acid (NOTA), 4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] Hexadecane (TE2A), 1,4,8,11-Tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), terpyridine-bis(methyleneamintetraacetic acid) (TMT), 1,4,7,10-Tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), triethylenetetraaminehexaacetic acid (TTHA), N,N'-bis[(6-carboxy-2-pyridyl))methyl]-4,13-diaza-18-crown-6(H2 macropa) and 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-carbamoyl]-ethyl}heptanediic acid A chelating agent residue selected from bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-amide](THP); The residue is provided by a covalent bond between a carboxyl group contained in the chelating agent and the remainder of the compound, preferably via an ester or amide bond. In formula (I), this ester or amide bond is, in this example, X 3 It may be encompassed by, or preferably by X 3 Those skilled in the art will understand that this can be represented by the following.

[0085] Among these chelating agents, DOTA and DOTAGA are preferred. Thus, and preferably, R in formula (I) M -X 3 - is an expression

[0086] [ka]

[0087] The basis of (In the formula,

[0088] [ka]

[0089] The bond marked with is attached to the remainder of the compound of formula (I), and the chelating group may contain a chelated non-radioactive or radioactive cation. An example of a radioactive cation chelated with a chelate group of any choice is: 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 89 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 P m , 151 PM, 149 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb,211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac, and 227 Th cation, or 18 F-[AlF] 2+ like 18 It is selected from cationic molecules containing F.

[0090] Preferred chelated cations are, 44 Sc, 47 Sc, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 161 Tb, 166 Ho, 177 Lu, 188 Re, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 Th cation, or 18 It is selected from cationic molecules containing F.

[0091] In formula (I), the EDS group is contained at least once, and therefore, for example, one, two, or three EDS groups may be contained. Preferably, the compound or salt according to the present invention contains one or two EDS groups. As described above, the EDS group is L 1 There You may do so, and / or R 4 It may also be represented by:

[0092] The most preferred compounds of formula (I) and their salts include the linking group L, including in the preferred embodiments described above. 1 Including those containing one EDS group, and the preferred embodiments thereof described above, one is R 4 It is expressed by (i.e., r is 1), and one is L 1 It contains two EDS groups.

[0093] As presented above, the EDS group is (E-1A), (E-1B), (E-2A), and (E-2B):

[0094] [ka]

[0095] Having a structure selected from (In the formula,

[0096] [ka]

[0097] This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); s is 1, 2, or 3, preferably 1 or 2, more preferably 1; t is 1, 2, or 3, preferably 1 or 2, more preferably 2; R 5A Independently, for each occurrence when s>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 5A The bond between the phenyl ring and the s R 5A This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 5B Independently, for each occurrence where s>1, the substituent is one that has a lone pair of electrons on an atom directly attached to the phenyl ring represented by formula (E-1B), and the substituent is preferably selected from -OH and -NH2, more preferably -NH2, R 5B The bond between the phenyl ring and the s R 5B This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 6A Independently, for each occurrence when t>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 6A and The bond between the henyl ring and the t R 6A This indicates that the group substitutes t hydrogen atoms at any position on the phenyl ring; and R 6B Independently, for each occurrence when t>1, the substituent has a lone pair of electrons on an atom directly attached to the phenyl ring represented by formula (E-1B), and the substituent is preferably selected from -OH and -NH2, more preferably -OH, R 6B The bond between the phenyl ring and the t R 6B (This represents the substitution of t hydrogen atoms at any position on the phenyl ring.)

[0098] Generally, preferably, the EDS group (E-1A) contains substituent R 5A The substituent R is identical for s>1 and is selected from -NO2 and -COOH, more preferably -COOH, in the EDS group (E-2A), 6A For t>1, these are identical and selected from -NO2 and -COOH, more preferably -COOH.

[0099] Similarly, generally preferred is a substituent R in the EDS group (E-1B). 5B The substituent R is identical for s>1 and is selected from -OH and -NH2, more preferably -NH2, in the EDS group (E-2B), 6B For t>1, the two are identical and are selected from -OH and -NH2, more preferably -OH.

[0100] Thus, more preferably, the compound of formula (I) is formula (E-2A):

[0101] [ka]

[0102] Contains an EDS group having (In the formula,

[0103] [ka]

[0104] This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); and t is 1 or 2, R 6A (It is -NO2 or -COOH).

[0105] In the context of the present invention, the most preferred EDS group is the group

[0106] [ka]

[0107] That is the case. In accordance with the above definition, preferred compounds of formula (I) are those of formula (Ia)

[0108] [ka]

[0109] Explained by (In the formula, n, 1 , L 1 , X 2 , R 2 , R 3 , R 4 q, p, X 3 and R M (These are defined above, including in these preferred embodiments, and the EDS group is contained at least once and has the structure defined above, including in the preferred embodiments).

[0110] A more preferred compound of formula (I) is the following formula (Ib):

[0111] [ka]

[0112] Explained by (In the formula, n,1 , L 1 , X 2 , R 2 , R 3 , R 4 , X 3 and R M (These are defined above, including in these preferred embodiments, and the EDS group is contained at least once and has the structure defined above, including in the preferred embodiments).

[0113] A more preferred compound of formula (I) is the following formula (Ic):

[0114] [ka]

[0115] Explained by (In the formula, n, 1 , L 1 , X 2 , R 4 , X 3 and R M (The term is defined above, including these preferred embodiments, and the EDS group is contained at least once and has the structure defined above, including its preferred embodiments).

[0116] More preferred compounds of formula (I) are described by the following formulas (Id) and (Ie):

[0117] [ka]

[0118] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M (i) R4 is defined as above, including in these preferred embodiments, and (ii) R 10A(i) and (ii) apply; (ii) either has one EDS group having the structure defined above, including its preferred embodiment;

[0119] [ka]

[0120] (In the formula, R 9B , R 10B , R 11B , R 4 , X 3 and R M R is defined as above, including these preferred embodiments, 4 (This refers to an EDS group having the structure defined above, including its preferred embodiment.)

[0121] Particularly preferred compounds of formula (I) are described by the following formulas (If) and (Ig).

[0122] [ka]

[0123] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M (i)R is defined as above, including these preferred embodiments, 4 (ii)R 10A (i) and (ii) apply to either having one EDS group having the structure defined above, including its preferred embodiment;

[0124] [ka]

[0125] (In the formula, R 9B , R 10B , R 11B , R 4 , X 3 and R M R is defined as above, including these preferred embodiments, 4 (This refers to an EDS group having the structure defined above, including its preferred embodiment.)

[0126] In a preferred embodiment, the chelate group is bound to an alpha-emitting radionuclide. The alpha-emitting radionuclide is 212 Bi, 213 Bi and 225 Contains Ac As noted above, the introduction of electron-deficient substituents significantly increases the internal transport capability. This property results in higher tumor uptake and particularly longer retention in tumor tissue, as demonstrated by in vitro experiments (see examples). Since complexes of chelating agents and radionuclides that release alpha particles tend to decompose via physical recoil, the extended intracellular retention property reduces the probability of free circulating radionuclides in vivo, thus increasing safety and reducing unwanted radiation.

[0127] Particularly preferred compounds of the present invention are as follows: DOTAGA-y(3-I)fk(L-Asu[KuE]-2,4-DNBA)(PSMA-36):

[0128] [ka]

[0129] DOTAGA-F(4-NH2)y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-49):

[0130] [ka]

[0131] DOTAGA-F(4-NO2)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-52):

[0132]

Chem.

[0133] 2,4-DNBA-Dap(DOTAGA)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-53):

[0134]

Chem.

[0135] DOTAGA-F(4-NH2)y-2-nal-e(Abz-N 5 -orn-C 4 -EuE)(PSMA-60):

[0136]

Chem.

[0137] DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-2,4-DNBA)(PSMA-61):

[0138]

Chem.

[0139] DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-62):

[0140] [Chemistry]

[0141] 2,4-DNBA-Dap(DOTAGA)y-2-nal-e(Abz-N 5 -orn-C 4 -EuE)(PSMA-65):

[0142] [Chemistry]

[0143] DOTAGA-Dap(TMA)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-66):

[0144] [Chemistry]

[0145] DOTAGA-2-Nal-y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-71):

[0146] [Chemistry]

[0147] DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-3,5-DHBA)(PSMA-78):

[0148] [Chemistry]

[0149] is as follows. The advantageous properties of these inventive compounds can be found in the data in Tables 1 and 2 below, which are provided in Figure 1.

[0150] Table 1. Summary of all parameters investigated in vitro for EuK-based PSMA inhibitors. E stands for Glu, u for urea, and K for Lys. A single lowercase letter (such as "y") indicates the D-form of each amino acid. The median inhibitory concentration (IC) of the PSMA inhibitor. 50 ) are LNCaP cells (1.5*10 5 Cells / well, 1 hour, 4°C, HBSS + 1% BSA) and as radioligand ([ 125 Determined in a competitive binding assay using I]I-BA)KuE. 125 I]I-BA)KuE(1.25*10 5 Cells / well, PLL coated plate, ([ 125 For I]I-BA)KuE, c=0.2nM and 177 Internal distribution activity of Lu-labeled PSMA inhibitors, expressed as [%] relative to cellular uptake (c=1.0nM, DMEM / F-12 + 5% BSA, 37°C, 60 min). Data were corrected for nonspecific binding (10 μM 2-PMPA). IC 50 Internal migration data are expressed as mean ± standard deviation (n=3). Lipidity is expressed as logP (partition coefficient in n-octanol / PBS) of radiolabeled PSMA inhibitors. Data for logP are expressed as mean ± standard deviation (n=6). Albumin binding (HSA) is expressed as a logarithmic plot and as [%] after calibration (n=1). The composition describes the simplified N-to-C-terminal structural composition of the peptide spacer and linker without chelating agents. nd = undetermined. "-II-" indicates a simplified conjugation.

[0151] [Table 1]

[0152] Table 2. Summary of all parameters investigated in vitro for EuE-based PSMA inhibitors. Half-percentage inhibitory concentration (IC) of PSMA inhibitors. 50 ) are LNCaP cells (1.5*10 5 Cells / well, 1 hour, 4°C, HBSS + 1% BSA) and as radioligand ([ 125 Determined in a competitive binding assay using I]I-BA)KuE. 125 I]I-BA)KuE(1.25*10 5 Cells / well, PLL coated plate, ([ 125 For I]I-BA)KuE, c=0.2nM and 177 Internal distribution activity expressed as [%] relative to cellular uptake (c=1.0 nM. DMEM / F-12 + 5% BSA, 37°C, 60 min) for Lu-labeled PSMA inhibitors. Data were corrected for nonspecific binding (10 μM 2-PMPA). IC 50 Internal migration data are expressed as mean ± standard deviation (n=3). Lipidity is expressed as logP (partition coefficient in n-octanol / PBS) of the radiolabeled PSMA inhibitor. Data for logP is expressed as mean ± standard deviation (n=6). Albumin binding (HSA) is expressed as [%] after logarithmic plot and calibration (n=1). The composition describes the simplified N-to-C-terminal structural composition of the peptide spacer and linker without chelating agents. nd = undetermined. "-II-" indicates a simplified conjugation.

[0153] [Table 2]

[0154] The preferred labeling schemes for these most preferred compounds are as defined above in this specification. In a further embodiment, the present invention provides a pharmaceutical composition comprising or consisting of one or more compounds or salts of the present invention as disclosed above herein.

[0155] In a further embodiment, the present invention provides a diagnostic composition comprising or consisting of one or more compounds or salts of the present invention as disclosed above herein. In a further embodiment, the present invention provides a therapeutic composition comprising or consisting of one or more compounds or salts of the present invention as disclosed above herein.

[0156] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, and / or diluent. Examples of suitable pharmaceutical carriers, excipients, and / or diluents, well known in the art, include phosphate-buffered saline solutions, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, and the like. Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to a subject in a suitable dose. Administration of a suitable composition may be carried out by different methods, for example, intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal, or intrabronchial administration. Alternatively, the administration may be carried out by injection and / or delivery, for example, into a site in the pancreas, or into a cerebral artery or directly into brain tissue. The composition may also be administered directly to a target site, for example, by microparticle gun delivery to an external or internal target site such as the pancreas or brain. The administration plan is determined by the attending physician and clinical factors. As is well known in the medical field, the dosage for any given patient depends on a number of factors, including the patient's physique, body surface area, age, the specific compound to be administered, sex, time and route of administration, overall health status, and other drugs being administered concurrently. The pharmaceutically active substance may be present in amounts between 0.1 ng and 10 mg / kg body weight per dose, but doses below or above this exemplary range are conceivable, especially considering the factors mentioned above.

[0157] Preferably, no further pharmaceutically active, diagnostically active, or therapeutically active compounds are present, insofar as the pharmaceutical compositions, diagnostic compositions, and therapeutic compositions disclosed above contain one or more compounds of the present invention. Alternatively, further pharmaceutically active, diagnostically active, or therapeutically active compounds may be present, for example, as anticancer agents.

[0158] [In combination with chemotherapy or immunotherapy] 177 Similar to the treatment of neuroendocrine tumors with Lu]DOTATATE radiotherapy, the combination of the therapeutic procedure and the compound of the present invention will have a synergistic or cumulative therapeutic effect. 177 The combination of Lu PRRT and the oral chemotherapy agent capecitabine (Xeloda; Genentech), 177 The first phase 3 trial comparing 177Lu-octreotate with 177Lu-octreotate monotherapy was initiated in 2017 at Erasmus MC, Rotterdam (van Essen M, Krenning EP, Kam BL, de Herder WW, van Aken MO, Kwekkeboom DJ, Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumors. Eur J Nucl Med Mol Imaging. 2008;35:743~748).

