PSMA ligands for imaging and endoradiotherapy

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] The present disclosure relates to imaging and internal radiotherapy of diseases involving prostate specific membrane antigen (PSMA).Provided is a compound that binds to or inhibits PSMA, and has at least one moiety suitable for radiolabeling.Provided is also the medical use of such a compound.

[0002] In this specification, several documents are cited, including patent applications and manufacturer's instructions. The disclosures of these documents are not considered relevant to the patentability of this invention, but are hereby incorporated by reference in their entirety. More specifically, all relevant documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. [Background technology]

[0003] Prostate cancer (PCa) remains the most common malignancy in men after decades with a high proportion of poor survival rates. Prostate-specific membrane antigen (PSMA) or glutamic acid carboxypeptidase II (GCP II), 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), has demonstrated its suitability as an excellent target for the development of highly sensitive radiolabeled agents for internal radiotherapy and imaging of PCa (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):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 is an extracellular hydrolase whose catalytic center contains two zinc(II) ions with a bridging hydroxide ligand. Prostate-specific membrane antigen is highly upregulated in metastatic and hormone-refractory prostate cancer, but its physiological expression has also been reported in the kidney, salivary gland, small intestine, brain, and, to a lesser extent, healthy prostate tissue. In the intestine, PSMA promotes folate absorption by converting pteroylpoly-γ-glutamic acid to pteroylglutamic acid (folic acid). In the brain, PSMA hydrolyzes N-acetyl-L-aspartyl-L-glutamic acid (NAAG) to N-acetyl-L-aspartic acid and glutamic acid. The enzymatic function of PSMA in normal and pathological prostate has not been elucidated.

[0004] PSMA targeting molecules usually contain a linking unit that includes a zinc binding group (such as a 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' glutamic acid moiety (Machulkin, AE, et al., Small-molecule PSMA ligands. Current state, SAR and perspectives. Journal of drug targeting, 2016:1-15), which ensures high affinity and specificity for PSMA and is typically further linked to an effector functional group. The effector moiety is more flexible and to some extent resistant to structural modifications. The entrance tunnel of PSMA harbors two distinct and prominent structural features that are important for ligand binding. The first is the arginine patch, a positively charged region in the wall of the entrance tunnel that provides a structural explanation for the preference for negatively charged functional groups at the P1 site of PSMA. Upon binding, concerted repositioning of the arginine side chains can result in the opening of a second key structure, the S1 hydrophobic accessory pocket, which has been shown to accept the iodo-benzyl group of some 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 PSMA that can utilize a bidentate binding mode (Zhang, AX et al., A remote arene-binding site on prostate specific membrane antigen). revealed by antibody-recruiting small molecules. Journal of the American Chemical Society, 2010.132(36):12711-12716). The so-called arene-binding site is a simple structural motif formed by the side chains of Arg463, Arg511 and Trp541, which are part of the PSMA entrance lid. Binding to the arene-binding site by a distal inhibitor moiety can result in a substantial increase in inhibitor affinity for PSMA due to an avidity effect. Although PSMA I&T (see Figure 1) was developed with the intention of interacting with PSMA in this way, there is nevertheless no crystal structure analysis of the binding mode available. According to Zhang et al., the required property is a linker unit (suberic acid in the case of PSMA I&T) that promotes an open conformation of the PSMA entrance lid, thereby allowing the proximity of the arene-binding site. The structural composition of the linker determines the molecular weight and molecular weight of the linker for tumor targeting and biological activity. It has further been shown that spacer length has a significant effect on imaging 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 that are important for both high image quality and effective targeted internal radiation therapy.

[0006] Two categories of PSMA-targeted inhibitors are currently used in clinical practice. One is a tracer with a chelating unit for complexation of a radionuclide, 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 that contains 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 chelators for imaging, the most frequently used agents 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), PSMA-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):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(Suppl 1):1083-1083). PSMA HBED-CC or PSMA-11 was one of the first PSMA inhibitors and is currently used for imaging since the chelator HBED-CC does not allow therapeutic application. However, due to the unique physical characteristics and advantages of 18F for PET imaging such as longer half-life, lower positron energy, which results in higher image resolution and the possibility of large-scale production in cyclotrons, several groups have proposed its use for PCa imaging. 18 We focused on the development of F-labeled urea-based inhibitors. 18 F-labeled urea-based PSMA inhibitors [ 18 [18F]DCFPyl has shown 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: 1-9), and in comparative studies, 68The study showed superiority over [18F]DCFPyL and [68Ga]Ga-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):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):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(Suppl 2):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; 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; 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):1) are being applied in clinical practice to the symptomatic treatment of patients with prostate cancer. 111 In, 177 Lu, 90 Y and 213 By incorporating Bi, the chelating units DOTA and the related DOTAGA enable not only imaging but also therapeutic applications. 111 In]PSMA I&T has already been implemented clinically to assist surgeons in the resection of malignant tissues in radiation-guided surgery (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):1). Similarly, the recently developed and clinically tested PSMA inhibitor PSMA I&S (imaging and surgery) showed 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 The internal radiotherapy approach using [Lu]PSMA I&T showed potential efficacy, tolerability and good safety in patients receiving up to four cycles with 7.4 GBq. Dosimetric measurements obtained for organ radiation revealed that the kidneys and salivary glands in particular received the highest doses after the tumor lesion. Similar radiation values ​​were obtained with PSMA DKFZ 617 and [ 18 (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; 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. 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 renal excretion of radiolabeled compounds. Renal and hematological toxicity, which occasionally occurs after administration, is usually reversible, but there are legitimate concerns about chronic toxicity, especially in patients with long-term overall survival, such as PCa patients. Therefore, suitable concepts are needed to reduce unwanted radiation and simultaneously increase tumor uptake. Summary of the Invention [Problem to be solved by the invention]

[0009] In view of the above, the technical problem underlying the present invention is seen in the provision of means and methods for mitigating the radiation-induced side effects of PSMA-targeted radiolabeled diagnostics and therapeutics.A further technical problem is seen in the provision of means and methods for increasing the tumor uptake of such diagnostics and therapeutics.More generally, the technical problem is seen in the provision of improved PSMA-binding agents. [Means for solving the problem]