[0159] Further trials of the combination therapy, named peptide receptor chemoradionuclide therapy (PRCRT), have been published in recent years (Kong G, Callahan J, Hofman MS et al., High clinical and morphologic response using 90Y-DOTA-octreotate sequenced with 177Lu-DOTA-octreotate induction peptide receptor chemoradionuclide therapy (PRCRT) for bulky neuroendocrine tumors.Eur J Nucl Med Mol Imaging. 2017;44:476~489). Similar "combination treatment techniques" will be implemented in the near future to improve the efficacy of PSMA-targeted radioligand therapy.

[0160] In a further embodiment, the present invention provides one or more compounds or salts of the present invention, as disclosed above herein, for use in pharmaceuticals. Preferred pharmaceutical uses include nuclear imaging diagnostics, also known as nuclear molecular imaging, and / or nuclear medicine, such as targeted radiotherapy for diseases associated with overexpression, preferably PSMA, applied to diseased tissue.

[0161] In a further embodiment, the present invention provides compounds or salts of the present invention as defined above herein for use in methods for diagnosing and / or staging cancer, preferably prostate cancer.

[0162] Preferred indications include, but are not limited to, the detection or staging of cancers such as high-grade gliomas, lung cancer, and especially prostate cancer and metastatic prostate cancer; the detection of metastatic disease in patients with intermediate to high-risk primary prostate cancer; and the detection of metastatic sites, even in patients with biochemically recurrent prostate cancer where serum PSA levels are low. Another preferred indication is the imaging and visualization of angiogenesis.

[0163] From the perspective of medical indications for treatment, particularly radiotherapy, cancer is a favorable indication. Prostate cancer is a particularly favorable indication. In a further embodiment, the present invention provides compounds or salts of the present invention as defined above herein for use in methods for diagnosing and / or staging cancer, preferably prostate cancer.

[0164] With respect to embodiments characterized in this specification, particularly in the claims, each embodiment referred to in a dependent claim is intended to be combined with each embodiment of the claim (independent or dependent) to which the dependent claim depends. For example, in a case where independent claim 1 lists three alternatives A, B and C, dependent claim 2 lists three alternatives D, E and F, and claim 3 lists three alternatives G, H and I dependent on claims 1 and 2, the specification, unless otherwise specifically referred to, is A, D, G; A, D, H; A, D, I; A, E, G; A, E, H; A, E, I It is understood that embodiments corresponding to combinations of ;A, F, G;A, F, H;A, F, I;B, D, G;B, D, H;B, D, I;B, E, G;B, E, H;B, E, I;B, F, G;B, F, H;B, F, I;C, D, G;C, D, H;C, D, I;C, E, G;C, E, H;C, E, I;C, F, G;C, F, H;C, F, I are expressly disclosed.

[0165] Similarly, in cases where an independent and / or dependent claim does not enumerate substitutes, if a dependent claim refers back to multiple prior claims, any combination of subject matter included therein is considered expressly disclosed. For example, in the case of independent claim 1, dependent claim 2 referring back to claim 1, and dependent claim 3 referring back to both claims 2 and 1, the subject matter combination of claim 3 and 1 is expressly and obviously disclosed, as is the subject matter combination of claim 3, 2, and 1. In the case of a further dependent claim 4 referring to any one of claims 1 through 3, the subject matter combinations of claim 4 and 1, claim 4, 2, and 1, claim 4, 3, and 1, and claim 4, 3, 2, and 1 are expressly and obviously disclosed.

[0166] In particular, the present invention provides subject matter that can be summarized in the following items. 1. Compounds of formula (I) or pharmaceutically acceptable salts thereof

[0167] [ka]

[0168] (In the formula, m is an integer between 2 and 6, preferably between 2 and 4, more preferably 2; n is an integer between 2 and 6, preferably between 2 and 4, more preferably 2 or 4; R 1L is CH2, NH or O, preferably NH; R 2L is C or P(OH), preferably C; R 3L is CH2, NH or O, preferably NH; X 1 The bond is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds, and is preferably an amide bond; L 1 This is a divalent linking group having a structure selected from oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea), preferably having a structure selected from oligoamide and oligo(ester-amide). The linking group may have an EDS group; X 2 The bond is selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds, and is preferably an amide bond; R 2is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH; R 3 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I and -OH; r is 0 or 1, preferably 1; p is either 0 or 1; q is either 0 or 1; Preferably, p+q=1; R 4 The group is selected from optionally substituted aryl and EDS groups, and the aryl group may be substituted on its aromatic ring with one or more substituents selected from halogens, preferably I,-OH, and -NH2; X 3 These include amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, amine bonds, and formula

[0169] [ka]

[0170] Selected from the groups, in the formula, the bond marked with a carbonyl group is X 3 to R M It attaches to X, and other marked bonds are X 3 Attach it to the remainder of the compound of formula (I); Preferably an amide bond; R M This is a labeling group containing a chelate group which optionally contains a chelated non-radioactive or radioactive cation; Furthermore, in the formula, the EDS group is present at least once in the compound of formula (I), (E-1A), (E-1B), (E-2A), and (E-2B):

[0171] [ka]

[0172] Having a structure selected from, During the ceremony,

[0173] [ka]

[0174] This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); s is 1, 2, or 3, preferably 1 or 2, more preferably 1; t is 1, 2, or 3, preferably 1 or 2, more preferably 2; R 5A Independently, for each occurrence when s>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 5A The bond between the phenyl ring and the s R 5A This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 5B These can be expressed independently, for each occurrence in s>1, by equation (E-1B). A substituent having a lone pair of electrons on an atom directly attached to the phenyl ring, the substituent is preferably selected from -OH and -NH2, more preferably -NH2, R 5B The bond between the phenyl ring and the s R 5B This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R 6A Independently, for each occurrence when t>1, the electron-withdrawing substituent is preferably selected from -NO2 and -COOH, more preferably -COOH, and R 6A The bond between the phenyl ring and the t R 6AThis indicates that the group substitutes t hydrogen atoms at any position on the phenyl ring; and R 6B Independently, for each occurrence when t>1, the substituent has a lone pair of electrons on an atom directly attached to the phenyl ring represented by formula (E-1B), and the substituent is preferably selected from -OH and -NH2, more preferably -OH, R 6B The bond between the phenyl ring and the t R 6B (This represents the substitution of t hydrogen atoms at any position on the phenyl ring.)

[0175] 2. m is 2, n is 2 or 4, R 1L NH is R 2L C is and R 3L A compound or salt of item 1 in which is NH. 3. A compound or salt of item 1 or 2 where n is 2.

[0176] 4.X 1 A compound or salt of any of items 1 through 3, in which the bond is an amide bond. 5.n is 2, X 1 However, the carbon atom of the amide bond -C(O)-NH- is the group -(CH2) n - The compound or salt of item 4, which has an amide bond attached to it.

[0177] 6.L 1 A divalent linking group having a structure selected from oligoamides, which contain a total of 1 to 5, more preferably 1 to 3, most preferably 1 or 2, amide bonds in their main chain, and oligo(ester-amides), which contain a total of 2 to 5, more preferably 2 to 3, most preferably 2, amide and ester bonds in their main chain, wherein the linking group may have an EDS group, and is a compound or salt of any of items 1 to 5.

[0178] 7.L 1 The compounds or salts of item 6, which represent a divalent linking group having an oligoamide structure containing one or two amide bonds in its main chain, and the linking group may have an EDS group. 8. Linking group L 1 A compound or salt of any of items 1 to 7 having one EDS group.

[0179] 9.X 2 A compound or salt of any of items 1 through 8, in which the bond is an amide bond. 10.X 2 However, the nitrogen atom of the amide bond -C(O)-NH- is L 1 A compound or salt of item 9 that has an amide bond attached to it.

[0180] 11. Part of equation (I) - X 2 -L 1 -X 1 -but: *-C(O)-NH-R 7 -NH-C(O)-R 8 -C(O)-NH- (L-1), *-C(O)-NH-R 9A -NH-C(O)-R 10A -C(O)-NH-R 11A -NH-C(O)- (L-2A), and *-C(O)-NH-R 9B -C(O)-NH-R 10B -C(O)-NH-R 11B -NH-C(O)- (L-2B) A compound or salt from any of items 1 to 10 having a structure selected from (In the formula, the amide bond marked with * is R in formula (I) 2 It is attached to a carbon atom having, R 7 , R 8 , R 9A , R 9B , R 11A and R 11BEach of these groups is independently selected from optionally substituted C2-C10 alkanediyl groups, preferably optionally substituted linear C2-C10 alkanediyl groups, and each alkanediyl group may be independently substituted with one or more substituents selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and EDS groups, and R 10A and R 10B The C2-C10 alkanediyl group is selected from optionally substituted C2-C10 alkanediyl groups, preferably optionally substituted linear C2-C10 alkanediyl groups, and optionally substituted C6-C10 arenediyl groups, preferably phenylene groups, and each alkanediyl and arenediyl group may be independently substituted with one or more substituents selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2, and EDS groups. 10A Preferably, it is a C2-C10 alkanediyl substituted with the optional substitutions defined above, more preferably a linear C2-C10 alkanediyl substituted with the optional substitutions. 10B This is preferably a C6-C10 arenediyl substituted with any of the options defined above, more preferably a phenylene group, such as a para-phenylene group).

[0181] 12. R in equation (L-1) 7 and R 8 The total number of carbon atoms in the molecule is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituent, and the R of formula (L-2A) 9A , R 10A and R 11A The total number of carbon atoms in the molecule is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituent, and the R of formula (L-2B) 9B , R 10B and R 11B A compound or salt of item 11, wherein the total number of carbon atoms in it is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituent.

[0182] 13. Part-X 2 -L 1 -X 1 - has structure (L-1), R 8 It has an EDS group as at least one substituent, or Part-X 2 -L 1 -X 1 - has structure (L-2A), R 10A A compound or salt of item 11 or 12 having at least one EDS group as a substituent.

[0183] 14. Part-X 2 -L 1 -X 1 -but, *-C(O)-NH-CH(COOH)-R 12 -NH-C(O)-R 13 -C(O)-NH- (L-3), *-C(O)-NH-CH(COOH)-R 14 -NH-C(O)-R 15 -C(O)-NH-R 16 -CH(COOH)-NH-C(O)- (L-4), and *-C(O)-NH-CH(COOH)-R 17 -C(O)-NH-R 18 -C(O)-NH-R 19 -CH(COOH)-NH-C(O)- (L-5) A compound or salt of item 7 having a structure selected from (In the formula, the combination marked with * is R in formula (I) 2 It is attached to a carbon atom having, R 12 and R 14 These are independently selected from linear C2-C6 alkanediyl molecules, preferably from linear C3-C6 alkanediyl molecules. R 13 These are linear C2-C10 alkanediyl molecules, preferably linear C4-C8 alkanediyl molecules. R 15 and R 16These are independently selected from linear C2-C6 alkanediyl molecules, preferably from linear C2-C4 alkanediyl molecules. Furthermore, R 13 and R 15 Each of these may have one EDS group as a substituent, more preferably R 13 and R 15 Each of them has one EDS group as a substituent, R 17 This is a linear C2-C6 alkanediyl, preferably a linear C2-C4 alkanediyl. R 18 is a phenylene group, for example, a para-phenylene group, and R 19 (These are linear C2-C6 alkanediyl molecules, preferably linear C2-C4 alkanediyl molecules.)

[0184] 15. R in equation (L-3) 12 and R 13 The total number of carbon atoms in the group is 6 to 16, more preferably 6 to 14, excluding the carbon atoms contained in the EDS group as substituents, and R in formula (L-4) 14 , R 15 and R 16 The total number of carbon atoms inside is ED as substituents. A compound or salt of item 14, wherein the carbon atoms contained in the S group are 6 to 16, more preferably 6 to 14.

[0185] 16.R 2 The compound or salt of any of items 1 to 15, wherein the optionally substituted aralkyl group is an optionally substituted -CH2-phenyl and optionally substituted -CH2-naphthyl, more preferably an optionally substituted -CH2-(2-naphthyl), and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogens, preferably I and -OH.

[0186] 17.R 2The compound or salt of item 16, wherein the aralkyl group is of the formula -CH2-naphthyl, more preferably -CH2-(2-naphthyl). 18.R 3 The compound or salt of any of items 1 to 17, wherein the optionally substituted aralkyl group is an optionally substituted -CH2-phenyl and optionally substituted -CH2-naphthyl, more preferably an optionally substituted -CH2-phenyl, and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogens, preferably I and -OH.

[0187] 19.R 3 The compound or salt of item 18, wherein the phenyl ring is an aralkyl group of the formula -CH2-phenyl, and the phenyl ring is substituted with one substituent which is -OH, or with a combination of one substituent which is -OH and one substituent which is -I.

[0188] 20.R 2 However, the formula

[0189] [ka]

[0190] It is the basis of R 3 However, the formula

[0191] [ka]

[0192] The base of any compound or salt from item 1 to 15 (In the formula,

[0193] [ka]

[0194] R 2 and R 3These marks indicate the bonds that will be attached to the remainder of the compound in formula (I). 21.R 2 However, the formula

[0195] [ka]

[0196] It is the basis of R 3 However, the formula

[0197] [ka]

[0198] The compound or salt of item 20, which is the base of (In the formula,

[0199] [ka]

[0200] R 2 and R 3 These are marks indicating the bonds that attach to the rest of the molecule. 22. A compound or salt of any of items 1 through 21, where r is 1.

[0201] 23. A compound or salt from any of items 1 through 22, where p is 0 and q is 1. 24.R 4 However, any compound or salt of item 1 to 23, selected from phenyl, optionally naphthyl, and EDS groups.

[0202] 25.R 4 However, the compound or salt of item 24, selected from naphthyl, more preferably 2-naphthyl, and EDS groups. 26.X 3 However, an amide bond or formula

[0203] [ka]

[0204] The base of any compound or salt from item 1 to 25 (In the formula, the bond marked with a carbonyl group is X 3 to R M It attaches to X, and other marked bonds are X 3 (It attaches to the rest of the molecule.)

[0205] 27.X 3 However, carbon atoms are R M A compound or salt of item 26, which has an amide bond -C(O)-NH- attached to it. 28.R M A compound or salt of any of items 1 to 27, wherein the chelating group optionally contains a chelated non-radioactive or radioactive cation.

[0206] 29. The chelating group, (i) A macrocyclic ring structure comprising two or more, preferably three or more, ring atoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, and (ii) an acyclic, open-chain chelate structure having 8 to 20 main chain atoms, two or more, preferably three or more, heteroatoms selected from oxygen, sulfur, and nitrogen atoms. A compound or salt from any of items 1 to 28, selected from a chelate group containing at least one of the following.

[0207] 30. The chelating group is bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1,2-diaminetetraacetic acid (CDTA), 4-(1,4,8,11-tetraazacyclotetradeca-1-yl)-methylbenzoic acid (CPTA), N'-[5-[acetyl(hydroxy)amino]-pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4-oxobutanoyl]amino]pentyl] -N-hydroxybutanediamide (DFO), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (DO2A), 1,4,7,10-tetraazabicyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazabicyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(H Fluoride (DPDP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethylene glycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate (HP-DOA3), 6-Hydradinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-Triazacyclononane-1-succinate-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-Triazacyclononane triacetic acid (NOTA), 4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2] Hexadecane (TE2A), 1,4,8,11-Tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA), Terpyridine-bis(methyleneaminetetraacetic acid (TMT), 1,4,7,10-Tetraazacyclotridecane-N,N',N'',N'''-tetraacetic acid (TRITA), Triethylenetetraaminehexaacetic acid (TTHA), N,N'-Bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6(H2 macropa) and 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-carbamoyl]-ethyl}heptanediic acid A chelating agent residue selected from bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-ylmethyl)-amide](THP); A compound or salt of any of items 1 to 29, wherein the residue is provided by a covalent bond between a carboxyl group contained in the chelating agent and the remainder of the compound, via an ester or amide bond, more preferably an amide bond.

[0208] 31. The chelating agent is selected from DOTA and DOTAGA, up to 30 compounds. It's salt. 32.X 3 However, the compounds or salts of item 30 or 31 in which the chelating group is an amide bond attached to the rest of the molecule.

[0209] 33.R M -X 3 -but, formula

[0210] [ka]

[0211] The compound or salt of item 32, which is the base of (In the formula,

[0212] [ka]

[0213] The bond marked with is attached to the remainder of the compound of formula (I), and the chelating group may contain a chelated non-radioactive or radioactive cation. 34. The chelate group is a chelated cation, preferably, 44 Sc, 47 Sc, 51 Cr, 52m Mn, 58 Co, 52 Fe, 56 Ni, 57 Ni, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 68 Ga, 67 Ga, 89 Zr, 90 Y, 89 Y, 94m Tc, 99m Tc, 97 Ru, 105 Rh, 109 Pd, 111 Ag, 110m In, 111 In, 113m In, 114m In, 117m Sn, 121 Sn, 127 Te, 142 Pr, 143 Pr, 149 PM, 151 PM, 149 Tb, 153 Sm, 157 Gd, 161 Tb, 166 Ho, 165 Dy, 169 Er, 169 Yb, 175 Yb, 172 Tm, 177 Lu, 186 Re, 188 Re, 191 Pt, 197 Hg, 198 Au, 199 Au, 212 Pb, 203 Pb,211 At, 212 Bi, 213 Bi, 223 Ra, 225 Ac, and 227 Th cation, or 18 F-[AlF] 2+ like 18 A compound or salt from any of items 1 through 33 containing a chelated radioactive cation selected from cationic molecules containing F.

[0214] 35. The chelating group, 44 Sc, 47 Sc, 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 161 Tb, 166 Ho, 177 Lu, 188 Re, 212 Pb, 212 Bi, 213 Bi, 225 Ac, and 227 Th cation, or 18 cations containing F Compounds or salts of item 34 containing chelated cations selected from ion molecules.

[0215] 36. Any compound or salt of item 1 to 35, wherein the compound of formula (I) contains one or two EDS groups. 37. The compound of formula (I) has a linking group L 1 It contains one EDS group, or one is R 4 It is represented by, and one is L 1 A compound or salt of item 36 that contains either of the two EDS groups present in [the compound].

[0216] 38. Substituent R in EDS group (E-1A) 5A For s>1, they are identical and selected from -NO2 and -COOH; in the EDS group (E-2A), substituent R 6AThe compounds or salts of any of items 1 through 37, which are identical for t>1 and selected from -NO2 and -COOH. 39. Substituent R in EDS group (E-1B) 5B For s>1, they are identical and selected from -OH and -NH2; in the EDS group (E-2B), substituent R 6B The compounds or salts of any of items 1 through 38, which are identical for t>1 and selected from -OH and -NH2.

[0217] 40.Formula (E-2A):

[0218] [ka]

[0219] A compound or salt from any of items 1 to 39 containing an EDS group having (In the formula,

[0220] [ka]

[0221] This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); and t is 1 or 2, R 6A (This is selected from -NO2 or -COOH).

[0222] 41. The EDS group is given by formula (E-3)

[0223] [ka]

[0224] A compound having any of items 1 to 38 (In the formula,

[0225] [ka]

[0226] (The symbol indicates the bond that attaches the EDS group to the remainder of the compound of formula (I).) 42. The following equation (Ia)

[0227] [ka]

[0228] or any compound from items 1 to 41 having a pharmaceutically acceptable salt thereof. (In the formula, n, 1 , L 1 , X 2 , R 2 , R 3 , R 4 q, p, X 3 and R M (As defined in items 1 to 41, the EDS group is contained at least once and has a structure as defined in items 1 to 41).

[0229] 43. The following equation (Ib)

[0230] [ka]

[0231] or compounds of item 42 having a pharmaceutically acceptable salt thereof (In the formula, n, 1 , L 1 , X 2 , R 2 , R 3 , R 4 , X 3 and R M (As defined in items 1 to 42, the EDS group is contained at least once and has a structure as defined in items 1 to 42).

[0232] 44. The following equation (Ic)

[0233] [ka]

[0234] or compounds of item 43 having a pharmaceutically acceptable salt thereof (In the formula, n, 1 , L 1 , X 2 , R 4 , X 3 and R M (As defined in items 1 to 42, the EDS group is contained at least once and has a structure as defined in items 1 to 42).

[0235] 45. Compounds of item 44 having the following formula (Id) or (Ie) or a pharmaceutically acceptable salt thereof.

[0236] [ka]

[0237] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M It is defined as in items 1 through 44, and (i)R 4 However, it is either an EDS group having the structure defined in items 1 to 44, or (ii)R 10A However, it has one EDS group having a structure defined in items 1 to 44, or both (i) and (ii) apply;

[0238] [ka]

[0239] (In the formula, R 9B , R 10B , R 11B , R 4 , X 3 and R M This is defined in items 1 through 44, R 4(This refers to an EDS group having the structure defined in items 1 to 44). 46. ​​Compounds of item 45 having the following formula (If) or (Ig) or a pharmaceutically acceptable salt thereof.

[0240] [ka]

[0241] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M It is defined as in items 1 through 45, and (i)R 4 However, it is either an EDS group having the structure defined in items 1 to 45, or (ii)R 10A However, it has either one EDS group having a structure defined in items 1 to 45, or both (i) and (ii) apply;

[0242] [ka]

[0243] (In the formula, R 9B , R 10B , R 11B , R 4 , X 3 and R M It is defined as in items 1 through 45, R 4 (This refers to an EDS group having the structure defined in items 1 to 45).

[0244] 47. The following formula:

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] A compound of item 1 or a salt thereof having one of the following characteristics. 48. A pharmaceutical or diagnostic composition comprising, or consisting of, one or more compounds or salts of any one of items 1 to 47.

[0250] 49. (a) Cancer, including prostate cancer; or (b) Angiogenesis / angiogenesis For use in the diagnostic and / or treatment of any one of the compounds or salts listed in items 1 through 47. [Brief explanation of the drawing]

[0251] [Figure 1] This is a web chart diagram illustrating the characteristics of [nat / 177Lu]PSMA I&T, [nat / 177Lu]PSMA-62, and [nat / 177Lu]PSMA-66. [Figure 2] This figure shows the external migration kinetics of selected 177Lu-labeled PSMA inhibitors from LNCaP cells. 1.25*10⁵ cells / well were incubated in DMEM solution (5% BSA) at 37°C for 1 hour with their respective radioligands (c=1.0 nm). The supernatant was then removed and washed once with DMEM solution (5% BSA, 37°C). Subsequently, either A) DMEM solution (5% BSA) alone or B) blocked DMEM solution (5% BSA, 10 μm 2-PMPA) was added as an alternative. Total intracellular migration activity at t=0 min was corrected for nonspecific binding (10 μm 2-PMPA) and normalized to 100%. All data are expressed as mean ± standard deviation (n=3). [Figure 3] This figure shows the in vivo distribution (in %ID / g units) of 2.5–3.0 MBq (0.15–0.25 nmol) of [177Lu]PSMA-66 and [177Lu]PSMA I&T in LNCaP tumor-carrying CB-17 SCID mice (n=4 each). [Figure 4] This figure shows the maximum intensity projection (MIP) (dynamic scan, total frames 1-1.5 hours pi) (top left) of a μPET scan after injection of approximately 10.3 MBq (0.19 nmol tracer) of [68Ga]PSMA-36 in LNCaP tumor-carrying CB-17 SCID mice. Also shown is the TAC (logarithmic plot) of [68Ga]PSMA-36 in %ID / mL units from dynamic PET data (acquisition time 90 minutes, OSEM 3D reconstruction) of the blood pool (heart), kidney, tumor, muscle, lacrimal gland, and salivary gland in LNCaP tumor-carrying CB-17 SCID mice. [Figure 5-1] This figure shows the maximum projection (MIP) (dynamic scan, total frames 1-1.5 hours pi) (upper left) of a μPET scan after injection of approximately 11 and 13 MBq (0.15-0.25 nmol tracer) of the 68Ga-labeled PSMA inhibitors PSMA-62 and PSMA-66, respectively, into LNCaP tumor-carrying CB-17 SCID mice. [Figure 5-2] TAC (log plot) in %ID / mL units for each 68Ga-labeled PSMA inhibitor from dynamic PET data (acquisition time 90 minutes, OSEM 3D reconstruction) of blood pool (heart), kidney, tumor, and muscle in LNCaP tumor-carrying CB-17 SCID mice for both 68Ga-labeled tracers. [Figure 6] This figure shows the in vivo distribution (in %ID / g units) of [177Lu]PSMA-62, [177Lu]PSMA-66, [177Lu]PSMA-71, and [177Lu]PSMA I&T in LNCaP tumor-carrying CB-17 SCID mice (n=4 each). [Modes for carrying out the invention]

[0252] The examples illustrate the present invention. [Examples]

[0253] Example 1 material and method 1. General Information Fmoc-(9-Fluorenylmethoxycarbonyl-) and all other protected amino acid analogs were purchased from Bachem (Bubendorf, Switzerland) or Iris Biotech (Marktredwitz, Germany). 2-Chlorotrityl chloride (2-CTC) resin was obtained from PepChem (Tubingen, Germany). Chematech (Dijon, France) delivered the chelating agent DOTAGA anhydrous. PSMA-DKFZ-617 was purchased from ABX advanced chemical compounds (Radeberg, Germany). All necessary solvents and other organic reagents were purchased from either Alfa Aesar (Karlsruhe, Germany), Sigma-Aldrich (Munich, Germany), or VWR (Darmstadt, Germany). Solid-phase peptide synthesis was performed manually using an Intelli-Mixer syringe shaker (Neolab, Heidelberg, Germany). Analytical reversed-phase high-performance liquid chromatography (RP-HPLC) was performed using a Shimadzu gradient RP-HPLC system (Shimadzu Deutschland GmbH, Neufahrn, Germany) with Nucleosil 100. The analysis was performed using a C18 column (5 μm, 125 × 4.0 mm, CS GmbH, Langerwehe, Germany). Peptide analysis was performed by applying 0.1% (v / v) trifluoroacetic acid (TFA) in H2O (solvent A) with acetonitrile (MeCN) (solvent B) at a constant flow rate of 1 mL / min (specific gradients are cited in the text). A Shimadzu SPD 20 A prominence UV / VIS detector (Shimadzu Deutschland GmbH) was used at λ = 220 nm and 254 nm. HSA binding was determined using a Chiralpak HSA (5 μm, 50 × 3 mm) analytical column connected to a Chiralpak HSA (5 μm, 10 × 3 mm) guard cartridge (Daicel Chemical Industries) purchased from Chiral Technologies Europe (Illkirch, France). Nonlinear regression on HSA coupling was performed using OriginPro 2016G (Northampron, USA). Retention time t R , and the volume factor K' are cited in the text. Separation RP-HPLC of the peptide was performed at a constant flow rate of 5 mL / min, and the multispheric factor was used. This was achieved using a Shimadzu RP-HPLC system with a 100 RP 18-5 column (250 × 20 mm, CS GmbH). Analytical and preparative radio-RP-HPLC of radioiodized reference ligands was performed using a Nucleosil 100 C18 column (5 μm, 125 × 4.0 mm). Radioactivity was detected by connecting the inlet of a UV photometer to a NaI(Tl) well scintillation detector from EG&G Ortec (Munich, Germany). 68 Ga and 177 Lu label The compound was analyzed as previously published [1, 2]. The electrospray ionization mass spectrometry (ESI-MS) spectrum was obtained from expression LCMS mass spectrometer (Advion Ltd., Harlow, UK) and Varian 500-MS IT mass spectrometer (Agilent Technologies, Santa Clara, USA) were used to obtain the data. For the Bradford assay, a V-630 UV-Vis spectrophotometer from JASCO Germany GmbH (Gross-Umstadt, Germany) was used, and the S9 fraction was centrifuged using an Avanti JXN-26 centrifuge from Beckman Coulter GmbH (Krefeld, Germany). Centrifugation of the radioactive S9 metabolite assay was performed using a Heraeus PICO 17 centrifuge from Thermo Fisher Scientific Messtechnik GmbH (Munich, Germany). NMR data were obtained using an AV 300 (300 MHz) or AV 400 (400 MHz) from Bruker (Billerica, USA) with 300K applied. Incubation of the S9 fraction for ex vivo metabolite analysis was performed using a Biometra UNO Thermoblock (Biometra, Gottingen, Germany).