[0010] The technical problem is solved by the subject matter outlined in the appended claims and further described below. The details are explained. In particular, the present invention provides in a first aspect a compound of formula (I) or a pharma- ceutically acceptable salt thereof

[0011] [ka]

[0012] (In the formula, m is an integer of 2 to 6, preferably 2 to 4, more preferably 2; n is an integer of 2 to 6, preferably 2 to 4, more preferably 2 or 4; R 1L is CH, NH or O, preferably NH; R 2L is C or P(OH), preferably C; R 3L is CH, NH or O, preferably NH; X 1 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; L 1is 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(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 can have an EDS group; 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; R 2 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or the aralkyl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen, preferably I and -OH; R 3 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or the aralkyl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen, preferably I and -OH; r is 0 or 1, preferably 1; p is 0 or 1; q is 0 or 1; Preferably, p+q=1; R 4 is selected from an aryl group and an EDS group; X 3 is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, and a

[0013] [ka]

[0014] wherein the bond marked with a carbonyl group is selected from the group 3 R M The other marked bonds are attached to X 3 to the remainder of the compound of formula (I); Preferably it is an amide bond; R M is a labeling group comprising a chelating group optionally containing a chelated non-radioactive or radioactive cation; and wherein the EDS group is contained at least once in the compound of formula (I), and is selected from the group consisting of (E-1A), (E-1B), (E-2A) and (E-2B):

[0015] [ka]

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

[0017] [ka]

[0018] marks the bond attaching 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 is independently, for each occurrence where s>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 5A and The bond between the phenyl ring and sR5A represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 5B is independently, for each occurrence where s>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably selected from -OH and -NH, more preferably -NH; R 5B The bond between the phenyl ring and s R 5B represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 6A is independently, for each occurrence for t>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 6A The bond between and the phenyl ring is 6A represents that the group replaces t hydrogen atoms at any position on the phenyl ring; and R 6B is independently, for each occurrence for t>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably selected from -OH and -NH, more preferably -OH; R 6B The bond between and the phenyl ring is 6B represents that the group replaces t hydrogen atoms at any position on the phenyl ring.

[0019] The introduction of EDS substituents as shown 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, provides several unexpected advantages, including increased affinity, improved internalization, increased tumor cell retention, reduced non-specific binding, decreased kidney accumulation and increased tumor uptake.

[0020] In particular, reduced non-specific uptake in organs other than the prostate results in less unwanted radiation and reduces radiation-induced side effects. To illustrate these advantages, reference is made to the properties of particularly preferred compounds, designated herein as PSMA-71 and PSMA-66, which are discussed in more detail below.

[0021] especially,[ 177 Nanomolar affinity (5.3 ± 2.0 nM vs. 7.9 ± 2.4 nM), significantly improved internalization (206.8 ± 1.7% vs. 75.5 ± 1.6%), and improved IL-16 / ... 177 The biodistribution data show superiority of [Lu]PSMA-71. 177 Lu]PSMA-71, 177 Lu]PSMA I&T showed significantly higher tumor uptake (14.29±0.89 vs. 4.06±1.12%ID / g, respectively), while kidney accumulation was similar (32.36±2.49 vs. 34.66±17.20%ID / g, respectively).

[0022] Similarly, reduced nanomolar affinity (3.8±0.3 nM vs. 7.9±2.4 nM), significantly improved internalization (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 min incubation) together with reduced in vivo nonspecific binding, reduced kidney accumulation (117.5±6.9% ID / g vs. 128.9±10.7% ID / g) and a more than two-fold increase in tumor uptake (10.0±0.4% vs. 4.7±1.0% ID / g) were consistent with [ 177 In a direct comparison with PSMA I&T [ 177 Lu]PSMA-66.

[0023] As pointed out above, salts of the compounds of the present invention, including compounds of formula (I) (and including their preferred embodiments) are also suitable for use in the context of the present invention. These salts are understood to be generally pharma- ceutically acceptable salt forms of these compounds, which may be formed by protonation of an atom having a lone pair of electrons that is susceptible to protonation, such as, for example, salts of an amino group with an inorganic or organic acid, or a carboxylic acid group with a physiologically acceptable cation, as is well known in the art. Exemplary base addition salts include, for example, natrium-1, natrium-2, natrium-3, natrium-4, natrium-5, natrium-6, natrium-7, natrium-8, natrium-9, natrium-10, natrium-11, natrium-12, natrium-13, natrium-14, natri aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumine, diethanolamine or ethylenediamine salts; aralkylamine salts such as N,N-dibenzylethylenediamine, benetamine salts; heterocyclic aromatic amine salts such as pyridine, picoline, quinoline or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium or tetrabutylammonium salts; and basic amino acid salts such as arginine or lysine salts. Exemplary acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrochloride, hydroiodide, sulfate, nitrate, phosphate (such as, for example, phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, or perchlorate; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate, or ascorbate; sulfonate salts 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 pharma- ceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecyl sulfate, ethoxylated ethyl ester, ethyl ketone ... Detate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrochloride, hydrochloride, iodide Hydrogen salt, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), Salts include palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, e.g., S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, pp. 1-19 (1977)).

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

[0026] When the compounds of the invention are provided in crystalline form, the structure may contain solvent molecules. The solvent is typically a pharma- ceutically acceptable solvent, and includes, inter alia, water (hydrates) or organic solvents. Examples of possible solvates include ethanoates and iso-propanolates.

[0027] The term "codrug" refers to two or more therapeutic compounds linked together via a covalent chemical bond. 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 "co-crystal" refers to a multi-component 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 the target molecule or ion (i.e., the compound of the present invention) and one or more neutral molecular co-crystal formers. 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, i.e. compounds that are metabolized in vivo to active metabolites.Suitable prodrugs are, for example, esters.Specific examples of suitable groups are shown, inter alia, in paragraphs

[0082] to

[0118] under the heading of prodrugs and protective groups in US 2007 / 0072831.

[0030] To the extent that the compounds of the invention exhibit a pH-dependent charge state, it is understood that all possible charge states are encompassed. A preferred pH range in this regard is 0-14.

[0031] To the extent that the compounds according to the invention retain a net charge, it is understood that the compounds are provided in an electrically neutral form, which is achieved by one or more counterions, the preferred counterions being defined above in connection with the term "salt".

[0032] In formula (I), m is an integer of 2 to 6. Preferably, m is an integer of 2 to 4, more preferably 2. R 1L is CH2, NH or O, preferably NH. R 2L 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, in which m is 2 and R 1L is NH and R 2L is C, and R 3L is NH.

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

[0034] X in formula (I) 1is selected from an amide bond (i.e., -C(O)-NH-), an ether bond (i.e., -O-), a thioether bond (i.e., -S-), an ester bond (i.e., -C(O)-O-, a thioester bond (i.e., -C(S)-O- or -C(O)-S-), a urea bridge (i.e., -NH-C(O)-NH-), and an amine bond (i.e., -NH-). X 1 is preferably an amide bond.

[0035] Further, in formula (I), it is more preferable that n is 2 and X 1 But the amide bond -C (O)-NH- carbon atom is a group -(CH2) n - an amide bond attached to X 1 However, the carbon atom of the amide bond -C(O)-NH- is a group -(CH2) n Among these, more preferably, n is 2 and X is an amide bond attached to 1 However, the carbon atom of the amide bond -C(O)-NH- is a group -(CH2) n - is an amide bond attached to the

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

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

[0038] L 1 The term "oligo" in the terms 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(thioether-ester), oligo(thioether-thioester), oligo(thioether-urea), oligo(ester-thioester), oligo(ester-urea) and oligo(thioester-urea) as used in the definition of is understood to refer preferably 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 one of ordinary skill in the art, when two different bond types are shown in parentheses, both bond types are contained in the associated group (e.g., in "oligo(ester-amide)", an ester bond and an amide bond are contained).

[0039] More preferably, 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 one or two amide bonds in the main chain.

[0040] In addition, L 1 is an EDS group (i.e., a group having a high electron density substituent or an "electron dense substituent") as defined herein, i.e., L 1 Preferably, any EDS group is linked to a divalent linking group L 1 It is attached as a substituent to the main chain of L 1 is an oligoamide, oligoether, oligothioether, oligoester, oligothioester, oligourea, oligo(ether-amide), oligo(thioether-amide), oligo(ester-amide), oligo(thioester-amide), oligo(urea-amide), oligo(ether-thioether ... and most preferably, structures selected from oligoamides and oligo(ester-amides), and most preferably, structures selected from oligo(ester-amides) and oligo(ester-amides) in the compounds of formula (I), wherein the backbone is selected from X in the compounds of formula (I). 1 and X 2 In this respect, L 1 Further preferred definitions for 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 one or two amide bonds in the main chain.

[0041] According to the above, L 1 can have one or more, for example two or three, EDS groups. However, preferably, L 1 does not have an EDS group, or L 1 has one EDS group, more preferably L 1 has one EDS group.

[0042] L 1 has an EDS group (including the more preferred case where the EDS has one 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 the structure (E-2A).

[0043] As will be appreciated by those skilled in the art, L 1 The indication that may carry an EDS group serves as information about the possible positions of this group in the compounds according to the invention. 1 The fact that L may have an EDS group is 1 No limitation is imposed on the presence of other groups which may be present as alternative or additional substituents on the main chain of the linking group L. 1 contains independently one or more, for example two, groups attached as substituents to its backbone selected from -OH, -OCH3, -COOH, -COOCH3, -NH2 and -NHC(NH)NH2. More preferably, the linking group L 1contains one or more, for example two, groups -COOH attached as substituents to its backbone.

[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- ... 1 Attach to.

[0045] Thus, and preferably, X 1 and X 2 are both amide bonds, particularly amide bonds arranged in a preferred orientation as further defined above. In accordance with the above, preferably the moiety -X 2 -L 1 -X 1 -teeth: *-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 (In the formula, the amide bond marked with * represents R in formula (I). 2 is attached to a carbon atom having R 7 , R 8 , R 9A , R 9B , R 11A and R 11Bare independently selected from optionally substituted C2-C10 alkanediyl, preferably optionally substituted straight chain C2-C10 alkanediyl, each of the alkanediyl groups being independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and EDS groups. and R 10A and R 10B is selected from optionally substituted C2-C10 alkanediyl, preferably an optionally substituted straight chain C2-C10 alkanediyl, and optionally substituted C6-C10 arenediyl, preferably phenylene, the alkanediyl and arenediyl groups each being optionally substituted with one or more substituents independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and EDS groups. 10A R is preferably an optionally substituted C2-C10 alkanediyl as defined above, more preferably an optionally substituted straight-chain C2-C10 alkanediyl. 10B is preferably an optionally substituted C6-C10 arenediyl as defined above, more preferably a phenylene group, such as a para-phenylene group.

[0046] In the groups of formulae (L-1), (L-2A) and (L-2B), preferably R 7 The optional substituent on is -COOH, and R 8 is an EDS group, and R 9A and R 9B The optional substituent on is -COOH, and R 10A The optional substituents on are EDS groups, and R 11A and R 11B The optional substituent on is -COOH.

[0047] Also preferably, each of the groups of formulae (L-1) and (L-2A) contains as at least one substituent, as explained above, preferably R 8 and R10A As a substituent, the EDS group is preferably 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 the structure (E-2A).

[0048] Further, preferably, R in formula (L-1) 7 and R 8 The total number of carbon atoms in R in formula (L-2A) is 6 to 20, more preferably 6 to 16, excluding the carbon atoms contained in any substituent. 9A , R 10A and R 11A The total number of carbon atoms in R in formula (L-2B) is 6 to 20, more preferably 6 to 16, excluding the carbon atoms contained in any substituent. 9B , R 10B and R 11B The total number of carbon atoms in the alkyl group 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 meanings of -X in formula (I), even more preferred is 2 -L 1 -X 1 - has the structure (L-1) when n is 4, and -X 2 -L 1 -X 1 - is understood to have the structure (L-2A) or (L-2B) when n is 2.