[0254] 2. Synthesis Protocol (SP) SP-1: 2-CTC resin loading: 2-CTC resin (1.6 mmol / g) was loaded with Fmoc-AA-OH (1.5 equivalents) in anhydrous dichloromethane (DCM) with N,N-diisopropylethylamine (DIPEA) (4.5 equivalents) at room temperature (RT) for 2 hours. The remaining trityl chloride was capped by adding 2 mL / g methanol (MeOH) and letting it stand for 15 minutes. After this, the resin was filtered and the DCM (2 × ), dimethylformamide (DMF) (2 × ) and MeOH(2 × Each was thoroughly cleaned and stored overnight under vacuum. Loading was determined using the weight difference.

[0255]

number

[0256] Formula 1. Determination of resin loading: m 合計 : Mass of the loaded resin (Fmoc-AA-OH and HCl); M As : Molar mass of amino acids; M 正味 Weight: Mass of the resin used; M HCl : Molar mass of hydrochloric acid SP-2: Peptide synthesis via TBTU / HOBt coupling: A solution of Fmoc-AA-OH (2.0 equivalents), N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) (2.0 equivalents), N-hydroxybenzotriazole (HOBt) (2.0 equivalents), and DIPEA (4.5 equivalents) in DMF (8 ml / g resin) is added to the free amine peptide bound to the resin, and the mixture is shaken at room temperature for 2 hours. × The peptide was washed with ). Coupling with secondary or aromatic amines was performed using different protocols. Fmoc-AA-OH (3.0 equivalents) was dissolved in DMF (8 mL / g resin) together with 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (3.0 equivalents), 1-hydroxy-7-azabenzotriazole (HOAt) (3.0 equivalents), and DIPEA (6.0 equivalents), and stirred for 15 minutes. The pre-activated solution was added to the peptide bound to the resin and shaken at room temperature for 2 hours. After the reaction was complete, the resin was heated in DMF (6 mL / g resin). × Washed with (). Overall, all peptide scaffolds were synthesized as described above (Weineisen, M.; Schottelius, M.; Simecek, J.; Eiber, M.; Schwaiger, M.; Weste r,H. Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endoradiotherapy of prostate cancer.Journal of Nuclear Medicine 2014, 55, 1083~1083;Weineisen,M.;Simecek,J.;Schottelius,M.;Schwaiger,M.;Wester,H.-J. Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI research 2014, 4, 1).

[0257] SP-3: Fmoc deprotection on resin: The Fmoc-protecting peptide bound to the resin was treated with 20% piperidine (v / v) in DMF for 5 minutes, and then for 15 minutes on the second occasion. After that, the resin was treated with DMF (8 × It was thoroughly washed with )

[0258] SP-4: Dde deprotection on resin: N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl)(Dde) protected peptide (1.0 equivalent) was dissolved in a 2.0% hydrazine monohydrate (N2H4·H2O)(v / v) solution in DMF. After 15 minutes, the deprotected peptide was bound to the resin, and DMF(6 × The peptide was washed with ) or precipitated in diethyl ether (Et2O) to obtain the crude product. If Fmoc and Dde protecting groups were present and only Dde deprotection was required, the peptide loaded onto the resin was treated at room temperature for 3 hours with a solution containing NH2OH·HCl (630 mg), imidazole (460 mg), DCM (0.5 mL), DMF (0.5 mL), and N-methyl-2-pyrrolidone (NMP) (2.5 mL). Subsequently, the peptide loaded onto the resin was treated with DMF (6 × It was thoroughly washed with )

[0259] SP-5: Alloc / allyl deprotection on resin: The alloc / allyl protecting group was removed from the peptide bound to the resin using a DCM solution (6.0 mL) containing triisopropylsilane (TIPS) (50.0 equivalents) and (triphenyl)palladium (0)(Pd(PPh3)4) (0.3 equivalents). The resin was treated with this solution at room temperature for 1.5 hours. Finally, the resin was treated with DCM (3 × The Pd(PPh3)4 was removed by washing with ).

[0260] SP-6: tBu / Boc deprotection: The tert-butyl (tBu) / tert-butyloxycarbonyl (Boc) protecting group was removed by dissolving the crude product in TFA (approximately 500 μL) and stirring at room temperature for 40 minutes. The TFA was then almost completely removed using a nitrogen stream. After precipitation in Et2O, the crude product was centrifuged and the supernatant was removed. The dried pellet was further used for the following synthesis steps.

[0261] SP-7.1:A) Peptide cleavage from resin with preservation of side-chain protecting groups: Fully protected, resin-bound peptides were dissolved in a mixture of DCM / trifluoroethanol (TFE) / acetic acid (AcOH) (6 / 3 / 1; v / v / v) and shaken for 30 minutes. The solution was filtered off, and the resin was dissolved in another cleavage solution for a further 30 minutes. The fractions were combined, and the solvent was concentrated under reduced pressure. The filtrate was redissolved in toluene and concentrated under reduced pressure to remove AcOH. Precipitation in water or Et2O yielded the crude side-chain protected peptide.

[0262] SP-7.2:B) Peptide cleavage from resin with simultaneous deprotection of all acid-unstable protecting groups: Fully protected, resin-bound peptides were dissolved in a mixture of TFA / TIPS / water (95 / 2.5 / 2.5; v / v / v) and shaken for 30 minutes. The solution was filtered off, and the resin was treated in the same manner for another 30 minutes. The fractions were then combined, and the solvent was changed to a constant level. The peptide was concentrated under a nitrogen atmosphere. The crude peptide was precipitated in Et2O and left overnight to dry.

[0263] SP-8: Deacetylation of the carbohydrate portion: Deacetylation was completed by dissolving a PSMA inhibitor in MeOH containing KCN (0.5 equivalents) overnight at room temperature while simultaneously stirring (Herzig, J., Nudelman, A., Gottlieb, H., Fischer, B. Studies in sugar chemistry. 2. A simple method for O-deacylation of polyacylated sugars. The Journal of Organic Chemistry 1986, 51, 727~730). The final product was purified by RP-HPLC.

[0264] SP-9: Preparation of non-radioactive metal-complexed PSMA inhibitors: SP-9.1: nat Ga compounds: nat Ga III For complex preparation, a 2.0 mm aqueous (aq.) solution of PSMA inhibitor (50 μL) and a 2.0 mm aq. solution of Ga(NO3)3 (50 μL) were mixed and heated at 40°C for 30 minutes. Chelate formation was evaluated using RP-HPLC and ESI-MS. The resulting 1.0 mm solution was diluted and subjected to in vitro IC. 50 Used for decision-making and HSA joining.

[0265] SP-9.2: nat Lu compounds: corresponding nat Lu III The complex was prepared from a 2.0 mm aqueous solution of a PSMA inhibitor with an excess of 2.5 molars of LuCl3 (20 mm aq. solution), and heated at 95°C for 30 minutes. After cooling, nat Lu III Chelate formation was confirmed using RP-HPLC and ESI-MS. nat A 1.0 mm aqueous solution of the Lu complex is then diluted and, without further treatment, subjected to in vitro IC. 50 It was used in the test.

[0266] 3. Components of PSMA-36 and EuE-based PSMA inhibitors Di-tert-butyl(((S)-6-amino-1-(tert-butoxy)-1-oxohexane-2-yl)carbamoyl)-L-glutamate

[0267] [ka]

[0268] ((OtBu)KuE(OtBu)2)(1): The synthesis of the tert-butyl protected Lys-urea-Glu bond motif (EuK) was carried out by liquid-phase synthesis as previously described [3]. Briefly, a solution of DCM containing L-di-tert-butyl-glutamate·HCl (2.0 g, 7.71 mmol, 1.0 equivalent) was cooled on ice for 30 minutes, and then treated with trimethylamine (TEA) (2.69 mL, 19.28 mmol, 2.5 equivalents) and 4-(dimethylamino)pyridine (DMAP) (3.3 mg, 0.3 mmol, 0.04 equivalents). After further stirring for 5.0 minutes, 1,1'-carbonyldiimidazole (CDI) (1.38 g, 8.84 mmol, 1.1 equivalents) was dissolved in DCM and slowly added over a period of 30 minutes. The reaction mixture was stirred overnight and heated to room temperature. A saturated (sat.) NaHCO3 solution (8 mL) was used, and accordingly... water (2 × ) and brine (2 × The reaction was stopped by washing with ), and the mixture was dried in a saturated Na2SO4 solution. The remaining solvent was removed under vacuum, and the crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamide)pentanediate was used without further purification. RP-HPLC (15 min, 10-90% B): t R =12.2 min; K'=5.8. Monoisotopic mass calculation value (C 17 H 27 N3O5): 353.4; Measured value: m / z = 376.1 [M + Na] +The crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamide)pentanedioate (2.72 g, 7.71 mmol, 1.0 equivalent) was dissolved in 1,2-dichloroethane (DCE) and cooled on ice for 30 minutes. To this solution, TEA (2.15 mL, 15.42 mmol, 2.0 equivalent) and H-Lys(Cbz)-OtBu·HCl (2.87 g, 7.71 mmol, 1.0 equivalent) were added, and the solution was stirred overnight at 40°C. The remaining solvent was evaporated, and the crude product was purified using silica gel flash chromatography with an eluent mixture containing ethyl acetate (siRNA) / hexane / TEA (500 / 500 / 0.8; v / v / v). After solvent removal, (9R,13S)-tri-tert-butyl-3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate was obtained as a colorless oil. RP-HPLC (15 minutes, 40-100% B): R =14.5 min; K'=6.25. Monoisotopic mass calculation value (C 32 H 51 N3O9) = 621.8; Measured value: m / z = 622.3 [M + H] + For the synthesis of (OtBu)KuE(OtBu)2(1), (9R,13S)-tri-tert-butyl-3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (3.4 g, 5.47 mmol, 1.0 equivalent) was dissolved in ethanol (EtOH) (75 mL), and palladium (0.34 g, 0.57 mmol, 0.1 equivalent) (10%) on activated carbon was added to this solution. The flask containing the reaction mixture was first purged with a hydrogen stream, and the solution was stirred overnight at room temperature under light hydrogen pressure (balloon). The crude product was purified on Celite, and the solvent was evaporated under vacuum. The desired product 1 was obtained as a waxy solid (1.9 g, 3.89 mmol, yield 71.6%). RP-HPLC (15 minutes, 10-90% B): R =12.6 min; K'=6.4. Monoisotopic mass calculation value (C 24 H 45 N3O7) = 487.6; Measured value: m / z = 488.3 [M + H]+ ,510.3[M+Na] + .

[0269] (S)-5-(tert-butoxy)-4-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-5-oxopentanoic acid ((OtBu)EuE(OtBu)2)(2):

[0270] [ka]

[0271] The tert-butyl-protected Glu-urea-Glu bond motif (EuE) was synthesized in the same manner as described in 1[3], using HL-Glu(OBzl)-OtBu·HCl instead of HL-Lys(Cbz)-OtBu·HCl. The desired product was obtained as a waxy and highly hygroscopic solid (4.10 g, 8.39 mmol, 84% yield). RP-HPLC (15 min, 10-90% B): R =11.3 minutes;K '=7.69. Monoisotopic mass calculation value (C 23 H 49 N2O9) = 488.3; Measured value: m / z = 489.4 [M + H] + ,516.4[M+Na] + .

[0272] (S)-NHFmoc-Asu(OtBu)-OBzl(5): A solution of (S)-Fmoc-Asu(OtBu)-OH (50 mg, 107.0 μmol, 1.0 equivalent) in DMF was added to HOAt (21.8 mg, 0.16 mmol, 1.5 equivalents), HATU (61.0 mg, 161.0 μmol, 1.5 equivalents), and DIPEA (73.2 μL, 0.48 mmol, 4.5 equivalents). After stirring at room temperature for 15 minutes, benzyl alcohol (22.2 μL, 0.32 mmol, 3.0 equivalents) was added, and the solution was stirred overnight. Finally, the solvent was removed under vacuum. The completion of reaction 5 was analyzed by RP-HPLC (15 minutes, 10-90% B):t R=17.1 min; K'=7.55. Monoisotopic mass calculation value for 5 (C 34 H 39 NO6): 557.28; Measured value: m / z = 580.7 [M + Na] + .

[0273] (S)-NHFmoc-Asu-OBzl(6): Deprotection of crude product 5 by tBu was carried out at room temperature for 45 minutes using a stirred mixture (v / v) of TFA (95%) and DCM (5%). After evaporation of the solution, crude product 6 was purified by preparative RP-HPLC (15 minutes, 60-80% B):t R =9.3 min; K'=8.9. Monoisotopic mass calculation value for 6 (C 30 H 31 NO6) = 501.22; Measured value: m / z = 524.5 [M + Na] + .