[0050] In accordance with the above definition, even more preferably, the moiety -X 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 (wherein the bond marked with * represents R in formula (I) 2 is attached to a carbon atom having R 12 and R 14 is independently selected from linear C2 to C6 alkanediyl, preferably linear C3 to C6 alkanediyl; R 13 is a linear C2 to C10 alkanediyl, preferably a linear C4 to C8 alkanediyl, R 15 and R 16 is independently selected from linear C2-C6 alkanediyl, preferably linear C2-C4 alkanediyl; And R 13 and R 15 Each of may have one EDS group as a substituent, preferably R 13 and R 15 each of which has one EDS group as a substituent; R 17 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 is a straight-chain C2 to C6 alkanediyl, preferably a straight-chain C2 to C4 alkanediyl).

[0051] In this context too, preferably, R 13 and R 15The EDS group optionally attached to 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 the structure (E-2A).

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

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

[0054] Specifically preferred is where in formula (I) n is 2 and the moiety -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) Have one of (wherein the bond marked with * represents R in formula (I)2 where EDS is an EDS group as defined herein, including preferred embodiments thereof, and Ph is a para-phenylene group.

[0055] Also 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 the structure (E-2A).

[0056] In formula (I), R 2 R is an optionally substituted aryl group or an optionally substituted aralkyl group, preferably an optionally substituted aralkyl group. As will be understood, as used herein, the term "aralkyl group" refers to an alkyl group in which a hydrogen atom is replaced by an aryl group as a substituent. Preferably, the aralkyl group is a group in which one aryl group is bonded to an alkanediyl group. 2 The aryl or aralkyl group represented by the formula: may be substituted on its aromatic ring with one or more substituents selected from halogen, preferably I and -OH. The aryl moiety is preferably selected from phenyl and naphthyl, such as 2-naphthyl. The alkanediyl moiety of the aralkyl group is preferably a C1-C4 alkanediyl group, more preferably a -CH2- group. Thus, R 2 is more preferably selected from optionally substituted -CH-phenyl and optionally substituted -CH-naphthyl, in particular optionally substituted -CH-(2-naphthyl). Optionally substituted -CH-(2-naphthyl) is R 2 This is a particularly preferred option.

[0057] Optionally substituted aryl groups and the aryl moieties of optionally substituted aralkyl groups, including these preferred embodiments, may be substituted with one or more substituents selected from halogen, preferably I and -OH. Thus, there may be one or more, for example two or three, substituents selected from halogen, preferably I and -OH. However, preferably, R 2 is non-substitutive.

[0058] In view of the above, R 2 is most preferably unsubstituted -CH- (naphthyl), the naphthyl group being R 2 is provided as -CH2-(2-naphthyl), it being understood that most preferably it is a 2-naphthyl group.

[0059] In formula (I), R 3 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 halogen, preferably I and -OH. The aryl moiety of the aryl and aralkyl group is preferably selected from phenyl and naphthyl, such as 2-naphthyl. More preferably, the aryl moiety of the aryl and aralkyl is phenyl. The alkanediyl moiety of the aralkyl group is preferably a C1-C4 alkanediyl group, more preferably a -CH2- group. Thus, R 3 is more preferably optionally substituted -CH2-phenyl.

[0060] Optionally substituted aryl groups and the aryl moieties of optionally substituted aralkyl groups, including these preferred embodiments, may be substituted with one or more substituents selected from halogen, preferably I and -OH. Thus, there may be one or more, for example two or three, substituents selected from halogen, preferably I and -OH. Preferably, R 3is substituted with one substituent which is -OH, or a combination of one substituent -OH and one substituent -I.

[0061] Thus, particularly preferred are R 3 is -CH2-phenyl 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 in 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 the formula

[0063] [ka]

[0064] is a group of R 3 is the formula

[0065] [ka]

[0066] Based on (In the formula,

[0067] [ka]

[0068] is R 2 and R 3 and (b) each marking the bond attaching the compound to the remainder of the formula (I). Even more strongly preferred is R 2 and R 3 is a combination of R 2 is the formula

[0069] [ka]

[0070] is a group of R 3 is the formula

[0071] [ka]

[0072] Based on (In the formula,

[0073] [ka]

[0074] are R 2 and R 3 (The bond attaching the amine to the remainder of the compound is marked.) In formula (I), r can be 0 or 1, and 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 formula (I) 4 is selected from aryl groups and EDS groups. Aryl is preferably selected from phenyl and naphthyl, such as 2-naphthyl. Thus, R 4 R is more preferably selected from phenyl, naphthyl, such as 2-naphthyl, and an EDS group. 4 is most preferably 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 is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, and a

[0077] [ka]

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

[0079] [ka]

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

[0081] R M is a labeling group that comprises a chelating group that optionally contains a chelated non-radioactive or radioactive cation. As will be appreciated by those skilled in the art, R M The above definition, which includes a chelating group, M is a chelating group, in which case the chelating group is typically X 3 Directly bonded to and R M may include cases where, together with the chelating group, it comprises, for example, a further linker moiety, in which case the chelating group is connected to X via this further linker moiety. 3 It can be indirectly linked to

[0082] R MThe chelating group provided by is suitable for forming a chelate with a radioactive or non-radioactive cation. 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] The chelating group, optionally containing a chelated non-radioactive or radioactive cation, is preferably (i) a macrocyclic ring structure with 8 to 20 ring atoms, of which two or more, preferably three or more, are selected from oxygen, sulfur and nitrogen atoms; and (ii) acyclic, open-chain chelate structures with 8 to 20 main chain atoms, of which two or more, preferably three or more, are heteroatoms selected from oxygen, sulfur and nitrogen atoms; The chelating group is selected from the group consisting of at least one of:

[0084] Exemplary chelating groups and thus exemplary groups 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-tetraazacyclotetradec-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-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(phosphat) (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-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy(carbooxy))-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic 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-pyridilmethyl)-4,13-diaza-18-crown-6 (H2 macropa), and 4-amino-4-{2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}heptanedioic acid. is a residue of a chelating agent selected from bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP); The residue is provided by covalent bonding of a carboxyl group contained in the chelating agent to the remainder of the compound via an ester or amide bond, preferably an amide bond. In formula (I), this ester or amide bond is in this case represented by X 3 or preferably X 3 It will be understood by those skilled in the art that the eigenvalue can be represented by:

[0085] Of these chelating agents, DOTA and DOTAGA are preferred. Thus, and preferably, R M -X 3 - is the formula

[0086] [ka]

[0087] Based on (In the formula,

[0088] [ka]

[0089] The bond marked is attached to the remainder of the compound of formula (I), and the chelating group may contain a chelated non-radioactive or radioactive cation). Exemplary radioactive cations, optionally chelated by a chelating group, are: 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 The cationic molecule is selected from the group consisting of F-containing cationic molecules.

[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 The cationic molecule is selected from the group consisting of F-containing cationic molecules.

[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 invention contains one EDS group or two EDS groups. As explained above, the EDS group is L 1 There is and / or R 4 It may be represented by:

[0092] The most preferred compounds of formula (I) and salts thereof, including the preferred embodiments thereof described above, are those which do not contain a linking group L 1 and the preferred embodiments thereof described above, 4 (i.e., r is 1), and one is L 1 It contains two EDS groups.

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

[0094] [ka]

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

[0096] [ka]

[0097] marks the bond attaching 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 is independently, for each occurrence where s>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 5A The bond between the phenyl ring and s R 5A represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 5B is independently, for each occurrence where s>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably selected from -OH and -NH, more preferably -NH; R 5B The bond between the phenyl ring and s R 5B represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 6A is independently, for each occurrence for t>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 6A Tofu The bond between the phenyl ring is 6A represents that the group replaces t hydrogen atoms at any position on the phenyl ring; and R 6B is independently, for each occurrence for t>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably selected from -OH and -NH, more preferably -OH; R 6B The bond between and the phenyl ring is 6B represents that the group replaces t hydrogen atoms at any position on the phenyl ring.

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

[0099] Also generally preferred is the substituent R 5B are the same for s>1 and are selected from -OH and -NH2, more preferably -NH2; in the EDS group (E-2B), the substituent R 6B are the same for t>1 and are selected from -OH and -NH2, more preferably -OH.

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

[0101] [ka]

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

[0103] [ka]

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

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

[0106] [ka]

[0107] It is. In accordance with the above definition, preferred compounds of formula (I) are represented by the following 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 is as defined above, including preferred embodiments thereof, and the EDS group is contained at least once and has a structure as defined above, including preferred embodiments thereof.

[0110] More preferred compounds of formula (I) are those of 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 is as defined above, including preferred embodiments thereof, and the EDS group is contained at least once and has a structure as defined above, including preferred embodiments thereof.

[0113] Even more preferred compounds of formula (I) are those of formula (Ic)

[0114] [ka]

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

[0116] Even more preferred compounds of formula (I) are illustrated by the following formulae (Id) and (Ie):

[0117] [ka]

[0118] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M is as defined above, including preferred embodiments thereof, and (i) R is an EDS group having a structure as defined above, including preferred embodiments thereof, or (ii) R 10Ahas one EDS group having a structure as defined above, including preferred embodiments thereof, or both (i) and (ii) apply;

[0119] [ka]

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

[0121] Particularly preferred compounds of formula (I) are illustrated by the following formulae (If) and (Ig):

[0122] [ka]

[0123] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M is defined as above, including these preferred embodiments, and (i) R 4 is an EDS group having a structure as defined above, including preferred embodiments thereof; or (ii) R 10A has one EDS group having a structure as defined above, including preferred embodiments thereof, or both (i) and (ii) apply;

[0124] [ka]

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

[0126] In a preferred embodiment, the chelating group has bound thereto an alpha-emitting radionuclide, the alpha-emitting radionuclide being 212 Bi, 213 Bi and 225 Contains Ac. As pointed out above, the introduction of electron-deficient substituents greatly increases the internalization ability. This property leads to higher tumor uptake and particularly longer retention in tumor tissue, as shown by in vitro experiments (see Examples). Since complexes of chelators and alpha particle-emitting radionuclides tend to decomplex via physical recoil effects, the property of extended intracellular retention reduces the probability of free circulating radionuclides in vivo, thus increasing safety and reducing undesired radiation.

[0127] Particularly preferred compounds of the present invention are 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 pictorially in FIG.

[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. Single lowercase letters (such as "y") indicate the D-form of the respective amino acid. The half maximal inhibitory concentrations (IC 50 ) in LNCaP cells (1.5*10 5 cells / well, 1 h, 4°C, HBSS+1% BSA) and as radioligand ([ 125 I]I-BA) was determined in a competitive binding assay using KuE. 125 I]I-BA)KuE(1.25*10 5 Cells / well, PLL-coated plate, ([ 125 I]I-BA)KuE c = 0.2 nM and 177 Internalization activity expressed as relative cellular uptake [%] for Lu-labeled PSMA inhibitors (c=1.0 nM, DMEM / F-12 +5% BSA, 37°C, 60 min). Data were corrected for non-specific binding (10 μM 2-PMPA). IC 50 and internalization data are expressed as mean ± standard deviation (n=3). Lipophilicity 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 in [%] after log plot and calibration (n=1). Configuration describes simplified N-to-C-terminal structural composition of peptide spacer and linker without chelator. nd=not determined. "-II-" denotes simplified conjugation.

[0151] [Table 1]

[0152] Table 2. Summary of all parameters investigated in vitro for EuE-based PSMA inhibitors. Half inhibitory concentrations (IC 50 ) in LNCaP cells (1.5*10 5 cells / well, 1 h, 4°C, HBSS+1% BSA) and as radioligand ([ 125 I]I-BA) was determined in a competitive binding assay using KuE. 125 I]I-BA)KuE(1.25*10 5 Cells / well, PLL-coated plate, ([ 125 I]I-BA)KuE c = 0.2 nM and 177 c = 1.0 nM for Lu-labeled PSMA inhibitors. Internalization activity expressed as relative cellular uptake [%] to 100 mM of 2-PMPA (DMEM / F-12 + 5% BSA, 37°C, 60 min). Data were corrected for non-specific binding (10 μM 2-PMPA). IC 50 and internalization data expressed as mean ± standard deviation (n=3). Lipophilicity expressed as logP (partition coefficient in n-octanol / PBS) of radiolabeled PSMA inhibitors. Data for logP expressed as mean ± standard deviation (n=6). Albumin binding (HSA) in [%] after log plot and calibration (n=1). Configuration describes simplified N-to-C-terminal structural composition of peptide spacer and linker without chelator. nd=not determined. "-II-" denotes simplified conjugation.