[0274] A solution of 6 (51.8 mg, 10.3 μmol, 1.0 equivalent) of OBzl-(S)-Fmoc-Asu[(OtBu)KuE(OtBu)2](7):DMF was added to HOBt (20.9 mg, 0.15 mmol, 1.5 equivalents), TBTU (36.3 mg, 15.5 μmol, 1.5 equivalents), and DIPEA (79.4 μL, 59.7 mg, 0.46 mmol, 4.5 equivalents). After stirring for 15 minutes, 1 (75.6 mg, 15.5 μmol, 1.5 equivalents) was added, and the mixture was further stirred at room temperature for 20 hours. Crude product 7 was purified by preparative RP-HPLC (15 minutes, 70-80% B):t R =8.9 min; K'=1.97. Monoisotopic mass calculation value for 7 (C 54 H 74 N4O 12 ) = 970.53; Measured value: m / z = 971.8 [M+H] + .

[0275] (S)-Fmoc-Asu[(OtBu)KuE(OtBu)2](8): For benzyl alcohol (Bzl) deprotection, 7 (57.2 mg, 65.0 μmol, 1.0 equivalent) was dissolved in EtOH (2.0 mL), and palladium (10%) (5.72 mg, 9.0 μmol, 0.1 equivalent) on activated carbon was added. The flask was pre-purged with a hydrogen stream, and the solution was stirred under light hydrogen pressure (balloon). After stirring for 70 minutes, the crude product was filtered through Celite, EtOH was evaporated under vacuum, and the product was purified using preparative RP-HPLC (15 minutes, 70-70.5% B):t R =6.5 min; K'=0.54. Monoisotopic mass calculation value for 5 (C 47 H 68 N4O 12 ) = 880.48; Measured value: m / z = 881.8 [M+H] + .

[0276] OPfp-(S)-Fmoc-Asu[(OtBu)KuE(OtBu)2](9):

[0277] [ka]

[0278] A solution of 8 (13.6 mg, 15.4 μmol, 1.0 equivalent) in dry DMF was added to DIC (4.77 μL, 1.94 mg, 30.8 μmol, 2.0 equivalents) and PfpOH (5.67 mg, 30.8 μmol, 2.0 equivalents). After stirring for 5 minutes, pyridine (2.49 μL, 31.0 μmol, 2.0 equivalents) was added, and the solution was stirred overnight at room temperature. The completion of reaction 9 was analyzed by RP-HPLC (15 minutes, 10-90% B):t R =17.2 min; K'=7.6. Monoisotopic mass calculation value for 9 (C 53 H 67 F5N4O 12 ): 1046.47; Measured value: m / z = 1069.8 [M + Na] + .

[0279] NHS-2,4-dinitrobenzoate (NHS-DNBA) (27):

[0280] [ka]

[0281] A solution of 2,4-dinitrobenzoic acid (DNBA) in dry THF (10.0 mg, 47.1 μmol, 1.0 equivalent) was added to N,N'-dicyclohexylcarbodiimide (DCC) (9.7 mg, 47.1 μmol, 1.0 equivalent) and N-hydroxysuccinimide (NHS) (10.8 mg, 94.3 μmol, 2.0 equivalents), and the reaction mixture was stirred overnight. The crude product was purified using RP-HPLC. RP-HPLC (15 min, 10-90% B):t R =10.21 min; K'=4.1. Monoisotopic mass calculation value (C 11 H7N3O8) = 309.02; Measured value: Not detected by ESI-MS. DOTAGA-3-iodo-D-Tyr-D-Phe-D-Lys-OH(DOTAGA-y(3-I)fk)(30):

[0282] [ka]

[0283] The synthesis of 30 was completed via the [2,3] solid-phase method as previously described. Briefly, the initial starting point was loading of 2-CTC resin with Fmoc-D-Lys(Boc)-OH of SP-1. After lysine conjugate, Fmoc was deprotected with SP-3, and Fmoc-D-phenylalanine was coupled using SP-2. The same procedure was used to couple Fmoc-D-Tyr(3-I)-OH. After the reaction was complete, the Fmoc protecting group was cleaved with SP-3, and the peptide bound to the resin was condensed with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in DMF. The reaction mixture was stirred at room temperature for 48 hours. Finally, the crude product was cleaved from the resin with SP-7.2, precipitated in Et2O, and centrifuged. The supernatant was removed, and 30 was purified using RP-HPLC. RP-HPLC (15 minutes, 10-90% B): R =6.2 min; K'=2.1. Monoisotopic mass calculation value (C 43 H 61 IN8O 14 ) = 1,040.34; Measured value: m / z = 1,040.5 [M+H] + m / z = 521.3 [M + 2H] 2+ m / z = 1,063.4 = [M + Na] + .

[0284] DOTAGA-y(3-I)fk(L-Asu[KuE]) (PSMA-8):

[0285] [ka]

[0286] A solution of DMF containing 30 (5.0 mg, 4.8 μmol, 1.0 equivalent), 9 (7.5 mg, 7.2 μmol, 1.5 equivalent), and DIPEA (3.3 μL, 21.6 μmol, 4.0 equivalent) was added. The reaction solution was stirred overnight at room temperature. After the reaction was complete, the solvent was removed under vacuum, and the crude product was treated with a mixture of piperidine (20 / 80 v / v) in DMF for 15 minutes to achieve Fmoc deprotection. The solvent was reduced to approximately 300 μL by evaporation under vacuum, precipitated in Et2O, and centrifuged. The resulting pellet was treated with SP-6 for tBu removal. The final product was purified by RP-HPLC (15 minutes, 10-90% B):t R =6.09 min; K'=2.05. Monoisotopic mass calculation value (C 63 H 93 IN 12 O 23 ) = 1,512.55; Measured value: m / z = 1,513.9 [M+H] + ,757.8[M+2H] 2+ .

[0287] DOTAGA-y(3-I)fk(L-Asu[KuE]-2,4-DNBA)(PSMA-36):

[0288] [ka]

[0289] The synthesis of PSMA-36 was achieved by dissolving PSMA-8 (3.0 mg, 3.3 μmol, 1.0 equivalent) in DMF, and adding PSMA-27 (4.1 mg, 13.2 μmol, 4.0 equivalents) and DIPEA (2.3 μL, 13.2 μmol, 4.0 equivalents). The solution was stirred at room temperature for 10 hours, and the final product was purified by RP-HPLC (15 minutes, 10-50% B):t R =12.12 min; K'=5.06. Monoisotopic mass calculation value (C 70 H 95 IN 14 O 28 ) = 1,706.55; Measured value: m / z = 1,707.8 [M+H] +,854.7[M+2H] 2+ .

[0290] [ nat Lu]DOTAGA-y(3-I)fk(L-Asu[KuE]-2,4-DNBA)([ nat Lu]PSMA-36):RP-HPLC (15 minutes, 10-60%) B):t R =9.81 min; K'=3.91. Monoisotopic mass calculation value (C 70 H 92 IN 14 O 28 Lu) = 1,878.47; Measured value: m / z = 1,879.9 [M+H] + .

[0291] [ka]

[0292] Schematic diagram of the synthesis of PSMA-36. (a) HOAt, HATU, DIPEA, benzyl alcohol, [DMF]; (b) 95% TFA, 5% DCM; (c) 1, HOBt, TBTU, DIPEA, [DMF]; (d) Pd / C (10%), H2, [EtOH]; ( e) DIC, PFP, pyridine, [DMF]; (f) 30, DIPEA, [DMF]; (g) 20% piperidine in DMF, [DMF]; (h) TFA; (i) 27, DIPEA [DMF] 4. Synthesis of EuE-based PSMA inhibitors PSMA-52 and PSMA-53 DOTAGA-F(4-NO2)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-52):

[0293] [ka]

[0294] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After deprotection of Fmoc by SP-3, 2 (1.5 equivalents) was coupled to D-Orn(NHDde) by SP-2. In the next step, the Dde protecting group was cleaved by SP-4, and the free amino group was treated with succinic anhydride (4.0 equivalents) and DIPEA (1.5 equivalents) dissolved in DMF. The reaction solution was stirred overnight at room temperature. Next, Fmoc-D-Lys-OtBu·HCl (1.5 equivalents) was coupled by SP-2, and Fmoc was deprotected as described in SP-3. The subsequent conjugation with the Fmoc-protected amino acids Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Phe(4-NO2)-OH was carried out as described in SP-2. The N-terminal Fmoc deprotected amino acid was conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in the final step. The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified by RP-HPLC. RP-HPLC (15 min, 10-60% B): R =9.71 min; K'=3.86. Monoisotopic mass calculation value (C 76 H 100 N 14 O 29 ) = 1,672.68; Measured value: m / z = 1,673.0 [M+H] + .

[0295] [ nat Lu]DOTAGA-F(4-NO2)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)([ nat Lu]PSMA-52):RP-HPLC(15 min, 10~60% B):t R =9.4 min; K'=3.7. Monoisotopic mass calculation value (C 76 H 97 N 14 O29 Lu)=1,844.6; Measured value: m / z = 1,846.0 [M+H] + .

[0296] 2,4-DNBA-Dap(DOTAGA)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-53):<000​​​​​​​​​​The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After deprotection of Fmoc by SP-3, 2 (1.5 equivalents) was coupled to D-Orn(NHDde) by SP-2. In the next step, the Dde protecting group was cleaved by SP-4, and the free amino group was treated with succinic anhydride (4.0 equivalents) and DIPEA (1.5 equivalents) dissolved in DMF. The reaction mixture was stirred overnight at room temperature. Next, Fmoc-D-Lys-OtBu·HCl (1.5 equivalents) was coupled by SP-2, and Fmoc was deprotected as described in SP-3. The subsequent conjugation with the Fmoc-protected amino acids Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Dap(NHDde)-OH was performed as described in SP-2. After coupling with Fmoc-L-Dap(NHDde)-OH, Fmoc deprotection was achieved as described in SP-3. Next, the free amino group was conjugated to 2,4-dinitrobenzoic acid (2,4-DNBA) using 2,4-DNBA (2.0 equivalents), HOBt (2.0 equivalents), TBTU (2.0 equivalents), and DIPEA (4.0 equivalents) in DMF. After the reaction was complete, Dde deprotection was achieved using SP-5. In the final step, the N-terminal free amino acid L-Dap was conjugated with chelating agents using DOTAGA anhydride (2.0 equivalents) and DIPEA (2.0 equivalents). The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydride was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified via RP-HPLC. RP-HPLC (15 minutes, 10-60% B): R =11.71 min; K'=4.86. Monoisotopic mass calculation value (C 77 H 100 N 16 O 32 ) = 1,760.67; Measured value: m / z = 1,762.1 [M+H] + .

[0299] [ natLu]2,4-DNBA-Dap(DOTAGA)-y-2-nal-k(Suc-N 5 -orn-C 4 -EuE)([ nat Lu]PSMA-53):RP-HPLC(15 min, 10~60% B):t R =8.3 min; K'=3.15. Monoisotopic mass calculation value (C 77 H 97 N 16 O 32 Lu) = 1,932.59; Measured value: m / z = 1,933.7 [M+H] + .

[0300] [ka]

[0301] A schematic diagram illustrating the general synthesis procedure for EuE-based PSMA inhibitors PSMA-52 and PSMA-53, as exemplified by PSMA-52. (a) 20% piperidine in DMF, 2, HOBt, TBTU, DIPEA[DMF]; (b) succinic anhydride, DIPEA[DMF]; (c) Fmoc-D / L-Lys-OAll·HCl, HOBt, TBTU, DIPEA[DMF]; (d) 20% piperidine in DMF, Fmoc-D-2-Nal-OH, HOBt, TBTU, DIPEA[DMF]; (e) 20% piperidine in DMF, Fmoc--D-Tyr(OtBu)-OH, HOBt, TBTU, DIPEA[DMF]; (f) 20% piperidine in DMF, Fmoc-D-Phe(4-NH2)-OH, HOBt, TBTU, DIPEA[DMF]; (g) DOTAGA anhydride, DIPEA[DMF]; (h) TFA; 5. Synthesis of PSMA-61 and PSMA-62 DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-2,4-DNBA)(PSMA-61):

[0302] [ka]

[0303] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection with SP-3, 2 (1.5 equivalents) were coupled to D-Orn(NHDde) with SP-2. In the next step, the Dde protecting group was cleaved with SP-4, and the free amino group was treated with Fmoc-D-Asp-OAll·HCl (1.5 equivalents) with SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was deprotected with SP-3 and conjugated to 2,4-DNBA using 2,4-DNBA (1.5 equivalents), HOBt (2.0 equivalents), TBTU (2.0 equivalents), and DIPEA (4.0 equivalents) in DMF. After the reaction was complete, allyl deprotection was performed with SP This was achieved by step -5. The next step involved repeated conjugations with Fmoc-D-Lys-OtBu·HCl (1.5 equivalents), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Phe(4-NHBoc)-OH using SP-2. The N-terminal Fmoc deprotected amino acid L-Phe(4-NHBoc)-OH was conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in the final step. The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified via RP-HPLC.

[0304] RP-HPLC (15 minutes, 10-90% B): R =6.40 min; K'=2.2. Monoisotopic mass calculation value (C 83 H 105 N 17 O 32 ) = 1,851.71; Measured value: m / z = 1,852.5 [M+H] + ,926.7[M+2H] 2+ . [ natLu]DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-2,4-DNBA)([ nat Lu]PSMA-61):RP-HPLC (15 minutes, 10~90% B):t R =8.22 points; K'=3.11.モノアイソトピック mass calculation value (C 83 H 102 N 17 O 32 Lu) = 2,023.63; Actual value: m / z = 1,013.1 [M+2H] 2+ .