[0153] [Table 2]

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

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

[0156] The pharmaceutical composition may further comprise a pharma- ceutically acceptable carrier, excipient and / or diluent. Examples of suitable pharmaceutical carriers, excipients and / or diluents are well known in the art and include phosphate buffered saline solution, water, emulsions such as oil / water emulsions, various types of wetting agents, sterile solutions, etc. Compositions containing such carriers can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to subjects in suitable doses. The administration of suitable compositions may be carried out by different methods, for example, by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchial administration. Particularly preferred are Preferably, the administration is performed by injection and / or delivery, for example, to a site in the pancreas or into a cerebral artery or directly into brain tissue. The composition may also be administered directly to the target site, for example, by biolistic delivery to an external or internal target site, such as the pancreas or brain. The administration schedule 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 size, body surface area, age, the particular compound to be administered, sex, time and route of administration, overall health, and other drugs being administered concomitantly. The pharmacologic active substance may be present in an amount between 0.1 ng and 10 mg / kg body weight per dose, although doses below or above this exemplary range are envisioned, especially taking into account the factors mentioned above.

[0157] Insofar as the pharmaceutical, diagnostic and therapeutic compositions disclosed above comprise one or more compounds of the invention, preferably there are no further pharma- ceutically, diagnostically or therapeutically active compounds present. Alternatively, further pharma-ceutically, diagnostically or therapeutically active compounds may be present, for example as anti-cancer agents.

[0158] Combined with chemotherapy or immunotherapy 177 As with the treatment of neuroendocrine tumors with [Lu]DOTATATE radiotherapy, the combination of therapeutic treatments with compounds of the present invention will have synergistic or additive treatment effects. 177 The combination of Lu PRRT with the oral chemotherapy drug capecitabine (Xeloda; Genentech) and 177 The first phase 3 trial comparing 177Lu-octreotate with capecitabine alone 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 tumours. Eur J Nucl Med Mol Imaging. 2008;35:743~748).

[0159] Further testing of a combination therapy termed peptide receptor chemoradionuclide therapy (PRCRT) was recently published (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 approaches" will be implemented in the near future to improve the efficacy of PSMA-targeted radioligand therapy.

[0160] In a further aspect, the present invention provides one or more compounds or salts of the invention as disclosed hereinabove for use in medicine. A preferred medical use is in nuclear imaging, also named nuclear molecular imaging, and / or in nuclear medicine, such as targeted radiotherapy of diseases associated with overexpression, preferably PSMA, to diseased tissue.

[0161] In a further aspect, the present invention provides a compound or salt of the invention as defined herein above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer.

[0162] Preferred applications include, but are not limited to, detection or staging of cancers such as high-grade glioma, lung cancer, and especially prostate cancer and metastatic prostate cancer, detection of metastatic disease in patients with medium-risk to high-risk primary prostate cancer, and detection of metastatic sites even in patients with biochemical recurrent prostate cancer, even when serum PSA value is low.Another preferred application is the imaging and visualization of angiogenesis.

[0163] In terms of medical indications amenable to treatment, particularly radiation treatment, cancer is a preferred indication, with prostate cancer being a particularly preferred indication. In a further aspect, the present invention provides a compound or salt of the invention as defined herein above for use in a method of diagnosing and / or staging cancer, preferably prostate cancer.

[0164] With regard to the embodiments characterized in this specification, and in particular in the claims, each embodiment mentioned in a dependent claim is intended to be combined with each embodiment of each claim (independent or dependent) from which the dependent claim depends. For example, in a case where independent claim 1 recites three alternatives A, B and C, dependent claim 2 recites three alternatives D, E and F, and claim 3 is dependent on claims 1 and 2 and recites three alternatives G, H and I, the specification shall, unless specifically mentioned otherwise, refer to 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, even in cases where the independent and / or dependent claims do not recite alternatives, it is understood that when a dependent claim refers back to more than one preceding claim, any combination of the subject matter encompassed by these is considered to be clearly and unambiguously disclosed. For example, in the case of independent claim 1, dependent claim 2 which refers back to claim 1, and dependent claim 3 which refers back to both claims 2 and 1, the combination of the subject matter of claims 3 and 1 would be clearly and unambiguously disclosed, as would the combination of the subject matter of claims 3, 2 and 1. In the case of a further dependent claim 4 which refers back to any one of claims 1 to 3, the combinations of the subject matter of claims 4 and 1, claims 4, 2 and 1, claims 4, 3 and 1, and claims 4, 3, 2 and 1 would be clearly and unambiguously disclosed.

[0166] In particular, the present invention provides the subject matter outlined in the following paragraphs: 1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof

[0167] [ka]

[0168] (In the formula, m is an integer of 2 to 6, preferably 2 to 4, more preferably 2; n is an integer of 2 to 6, preferably 2 to 4, more preferably 2 or 4; R 1L is CH, NH or O, preferably NH; R 2L is C or P(OH), preferably C; R 3L is CH, NH or O, preferably NH; X 1 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; L 1 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(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 can have an EDS group; 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; R 2is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or the aralkyl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen, preferably I and -OH; R 3 is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or the aralkyl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen, preferably I and -OH; r is 0 or 1, preferably 1; p is 0 or 1; q is 0 or 1; Preferably, p+q=1; R 4 is selected from an optionally substituted aryl group and an EDS group, the aryl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen, preferably I, -OH and -NH2; X 3 is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, and a

[0169] [ka]

[0170] wherein the bond marked with a carbonyl group is selected from the group 3 R M The other bonds marked with X 3 to the remainder of the compound of formula (I); Preferably it is an amide bond; R M is a labeling group comprising a chelating group optionally containing a chelated non-radioactive or radioactive cation; and wherein the EDS group is contained at least once in the compound of formula (I), and is selected from the group consisting of (E-1A), (E-1B), (E-2A) and (E-2B):