[0305] DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-62):

[0306]

change

[0307] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection with SP-3, 2 (1.5 equivalents) were coupled to D-Orn(NHDde) with SP-2. In the next step, the Dde protecting group was cleaved with SP-4, and the free amino group was treated with Fmoc-D-Asp-OAll·HCl (1.5 equivalents) with SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was deprotected with Fmoc using SP-3 and protected with Dde-OH (2.0 equivalents) and DIPEA (4.0 equivalents) in DMF at room temperature. The reaction mixture was stirred overnight. Subsequently, allyl deprotection of D-Asp was achieved by applying SP-5. The next step involved repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 equivalents), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Phe(4-NHBoc)-OH using SP-2. Selective Dde deprotection was achieved by applying SP-4 to conjugate TMA to D-Asp, yielding a free amino group. TMA was coupled using TMA (2.0 equivalents), HOBt (1.5 equivalents), TBTU (1.5 equivalents), and DIPEA (10 equivalents) in DMF. The reaction mixture was stirred at room temperature for 8 hours. After conjugation of TMA, F Fmoc deprotection of moc-L-Phe(4-NHBoc)-OH was achieved using SP-3. The N-terminal Fmoc-deprotected amino acid L-Phe(4-NHBoc)-OH was conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in the final step. The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified via RP-HPLC. RP-HPLC (15 min, 10-70% B): R =7.48 min; K'=2.74. Monoisotopic mass calculation value (C 83 H 105 N 17 O 32) = 1,849.72; Measured value: m / z = 1,850.5 [M+H] + ,925.7[M+2H] 2+ .

[0308] [ nat Lu]DOTAGA-F(4-NH2)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)([ nat Lu]PSMA-62):RP-HPLC(15 min, 10~70% B):t R =7.27 min; K'=2.64. Monoisotopic mass calculation value (C 85 H 104 N 15 O 32 Lu) = 2,021.64; Measured value: m / z = 1,012.3 [M+2H] 2+ .

[0309] 6. Synthesis of PSMA-65, PSMA-66, and PSMA-71 2,4-DNBA-Dap(DOTAGA)y-2-nal-e(Abz-N 5 -orn-C 4 -EuE)(PSMA-65):

[0310] [ka]

[0311] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection with SP-3, 2 (1.5 equivalents) was coupled to D-Orn(NHDde) with SP-2. In the next step, the Dde protecting group was cleaved with SP-4, and the free amino group was treated with Fmoc-4-Abz-OH (1.5 equivalents), HOAt (1.5 equivalents), HATU (1.5 equivalents), and DIPEA (4.0 equivalents) in DMF. The reaction mixture was stirred overnight at room temperature. In the next step, the Abz residue was Fmoc deprotected with SP-3. The next step involved repeated conjugation with Fmoc-D-Glu-OtBu, Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Dap(Dde)-OH using SP-2. After Fmoc deprotection of Fmoc-L-Dap(Dde)-OH with SP-3, 2,4-DNBA was coupled using 2,4-DNBA (1.5 equivalents), HOBt (2.0 equivalents), TBTU (2.0 equivalents), and DIPEA (4.0 equivalents) in DMF. After the reaction was complete, the L-Dap(Dde)- residue was deprotected with Dde using SP-4 and conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents). The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous is complete, the peptide is cleaved from the resin with SP-7.2, and the crude product is E The solution was precipitated in t2O, centrifuged, and the supernatant was removed. The final product was purified via RP-HPLC. RP-HPLC (15 minutes, 10-60% B): t R =10.2 min; K'=4.1. Monoisotopic mass calculation value (C 79 H 96 N 16 O 32 ) = 1,780.64; Measured value: m / z = 1,781.3 [M+H] + .

[0312] [ nat Lu]2,4-DNBA-Dap(DOTAGA)y-2-nal-e(Abz-N 5 -orn-C 4 -EuE)([nat Lu]PSMA-65):RP-HPLC(15 min, 10~60% B):t R =9.8 min; K'=3.9. Monoisotopic mass calculation value (C 79 H 93 N 16 O 32 Lu) = 1,952.56; Measured value: m / z = 1,954.0 [M+H] + . DOTAGA-Dap(TMA)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-66):

[0313] [ka]

[0314] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection with SP-3, 2 (1.5 equivalents) were coupled to D-Orn(NHDde) with SP-2. In the next step, the Dde protecting group was cleaved with SP-4, and the free amino group was treated with Fmoc-D-Asp-OAll·HCl (1.5 equivalents) with SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was deprotected with Fmoc using SP-3 and protected with 2.0 equivalents of Dde-OH and 4.0 equivalents of DIPEA in DMF. The reaction mixture was stirred overnight. Subsequently, allyl deprotection of D-Asp was achieved by applying SP-5. The next step involved repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 equivalents), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-Dap(Dde)-OH using SP-2. Selective Dde deprotection was achieved by applying SP-4 to conjugate TMA to D-Asp and L-Dap, yielding free amino groups. TMA was coupled using TMA (4.0 equivalents), HOBt (3.0 equivalents), TBTU (3.0 equivalents), and DIPEA (20 equivalents) in DMF. The reaction mixture was stirred at room temperature for 8 hours. After the conjugation of TMA, Fmoc deprotection of Fmoc-L-Dap(TMA)-OH was achieved using SP-3. The N-terminal Fmoc-deprotected amino acid L-Dap was conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in the final step. The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified by RP-HPLC. RP-HPLC (15 min, 10-70% B): R =7.48 min; K'=2.74. Monoisotopic mass calculation value (C 88 H 107 N 15 O 37 ) = 1,965.70; Measured value: m / z = 1,966.4 [M+H] +984.1[M+2H] 2+ .

[0315] [ nat Lu]DOTAGA-Dap(TMA)y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-66)RP-HPLC (15 min, 10~70% B):t R =7.46 points; K'=2.73.モノアイソトピック mass calculation value (C 88 H 108 N 15 O 37 Lu) = 2,137.62; Measured value: m / z = 1,070.4 [M+2H] 2+ .

[0316] DOTAGA-2-Nal-y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)(PSMA-71):

[0317]

change

[0318] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection with SP-3, 2 (1.5 equivalents) were coupled to D-Orn(NHDde) with SP-2. In the next step, the Dde protecting group was cleaved with SP-4, and the free amino group was treated with Fmoc-D-Asp-OAll·HCl (1.5 equivalents) with SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was deprotected with Fmoc using SP-3 and protected with Dde-OH (2.0 equivalents) and DIPEA (4.0 equivalents) in DMF at room temperature. The reaction mixture was stirred overnight. Subsequently, allyl deprotection of D-Asp was achieved by applying SP-5. The next step involved repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 equivalents), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH, and Fmoc-L-2-Nal-OH using SP-2. Selective Dde deprotection was achieved by applying SP-4 to conjugate TMA to D-Asp, yielding a free amino group. TMA was coupled using TMA (2.0 equivalents), HOBt (1.5 equivalents), TBTU (1.5 equivalents), and DIPEA (10 equivalents) in DMF. The reaction mixture was stirred at room temperature for 8 hours. After the conjugation of TMA, Fmoc deprotection of Fmoc-L-2-Nal-OH was achieved using SP-3. The N-terminal Fmoc-deprotected amino acid L-2-Nal-OH was conjugated with chelating agents using DOTAGA anhydrous (2.0 equivalents) and DIPEA (2.0 equivalents) in the final step. The reaction mixture was stirred at room temperature for 48 hours. After the reaction with DOTAGA anhydrous was complete, the peptide was cleaved from the resin using SP-7.2, the crude product was precipitated in Et2O, centrifuged, and the supernatant was removed. The final product was purified by RP-HPLC. RP-HPLC (15 min, 10-80% B): R =7.57 min; K'=2.79. Monoisotopic mass calculation value (C 89 H 108 N 14 O 32 ) = 1,884.73; Measured value: m / z = 1,886.1 [M+H] +, 943.5[M+2H] 2+ .

[0319] [ nat Lu]DOTAGA-2-Nal-y-2-nal-k(d[N 5 -orn-C 4 -EuE]-TMA)([ nat Lu]PSMA-67):RP-HPLC(15 min, 10~90% B):t R =7.81 min; K'=2.91. Monoisotopic mass calculation value (C 89 H 105 N 14 O 32 Lu) = 2,056.64; measured value: m / z = 1, 029.7[M+2H] 2+ . 7. Radial labeling 68 Ga sign: 68 Ge / 68 The Ga-generating substance was eluted in aq. HCl (1.0 M), and a 1.25 mL fraction containing approximately 80% activity (600-800 MBq) was transferred to a reaction vial (ALLTECH, 5 mL). The vial was pre-loaded with each compound (5.0 nmol) and aq. 2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid (HEPES) solution (950 μL, 2.7 M). The reaction vial was heated at 95°C for 5 minutes, after which the radiolabeled compounds were immobilized on a pre-conditioned SPE cartridge (C8 light, SepPak). After pre-purging the cartridge with water (10 mL), elution of the radiolabeled PSMA inhibitor from the cartridge was achieved using a mixture of EtOH and water (1 / 1; v / v), phosphate-buffered saline (PBS) (1.0 mL), and again with water (1.0 mL). After radiolabeling was complete, EtOH was evaporated under vacuum, and the tracer was used without any further purification. Radiochemical purity was adjusted using radio-TLC (1.0 M sodium citrate buffer and 0.06 M NH4OAc / MeOH buffer (1 / 1; v / v)).

[0320] 177Lu label: 177 Lu-labeled compounds were prepared by slightly modifying the previously described [5] and used without further purification. Briefly, each tracer (0.75–1.0 nmol, 7.5–10 μL) was added to NH4OAc buffer (10 μL, 1.0 M, pH=5.9), 177 LuCl3(10~40MBq;A S >3000 GBq / mg, 740 MBq / mL, 0.04 M HCl (ITG, Garching, Germany) was added, and finally the mixture was packed with a small amount of pure water (maximum 100 μL) (Merck, Darmstadt, Germany). The reaction mixture was heated at 95°C for 40 minutes, and the radiochemical purity was determined using radio-TLC.

[0321] 125 Labeling: Briefly, stanylated precursor (SnBu3-BA)(OtBu)KuE(OtBu)2(PSMA-45) (approximately 0.1 mg) is added to peracetic acid (20 μL), [ 125 [I]NaI (5.0 μL, approximately 21.0 MBq) (74 TBq / mmol, 3.1 GBq / mL, 40 mM NaOH, Hartmann Analytic, Braunschweig, Germany), MeCN (20 μL), and AcOH (10 μL) were dissolved in a solution. The reaction solution was incubated at room temperature for 10 minutes, loaded onto a cartridge (C18 Sep Pak Plus, pre-conditioned with 10 mL MeOH and 10 mL of water), and rinsed with water (10 mL). After elution with a 1 / 1 mixture (v / v) of EtOH and MeCN (2.0 mL), the solution was evaporated to dryness under a gentle stream of nitrogen, treated with TFA (200 μL) for 30 minutes, and then the TFA was evaporated. 125 Crude product of [I]I-BA)KuE was purified by radio-RP-HPLC (20 minutes, 20-40% B):t R =13.0 min; K'=6.2. 8. Determination of HSA binding HSA binding experiments were performed as previously described [6]. The mobile phase consisted of a two-component gradient with a constant total flow rate of 0.5 mL / min. Mobile phase A was a 50 mm pH 6.9 NH4OAc solution, and mobile phase B was 2-propanol (RP-HPLC grade, VWR, Germany). The gradient of mobile phase A was set to 100% from 0 to 3 minutes, and mobile phase B was set to 20% from 3 minutes until the end of each experiment. On each experimental day, the column was calibrated with nine reference substances to verify performance and establish nonlinear regression. The PSMA inhibitor was dissolved at a concentration of 0.5 mg / mL in a mixture of 2-propanol and NH4OAc buffer (50 mm pH 6.9) (1 / 1; v / v). For each experiment, 10 μL of the solution containing the inhibitor was injected into the RP-HPLC system and the retention time was measured. Literature on HSA binding [%] was obtained from Valko et al. or Yamazaki et al. [6, 7]. Nonlinear regression was established using OriginPro 2016G.

[0322] 9. Determination of lipophilicity Lipophilicity: Radiolabeled PSMA inhibitors (0.5-1.0 MBq) dissolved in PBS (500 μL, pH=7.4) were added to n-octanol (500 μL) in a reaction vial (1.5 mL) and vortexed strictly for 3 minutes (n=6). For separation of the quantitative phase, the mixture was centrifuged at 6,000 g for 5 minutes (Biofuge 15, Heraus Sepatech, Osterode, Germany). The activity from each phase sample (100 μL) was measured using a γ counter, and logP was calculated. (o / w) The value was obtained.

[0323] 10. Cell experiments Cell Culture: PSMA-positive LNCAP cells (300265; Cell Lines Service GmbH) were cultured in Dulbecco's modified Eagle medium / nutrient mixture F-12 (1 / 1) (DMEM-F12, Biochrom) supplemented with fetal bovine serum (FCS) (10%, Biochrom), and maintained at 37°C in a humidified CO2 atmosphere (5%). One day (24 hours ± 2 hours) before all experiments using LNCaP cells, cultured cells were collected using a mixture of trypsin / ethylenediaminetetraacetic acid (0.05% / 0.02%) and PBS and centrifuged. After centrifugation, the supernatant was discarded, and the cell pellet was resuspended in culture medium. Subsequently, cells were counted using a hemocytometer (Neubauer) and seeded in 24-well plates. IC 50 The value was determined by transferring 150,000 cells / mL per well into a 24-well plate, while the internal migration rate was obtained by transferring 125,000 cells / mL per well into a 24-well PLL-coated plate.