[0171] [ka]

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

[0173] [ka]

[0174] marks the bond attaching 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 is independently, for each occurrence where s>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 5A The bond between the phenyl ring and s R 5A represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 5B is independently, for each occurrence where s>1, as shown in formula (E-1B) is a substituent having a lone pair of electrons at the atom directly attached to the phenyl ring, the substituent is preferably selected from -OH and -NH, more preferably -NH; R 5B The bond between the phenyl ring and s R 5B represents that the group replaces s hydrogen atoms at any position on the phenyl ring; R 6A is independently, for each occurrence for t>1, an electron-withdrawing substituent preferably selected from -NO2 and -COOH, more preferably -COOH; R 6A The bond between and the phenyl ring is 6Arepresents that the group replaces t hydrogen atoms at any position on the phenyl ring; and R 6B is independently, for each occurrence for t>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably selected from -OH and -NH, more preferably -OH; R 6B The bond between and the phenyl ring is 6B represents that the group replaces t hydrogen atoms at any position on the phenyl ring.

[0175] 2. m is 2, n is 2 or 4, and R 1L is NH and R 2L is C, and R 3L The compound or salt of item 1, wherein is NH. 3. A compound or salt according to item 1 or 2, wherein n is 2.

[0176] 4.X 1 The compound or salt of any one of items 1 to 3, wherein is an amide bond. 5. n is 2 and X 1 However, the carbon atom of the amide bond -C(O)-NH- is a group -(CH2) n 5. The compound or salt of claim 4, wherein the - is attached to an amide bond.

[0177] 6.L 1 is a divalent linking group having 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, and the linking group may have an EDS group.

[0178] 7.L 1 represents 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 8. The compound or salt of any one of items 1 to 7, wherein

[0179] 9.X 2 9. The compound or salt of any one of items 1 to 8, wherein is an amide bond. 10.X 2 However, the nitrogen atom of the amide bond -C(O)-NH- is L 1 10. The compound or salt of item 9, wherein the amide bond is attached to

[0180] 11. Moiety-X of formula (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), and *-C(O)-NH-R 9B -C(O)-NH-R 10B -C(O)-NH-R 11B -NH-C(O)- (L-2B) The compound or salt of any one of items 1 to 10 having a structure selected from (In the formula, the amide bond marked with * represents R in formula (I). 2 is attached to a carbon atom having R 7 , R 8 , R 9A , R 9B , R 11A and R 11Bare independently selected from optionally substituted C2-C10 alkanediyl, preferably optionally substituted straight chain C2-C10 alkanediyl, each of which may be substituted with one or more substituents independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and an EDS group; and R 10A and R 10B is selected from optionally substituted C2-C10 alkanediyl, preferably an optionally substituted straight chain C2-C10 alkanediyl, and optionally substituted C6-C10 arenediyl, preferably phenylene, the alkanediyl and arenediyl groups each being optionally substituted with one or more substituents independently selected from -OH, -OCH3, -COOH, -COOCH3, -NH2, -NHC(NH)NH2 and EDS groups. 10A R is preferably an optionally substituted C2-C10 alkanediyl as defined above, more preferably an optionally substituted straight-chain C2-C10 alkanediyl. 10B is preferably an optionally substituted C6-C10 arenediyl as 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 R in formula (L-2A) is 6 to 20, more preferably 6 to 16, excluding the carbon atoms contained in any substituent. 9A , R 10A and R 11A The total number of carbon atoms in R in formula (L-2B) is 6 to 20, more preferably 6 to 16, excluding the carbon atoms contained in any substituent. 9B , R 10B and R 11B The compound or salt according to item 11, wherein the total number of carbon atoms in is 6 to 20, more preferably 6 to 16, excluding carbon atoms contained in any substituents.

[0182] 13. Part-X 2 -L 1 -X 1 - has the structure (L-1), and R 8 has an EDS group as at least one substituent, or Part-X 2 -L 1 -X 1 - has the structure (L-2A), R 10A 13. The compound or salt of item 11 or 12, wherein said compound or salt has an EDS group as at least one 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) The compound or salt of item 7 having a structure selected from (wherein the bond marked with * represents R in formula (I) 2 is attached to a carbon atom having R 12 and R 14 is independently selected from linear C2 to C6 alkanediyl, preferably linear C3 to C6 alkanediyl; R 13 is a linear C2 to C10 alkanediyl, preferably a linear C4 to C8 alkanediyl, R 15 and R 16is independently selected from linear C2-C6 alkanediyl, preferably linear C2-C4 alkanediyl; And R 13 and R 15 Each of may have one EDS group as a substituent, more preferably R 13 and R 15 each of which has one EDS group as a substituent; R 17 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 is a straight-chain C2 to C6 alkanediyl, preferably a straight-chain C2 to C4 alkanediyl).

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

[0185] 16.R 2 is an optionally substituted aralkyl group selected from optionally substituted -CH2-phenyl and optionally substituted -CH2-naphthyl, more preferably optionally substituted -CH2-(2-naphthyl), the phenyl and naphthyl groups being optionally substituted with substituents selected from halogen, preferably I and -OH.

[0186] 17.R 2is an aralkyl group of the formula -CH2-naphthyl, more preferably -CH2-(2-naphthyl). 18.R 3 is an optionally substituted aralkyl group selected from optionally substituted -CH2-phenyl and optionally substituted -CH2-naphthyl, more preferably optionally substituted -CH2-phenyl, the phenyl and naphthyl groups being optionally substituted with substituents selected from halogen, preferably I and -OH.

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

[0188] 20.R 2 But, the formula

[0189] [ka]

[0190] is a group of R 3 But, the formula

[0191] [ka]

[0192] A compound or salt according to any one of items 1 to 15, which is a group represented by the formula: (In the formula,

[0193] [ka]

[0194] is R 2 and R 3and (b) each marking the bond attaching the compound to the remainder of the formula (I). 21.R 2 But, the formula

[0195] [ka]

[0196] is a group of R 3 But, the formula

[0197] [ka]

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

[0199] [ka]

[0200] is R 2 and R 3 (Each of the three nucleotides marks the bond that attaches them to the rest of the molecule). 22. A compound or salt of any one of items 1 to 21, wherein r is 1.