[0324] 11.Affinity (IC 50 ) After removing the culture medium, the cells were treated once with HBSS (500 μL, Hanks equilibrium salt solution, Biochrom, Berlin, Germany, supplemented with 1% BSA) and left on ice for 15 minutes to equilibrate in HBSS (200 μL, 1% BSA). Next, the cells were treated with HBSS (1% BSA, control) or with increased concentrations of each ligand (10 in HBSS (1% BSA)). -10 ~10 -4 Add a solution containing one of the following (25 μL per well), followed by HBSS (1% BSA) ([ 125I)I-BA)KuE (25 μL, 2.0 nm) was added. All experiments were performed at least three times for each concentration. After incubation on ice for 60 minutes, the experiment was terminated by removing the medium, followed by rinsing with HBSS (200 μL). The medium from both steps was combined into a single fraction to represent the amount of free radioligand. The cells were then lysed in NaOH (250 μL, 1.0 nm) and combined with the HBSS (200 μL) from the subsequent washing step. Quantification of bound and free radioligands was completed using a γ counter.

[0325] 12. Internal migration Following the removal of the culture medium, the cells were washed once with DMEM-F12 solution (500 μL, 5% BSA) and then equilibrated in DMEM-F12 solution (200 μL, 5% BSA) at 37°C for at least 15 minutes. Each well was then treated with either DMEM-F12 solution (25 μL, 5% BSA) or 2-PMPA solution (25 μL, 100 μm) for blockage. Next, each 68 Ga or 177 Lu-labeled PSMA inhibitors (25 μL; 2.0 nm and 10 nm, respectively) were added, and cells were incubated at 37°C for 5, 15, 30, and 60 minutes, respectively. The experiment was terminated by placing the 24-well plate on ice for 3 minutes, followed by removal of the medium. Each well was rinsed with HBSS (250 μL), and the fractions from these first two steps were combined to represent the amount of free radioligand. Removal of surface binding activity was completed by incubating the cells in ice-cold 2-PMPA solution (250 μL, 10 μm in PBS) for 5 minutes, followed by rinsing with ice-cold PBS (250 μL). Internal migration activity was determined through a combination of incubation of cells in NaOH (250 μL, 1.0 m) and subsequent washing steps using NaOH (250 μL, 1.0 m). Illumination and blocking were performed three times at each time point. Free, surface binding, and internal migration activity were quantified using a γ counter.

[0326] 13. External migration The externalization kinetics of radiolabeled PSMA inhibitors were determined using LNCaP cells prepared in the same manner as described for the internalization assay. After the initial step of washing the cells with DMEM-F12 solution (5% BSA), the cells were readjusted by standing them at 37°C for at least 15 minutes. Subsequently, LNCaP cells were incubated with each radiolabeled peptide (25 μL, 10.0 nm) in a total volume of 250 μL per well at 37°C for 60 minutes. After 60 minutes, the supernatant with unbound free fractions was removed and measured with a γ counter for calculation of the added total radioactivity. Acid washing steps were avoided to ensure the integrity of the enzymes during subsequent externalization and reuse tests. To determine the reuse rate, fresh DMEM-F12 solution (250 μL, 5% BSA) was given to the cells to allow for re-internalization. In contrast, re-internalization was inhibited by the addition of a DMEM-F12 solution containing 2-PMPA (225 μL DMEM-F12 (5% BSA) and 25 μL 100 μm 2-PMPA solution (PBS)). The cells were then incubated at 37°C for 0, 20, 40, and 60 minutes. The supernatant was removed, and the cells were washed with ice-cold HBSS (250 μL). The combination of the supernatant and the volume of the subsequent HBSS (200 μL) washing step corresponds to the exotransitioned radioligand at the time investigated. Furthermore, the cells were washed twice with ice-cold 2-PMPA HBSS solution (250 μL, 10 μm) and combined, which therefore represented the fraction of membrane-bound radioligand. Determination of the internalization fraction was achieved by lysis as described for the internalization assay using NaOH (250 μL, 1.0 m). The activity of free, externally transported, membrane-bound, and internally transported radioactive ligands was quantified using a gamma counter.

[0327] 14. Animal experiments All animal experiments were conducted in accordance with the general animal welfare law in Germany (Deutsches Tierschutzgesetz, approval number 55.2-1-54-2532-71-13). For tumor models, LNCaP cells (approximately 10 7Cells were suspended in serum-free DMEM-F12 medium and Matrigel (1 / 1;v / v) (BD Biosciences, Germany) and inoculated onto the right shoulder of male, 6-8 week old CB-17 SCID mice (Charles River Laboratories, Sulzfeld, Germany). The animals were used for the experiment after the tumor size reached 4-8 mm in diameter. 15. PET Imaging experiments were conducted using Siemens Inveon small animal PET, and the data were analyzed using the associated Inveon Research Workplace software. Mice were anesthetized with isoflurane and approximately 4.0–17 MBq of material was used. 68 Ga-labeled compounds were injected via the tail vein (approximately 150–300 μL). Dynamic imaging was performed for 90 minutes after injection while the patient was in bed. Static blockade images were obtained 1 hour pi later with an acquisition time of 15 minutes. PSMA blockade was achieved by simultaneous injection of 8 mg / kg of 2-PMPA-solution (PBS). All images were reconstructed using the OSEM3D algorithm without scanner or attenuation correction.

[0328] 16. In vivo distribution Each of the following amounts is approximately 4.0 to 12.0 MBq (approximately 150 to 300 μL): 68 Ga or 177 Lu-labeled PSMA inhibitors were injected into the tail vein of male CB-17 SCID mice carrying LNCaP tumors, and the mice were sacrificed after a specified time frame (n=4 each). Selected organs were removed, weighed, and measured with a gamma counter.

[0329] 17. References in Example 1 1. Simecek, J., et al., A Monoreactive Bifunctional Triazacyclononane Phosphinate Chelator with High Selectivity for Gallium-68. ChemMedChem, 2012. 7(8): p. 1375-1378. 2. Weineisen, M., et al., Development and first in human evaluation of PSMA I&T-A ligand for diagnostic imaging and endoradiotherapy of prostate cancer. Journal of Nuclear Medicine, 2014. 55(supplement 1): p. 1083-1083. 3. Weineisen, M., et al., Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI research, 2014. 4(1): p. 1. 4. Weineisen, M., et al., 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. Journal of Nuclear Medicine, 2015. 56(8): p. 1169-1176. 5. Sosabowski, J.K. and S.J. Mather, Conjugation of DOTA-like chelating agents to peptides and radiolabeling with trivalent metallic isotopes. Nat. Protocols, 2006. 1(2): p. 972-976. 6. Valko, K., et al., Fast gradient HPLC method to compounds determine binding to human serum albumin. Relationships with octanol / water and immobilized artificial membrane lipophilicity. Journal of pharmaceutical sciences, 2003. 92(11): p. 2236-2248. 7. Yamazaki, K. and M. Kanaoka, Computational prediction of the plasma protein-binding percent of diverse pharmaceutical compounds. Journal of pharmaceutical sciences, 2004. 93(6): p. 1480-1494. Example 2 result: 1. The effect of introducing 2,4-dinitrobenzoic acid into the linker region of PSMA I&T

[0330] [ka]

[0331] [Table 3]

[0332] Slightly higher affinity and a 251% increase in internal migration. 2. The binding motif was changed from EuK to EuE, and the peptide spacer was changed from -y(3-I)fk- to -y-2-nal-k-.

[0333] [ka]

[0334] [Table 4]

[0335] Compared to the reference PSMA I&T, the improved reference compound PSMA-46 shows higher It exhibited internal migration and improved affinity. Thus, based on the structure of PSMA-46, electron-deficient aromatic residues were introduced in the next development step.

[0336] 3,4-nitrophenylalanine and 2,4-DNBA were introduced into the peptide spacer of PSMA-46.

[0337] [ka]

[0338] [Table 5]

[0339] While affinity remained similar, the introduction of 4-nitrophenylalanine slightly increased internal translocation, but further introduction of nitro groups via 2,4-DNBA significantly increased internal translocation.

[0340] Two electron-withdrawing groups are preferred to increase internal migration. 4. Introduction of 4-aminophenylalanine

[0341] [ka]

[0342] [Table 6]

[0343] Both modifications, 2,4-DNBA and trimesic acid, allowed for a further increase in internal translocation. 5. Introduction of electron-deficient groups in peptide spacers

[0344] [ka]

[0345] [Table 7]

[0346] The electron-deficient aromatic modification 2,4-DNBA enabled increased internal translocation. 6. Trimesic acid was incorporated into the linker and peptide spacer of the PSMA inhibitor.

[0347] [ka]

[0348] [Table 8]

[0349] Substitution of 4-aminophenylalanine with Dap(TMA) yielded similar affinity but slightly reduced internal translocation capacity. Since both ligands appear very promising, both tracers were evaluated in further experiments.

[0350] The conclusion of these experiments is that electron-deficient aromatic residues are transferable and can undergo increased internal migration while maintaining high affinity. 7. The in vitro effects of internal migration on cell retention, 177 Lu]PSMA I&T and [ 177 Compared to Lu]PSMA-617, compound [ 177 Lu]PSMA-62 and [ 177We evaluated Lu]PSMA-66.

[0351] [ 177 Lu]PSMA-66 showed the highest intracellular activity in tumor cells after 1 hour, and [ 177 Lu]PSMA-62 followed, but [ 177 The internal migration of Lu]PSMA-62 is, 177 It was found to be higher than Lu]PSMA-66 (343.9% vs. 297.8%, respectively). Interestingly, even when reinternal migration was blocked with a 100 μM 2-PMPA solution, [ 177 The intracellular clearance of Lu]PSMA-66 was lower than all other compounds investigated. When reinternalization was blocked, reference [ 177 The difference compared to [Lu]PSMA I&T was more than double.

[0352] [ 177 Lu]PSMA-66 has nine free carboxyl groups, which are equivalent to nine negative charges in vivo (pH=7.4). The broadly charged nature of this compound may explain the extended intracellular retention due to electrostatic repulsion from the negatively charged cell membrane.

[0353] 8. In vivo experiments: In vivo distribution

[0354] [Table 9]

[0355] 1 hour after pi[ 177 Compared to tumor uptake of Lu]PSMA I&T (4.69±0.95%), a significant increase in tumor activity was achieved through improved internal penetration and affinity. 177 Lu]PSMA-16, [ 177 Lu]PSMA-40 and [ 177 As previously observed with Lu]PSMA-41, extension of the peptide spacer using 4-amino-D-phenylalanine resulted in higher renal uptake, confirming that this modification increases renal accumulation.

[0356] 177 Introduction of trimesic acid into the linker of Lu]PSMA-62 resulted in a decrease in kidney uptake compared to the reference (106.45 ± 17.18% vs 162.96 ± 23.20%, respectively), and slightly reduced tumor uptake. 177 Internal migration of Lu]PSMA-62 177 was higher in direct comparison with Lu]PSMA-49, so a decrease in tumor uptake was not expected. How much internal migration contributes to tumor uptake and whether it is not more important than affinity is unclear. 177 Since Lu]PSMA-49 is more affinity for PSMA (2.5 ± 0.6 nM vs 4.0 ± 0.2 nM, respectively), 177 direct comparison of Lu]PSMA-49 177 with Lu]PSMA-62 indicates that affinity is more decisive.

[0357]

Table 10

[0358] The results in Table 10 show clear differences among the tracers 177 Lu]PSMA-62, 177 Lu]PSMA-66 and 177 Lu]PSMA-71. Regarding renal clearance, it was clear that for all ligands, a reduction in kidney uptake was observed compared to 1 h p.i. (Table 9). 177 Lu]PSMA I&T showed the highest kidney uptake after 24 h p.i., while 177 Lu]PSMA-62 showed the lowest kidney uptake, which was consistent with the renal clearance observed in the PET study. The tumor uptake of 177 Lu]PSMA-61 after 24 h p.i. remained almost stable over 23 h (8.00 ± 0.75 vs 7.70 ± 1.35%ID / g, 1 h p.i. and 24 h p.i., respectively) 177 ​Lu]PSMA-62 and [ 177 Lu]PSMA-66 showed similar in vitro parameters regarding internal distribution and affinity, but [ 177 Tumor uptake of Lu]PSMA-66 is, 177 Compared to Lu]PSMA-62, the pi was significantly reduced from 1 hour pi to 24 hours pi (10.00±0.44 vs. 5.73±1.39%ID / g, respectively). (Time pi and 24-hour pi). Along with a more beneficial tumor-to-liver and tumor-to-muscle ratio, stronger tumor retention is [ 177 Compared to Lu]PSMA-66[ 177 Lu]PSMA-62 was deemed superior. The highest tumor uptake was observed for PSMA-71, and PSMA-71 also exhibited the highest HSA binding levels. Renal uptake of 24-hour pi was [ 177 Lu]PSMA was similar to I&T, while tumor uptake was [ 177 Lu]PSMA-71 was more than three times higher (4.06±1.12 vs. 14.29±0.89%ID / g, respectively). 177 Lu]PSMA I&T and [ 177 Lu]PSMA-71).

[0359] In this regard, [ 177 Lu]PSMA-71 is a particularly valuable tracer for internal radiotherapy applications and can be considered a candidate for clinical application. 9. In vivo PET imaging Effect of 2,4-dinitrobenzoate linker substitution on EuK-based inhibitors The EuK-based inhibitor PSMA-36 was evaluated using small animal PET scans, and the effect of 2,4-dinitrobenzoic acid in the linker on its in vivo distribution was examined.

[0360] The logarithmic TAC plot is [ 68[Ga]PSMA-36 exhibits specific renal and tumor uptake. A linear decrease in blood pool activity and in the muscle region suggests nonspecific binding and rapid elimination. Accumulation in tumors remained stable throughout the observation period. 177 Lu]PSMA-36 is, [ 177 [Lu]PSMA showed an internal penetration rate more than three times higher than I&T, but tumor uptake was only moderate at 3.5% ID / mL after 85 minutes pi. 68 The most significant difference compared to Ga]PSMA I&T was the high and stable uptake in the lacrimal and salivary glands, showing approximately 2% ID / mL in both regions. Reference [ 68 The only structural difference from Ga]PSMA I&T is the introduction of 2,4-dinitrobenzoic acid, so linker modification must be the reason for this enhanced uptake. However, further research is needed to confirm this effect.

[0361] Interestingly, clearance in these regions is slower compared to blood pools and muscles, suggesting the involvement of distinct retention mechanisms. PSMA has been reported to be involved in angiogenesis during neovascularization of the eyeball in mice, and therefore [ 68 This would explain the uptake of Ga]PSMA-36 [1]. Tracer accumulation in the salivary glands 177 This is a common problem in clinical therapeutic approaches using Lu-labeled PSMA inhibitors [2]. Drug uptake into the salivary glands depends on intracellular or extracellular pathways, and most commonly, on simple diffusion in the phospholipid bilayer of acinar cells. Salivary drug concentrations are reflected, with respect to passive diffusion, primarily by free, non-ionized fractions in plasma [3-5]. In this respect, it is highly unlikely that passive diffusion is the cause of salivary gland uptake. EuK-based PSMA inhibitors are highly charged in vivo and thus exhibit high polarity, so other mechanisms must be involved. Furthermore, while passive diffusion would be visualized as high background activity during PET scans across all regions, visualization does not occur for most PSMA ligands because rapid clearance removes the tracer from the blood pool.

[0362] Action of trimesic acid on EuE-based inhibitors Substitution of PSMA ligands with electron-deficient aromatic systems is [ 177 Lu]PSMA-62 and [ 177 This resulted in enhanced internal distribution of Lu]PSMA-66 (343.9% and 297.8%, respectively). Therefore, both ligands were evaluated and compared in PET studies.

[0363] Both tracers exhibited superior tracer kinetics with respect to renal, muscle, and blood pool uptake. Specific uptake in the kidney was [ 68 Compared to Ga]PSMA-62, 68 Ga]PSMA-66 was slightly higher (45.3% ID / mL vs. 3, respectively). 4.8% ID / mL). 68 Compared with Ga]PSMA-62, 68 Higher renal accumulation of Ga]PSMA-66 in PET scans correlated well with in vivo distribution studies. TACs for muscle and blood pool activity showed linear uptake and ongoing clearance from these compartments.

[0364] 10. References in Example 2 1. Grant, CL, et al., Prostate specific membrane antigen (PSMA) regulates angiogenesis independently of VEGF during ocular neovascularization. PloS one, 2012. 7(7): p. e41285. 2. Kulkarni, H.R., et al., PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013. Journal of Nuclear Medicine, 2016. 57(Supplement 3): p. 97S-104S. 3. Haeckel, R., Factors influencing the saliva / plasma ratio of drugs. Annals of the New York Academy of Sciences, 1993. 694(1): p. 128-142. 4. Jusko, W.J. and R.L. Milsap, Pharmacokinetic Principles of Drug Distribution in Salivaa. Annals of the New York Academy of Sciences, 1993. 694(1): p. 36-47.5. Aps, J.K. and L.C. Martens, Review: the physiology of saliva and transfer of drugs into saliva. Forensic science international, 2005. 150(2): p. 119-131. 6. Young, J.D., et al., 68Ga-THP-PSMA: a PET imaging agent for prostate cancer offering rapid, room temperature, one-step kit-based radiolabeling. Journal of Nuclear Medicine, 2017: p. jnumed. 117.191882. 7. Wustemann, T., et al., Design of Internalizing PSMA-specific Glu-ureido-based Radiotherapeuticals. Theranostics, 2016. 6(8): p. 1085. 8. Hao, G., et al., A multivalent approach of imaging probe design to overcome an endogenous anion binding competition for noninvasive assessment of prostate specific membrane antigen. Molecular pharmaceutics, 2013. 10(8): p. 2975-2985. 9. Soret, M., S.L. Bacharach, and I. Buvat, Partial-volume effect in PET tumor imaging. Journal of Nuclear Medicine, 2007. 48(6): p. 932-945. 10. Bao, Q., et al., Performance evaluation of the inveon dedicated PET preclinical tomograph based on the NEMA NU-4 standards. Journal of Nuclear Medicine, 2009. 50(3): p. 401-408.

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof 【Chemistry 1】 (In the formula, m is an integer between 2 and 6; n is an integer between 2 and 6; R １Ｌ CH ２ , NH or O; R ２Ｌ is C or P(OH); R ３Ｌ CH ２ , NH or O; X １ The bonds are selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds; L １ This is a divalent linking group having a structure selected from oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether), oligo(ether-ester), oligo(ether-thioester), oligo(ether-urea), oligo(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea), and oligo(thioester-urea); A linking group is a group in which 2 to 10 subunits are linked by a type of bond specified by the same term. The linking group may have an EDS group; X ２ These are selected from amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, and amine bonds; R ２ is an optionally substituted aryl group or an optionally substituted aralkyl group, and the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogen and -OH; R ３ is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or aralkyl group may be substituted on its aromatic ring with one or more substituents selected from halogens and -OH groups; r is either 0 or 1; p is either 0 or 1; q is either 0 or 1; R ４ The group is selected from optionally substituted aryl and EDS groups, and the aryl group has a halogen, -OH and -NH on its aromatic ring. ２ They may be substituted with one or more substituents selected from; X ３ These include amide bonds, ether bonds, thioether bonds, ester bonds, thioester bonds, urea crosslinks, amine bonds, and formula 【Chemistry 2】 Selected from the groups, in the formula, the bond marked with a carbonyl group is X ３ to R Ｍ Attach to it, and other marked bonds are X ３ Attach it to the remainder of the compound of formula (I); R Ｍ is ４４ Sc, ４７ Sc, ５１ Cr, ５２ｍ Mn, ５８ Co, ５２ Fe, ５６ Ni, ５７ Ni, ６２ Cu, ６４ Cu, ６７ Cu, ６６ Ga, ６８ Ga, ６７ Ga, ８９ Zr, ９０ Y, ８９ Y, ９４ｍ Tc, ９９ｍ Tc, ９７ Ru, １０５ Rh, １０９ Pd, １１１ Ag, １１０ｍ In, １１１ In, １１３ｍ In, １１４ｍ In, １１７ｍ Sn, １２１ Sn, １２７ Te, １４２ Pr, １４３ Pr, １４９ P ｍ , １５１ Pm, １４９ Tb, １５３ Sm, １５７ Gd, １６１ Tb, １６６ Ho, １６５ Dy, １６９ Er, １６９ Yb, １７５ Yb, １７２ Tm, １７７ Lu, １８６ Re, １８８ Re, １９１ Pt, １９７ Hg, １９８ Au, １９９ Au, ２１２ Pb, ２０３ Pb, ２１１ At, ２１２ Bi, ２１３ Bi, ２２３ Ra, ２２５ Ac, and ２２７ cations of Th, or １８ A chelate group containing a chelated radioactive cation, selected from cationic molecules containing F; Furthermore, in the formula, L １ The possesses and / or R ４ The EDS group represented by is present at least once in the compound of formula (I), (E-1A), (E-1B), (E-2A), and (E-2B): 【Transformation 3】 Having a structure selected from, During the ceremony, 【Chemistry 4】 This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); s is 1, 2, or 3; t is 1, 2, or 3; R ５Ａ Independently, for each occurrence when s > 1, -NO ２ and an electron-withdrawing substituent selected from -COOH, R ５Ａ The bond between the phenyl ring and the s R ５Ａ This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R ５Ｂ Independently, for each occurrence where s > 1, the substituents are those having a lone pair of electrons on an atom directly attached to the phenyl ring shown in formula (E-1B), and the substituents are -OH and -NH ２ Selected from, R ５Ｂ The bond between the phenyl ring and the s R ５Ｂ This indicates that the group substitutes s hydrogen atoms at any position on the phenyl ring; R ６Ａ is, independently for each occurrence where t > 1, an electron-withdrawing substituent selected from -NO ２ and -COOH, and the bond between R ６Ａ and the phenyl ring represents that t R ６Ａ groups replace t hydrogen atoms at any position on the phenyl ring; and R ６Ｂ Independently, for each occurrence when t > 1, the substituents are those having a lone pair of electrons on an atom directly attached to the phenyl ring shown in formula (E-2B), and the substituents are -OH and -NH ２ Selected from, R ６Ｂ The bond between the phenyl ring and the t R ６Ｂ This represents the substitution of t hydrogen atoms at any position on the phenyl ring.

2. m is 2, n is 2 or 4, and R １Ｌ is NH, R ２Ｌ is C, and R ３Ｌ is NH, the compound or salt according to claim 1.

3. L １ The compound or salt according to claim 1 or 2, wherein the divalent linking group has a structure selected from oligoamides containing a total of 1 to 5 amide bonds in its main chain, and oligo(ester-amides) containing a total of 2 to 5 amide and ester bonds in its main chain, and the linking group may have an EDS group.

4. Part -X in equation (I) ２ -L １ -X １ -but, *-C(O)-NH-R ７ -NH-C(O)-R ８ -C(O)-NH- (L-1)、 *-C(O)-NH-R ９Ａ -NH-C(O)-R １０Ａ -C(O)-NH-R １１Ａ -NH-C(O)- (L-2A)、および *-C(O)-NH-R ９Ｂ -C(O)-NH-R １０Ｂ -C(O)-NH-R １１Ｂ -NH-C(O)- (L-2B) A compound or salt according to any one of claims 1 to 3 having a structure selected from the above. (In the formula, the amide bond marked with an asterisk is R in formula (I)) ２ It is attached to a carbon atom having, R ７ , R ８ , R ９Ａ , R ９Ｂ , R １１Ａ and R １１Ｂ The C2-C10 alkanediyl groups are independently selected from optionally substituted C2-C10 alkanediyl groups, and each alkanediyl group is independently -OH, -OCH ３ , -COOH, -COOCH ３ , -NH ２ , -NHC(NH)NH ２ And may be substituted with one or more substituents selected from the EDS group, and R １０Ａ and R １０Ｂ The C2-C10 alkanediyl groups are selected from optionally substituted C2-C10 alkanediyl groups and optionally substituted C6-C10 arenediyl groups, and each of the alkanediyl and arenediyl groups is independently -OH, -OCH. ３ , -COOH, -COOCH ３ , -NH ２ , -NHC(NH)NH ２ (and may be substituted with one or more substituents selected from the EDS group).

5. Part-X ２ -L １ -X １ -but, *-C(O)-NH-CH(COOH)-R １２ -NH-C(O)-R １３ -C(O)-NH- (L-3)、 *-C(O)-NH-CH(COOH)-R １４ -NH-C(O)-R １５ -C(O)-NH-R １６ -CH(COOH)-NH-C(O)- (L-4)、および *-C(O)-NH-CH(COOH)-R １７ -C(O)-NH-R １８ -C(O)-NH-R １９ -CH(COOH)-NH-C(O)- (L-5) A compound or salt according to claim 4 having a structure selected from the above. (In the formula, the combination marked with an asterisk is R in formula (I)) ２ It is attached to a carbon atom having, R １２ and R １４ These are independently selected from linear C2-C6 alkanediyl groups. R １３ These are straight-chain C2-C10 alkanediyl molecules. R １５ and R １６ These are independently selected from linear C2-C6 alkanediyl groups. R １３ and R １５ Each of them has one EDS group as a substituent, R １７ These are straight-chain C2-C6 alkanediyl compounds. R １８ is a phenylene group, and R １９ (These are straight-chain C2-C6 alkanediyl molecules.)

6. R ２ However, -CH was substituted by choice. ２ -phenyl and optionally substituted -CH ２ - An aralkyl group optionally substituted with a substituent selected from naphthyl, wherein the phenyl and naphthyl groups are optionally substituted with substituents selected from halogens, the compound or salt according to any one of claims 1 to 5.

7. R ３ However, -CH was substituted by choice. ２ -phenyl and optionally substituted -CH ２ The compound or salt according to any one of claims 1 to 6, wherein the aralkyl group is optionally substituted with a substituent selected from naphthyl, and the phenyl and naphthyl groups are optionally substituted with substituents selected from halogen and -OH.

8. r is 1, R ４ However, the phenyl group and naphthyl group are selected from optionally substituted groups, and the phenyl group and naphthyl group are halogens, -OH and -NH ２ A compound or salt according to any one of claims 1 to 7, optionally substituted with substituents selected from the following.

9. X ３ However, an amide bond or formula 【Transformation 5】 The compound or salt according to any one of claims 1 to 8, which is the base of (In the formula, the bond marked with a carbonyl group is X) ３ to R Ｍ Attach to it, and other marked bonds are X ３ (It attaches to the rest of the molecule.)

10. The compound of formula (I) has a linking group L １ It contains one EDS group, or one is R ４ It is represented by, and one is L １ The compound or salt according to any one of claims 1 to 9, which contains either two EDS groups that the compound has.

11. Formula (E-2A): 【Transformation 6】 A compound or salt according to any one of claims 1 to 10, containing an EDS group having (In the formula, 【Transformation 7】 This marks the bond that attaches the EDS group to the remainder of the compound of formula (I); and t is 1 or 2, R ６Ａ No. ２ (or selected from -COOH).

12. The following formula: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 A compound or salt according to any one of claims 1 to 11, having one of the above.

13. One or more compounds or salts according to any one of claims 1 to 12 (provided that R M is 225 Ac, 161 Tb, or 212 Pb, and the following formula 【Chemistry 9】 A pharmaceutical or diagnostic composition comprising or consisting of compounds or salts having the same (excluding compounds or salts having the same).

14. (a) cancer, including prostate cancer; or (b) Angiogenesis / angiogenesis A compound or salt thereof according to any one of claims 1 to 12, for use in a method of diagnosis and / or treatment of the following:

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