[0201] 23. A compound or salt according to any one of items 1 to 22, wherein p is 0 and q is 1. 24.R 4 24. The compound or salt of any of items 1 to 23, wherein is selected from phenyl, optionally naphthyl, and an EDS group.

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

[0203] [ka]

[0204] A compound or salt according to any one of items 1 to 25, which is a group represented by the formula: (wherein the bond marked with a carbonyl group is X 3 R M The other bonds marked with X 3 to the rest of the molecule).

[0205] 27.X 3 But the carbon atom is R M 27. The compound or salt of item 26, wherein the amide bond -C(O)-NH- is attached to 28.R M 28. The compound or salt of any of items 1 to 27, wherein is a chelating group optionally containing a chelated non-radioactive or radioactive cation.

[0206] 29. The chelating group is (i) a macrocyclic ring structure with 8 to 20 ring atoms, of which two or more, preferably three or more, are selected from oxygen, sulfur and nitrogen atoms; and (ii) acyclic, open-chain chelate structures with 8 to 20 main chain atoms, of which two or more, preferably three or more, are heteroatoms selected from oxygen, sulfur and nitrogen atoms; 29. The compound or salt of any of items 1 to 28, wherein the chelating group comprises at least one of:

[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-tetraazacyclotetradec-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-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), 2-[1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid]-pentanedioic acid (DOTAGA), N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis(ho phosphate) (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 ate (HP-DOA3), 6-hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA), 1-(1-carboxy-3-carboxypropyl)-4,7-(carboxy)-1,4,7-triazacyclononane (NODAGA), 1,4,7-triazacyclononanetriacetic 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-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl}heptanedioic acid. is a residue of a chelating agent selected from bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide] (THP); 30. The compound or salt of any of items 1 to 29, wherein the residue is provided by covalent bonding of a carboxyl group contained in the chelating agent with the remainder of the compound via an ester or amide bond, more preferably an amide bond.

[0208] 31. The compound or compounds of claim 30, wherein the chelating agent is selected from DOTA and DOTAGA. Or salt. 32.X 3 is an amide bond by which the chelating group is attached to the remainder of the molecule.

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

[0210] [ka]

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

[0212] [ka]

[0213] The bond marked 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 chelating 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 34. The compound or salt of any of items 1 to 33, comprising a chelated radioactive cation selected from F-containing cationic molecules.

[0214] 35. The chelating group is 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 Positive ions including F 35. The compound or salt of claim 34, comprising a chelated cation selected from the group consisting of cation-containing molecules.

[0215] 36. A compound or salt according to any one of items 1 to 35, wherein the compound of formula (I) contains one or two EDS groups. 37. The compound of formula (I) comprises a linking group L 1 or one EDS group having R 4 One is represented by L 1 37. The compound or salt of item 36, wherein the compound or salt contains two EDS groups having

[0216] 38. Substituent R in EDS group (E-1A) 5A are the same for s>1 and are selected from -NO2 and -COOH; in the EDS group (E-2A), the substituent R 6A38. The compound or salt of any of items 1 to 37, wherein: 39. Substituent R in EDS group (E-1B) 5B are the same for s>1 and are selected from -OH and -NH2; in the EDS group (E-2B), the substituent R 6B 39. The compound or salt of any of items 1 to 38, wherein:

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

[0218] [ka]

[0219] 40. The compound or salt of any one of items 1 to 39, which contains an EDS group having the formula (In the formula,

[0220] [ka]

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

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

[0223] [ka]

[0224] 39. The compound of any one of items 1 to 38, (In the formula,

[0225] [ka]

[0226] marks the bond attaching the EDS group to the remainder of the compound of formula (I). 42. A compound represented by the following formula (Ia):

[0227] [ka]

[0228] or a pharma- ceutically 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 is defined as in items 1 to 41, and the EDS group is contained at least once and has a structure as defined in items 1 to 41.

[0229] 43. A compound represented by the following formula (Ib):

[0230] [ka]

[0231] or a pharma- ceutically acceptable salt thereof. (In the formula, n, 1 , L 1 , X 2 , R 2 , R 3 , R 4 , X 3 and R M is defined as in items 1 to 42, and the EDS group is contained at least once and has a structure as defined in items 1 to 42.

[0232] 44. The following formula (Ic)

[0233] [ka]

[0234] or a pharma- ceutically acceptable salt thereof. (In the formula, n, 1 , L 1 , X 2 , R 4 , X 3 and R M is defined as in items 1 to 42, and the EDS group is contained at least once and has a structure as defined in items 1 to 42.

[0235] 45. The compound of item 44 having the following formula (Id) or (Ie) or a pharma- ceutically acceptable salt thereof:

[0236] [ka]

[0237] (In the formula, R 9A , R 10A , R 11A , R 4 , X 3 and R M is defined as in items 1 to 44; (i) R 4 is an EDS group having the structure defined in items 1 to 44; or (ii) R 10A has one EDS group having a structure as 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 is defined in items 1 to 44, and R 4is an EDS group having the structure defined in items 1 to 44). 46. ​​The compound of item 45 having the following formula (If) or (Ig) or a pharma- ceutically acceptable salt thereof:

[0240] [ka]

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

[0244] 47. The formula:

[0245] [ka]

[0246] [ka]

[0247] [ka]

[0248] [ka]

[0249] The compound or salt thereof according to item 1, wherein 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 50. The compound or salt of any one of items 1 to 47 for use in a method for the diagnosis and / or treatment of [Brief description of the drawings]

[0251] [Figure 1] FIG. 1 is a web chart of characteristics for [nat / 177Lu]PSMA I&T and [nat / 177Lu]PSMA-62 and [nat / 177Lu]PSMA-66. [Diagram 2] Figure 1 shows the externalization kinetics of selected 177Lu-labeled PSMA inhibitors from LNCaP cells. 1.25*105 cells / well were incubated with the respective radioligand (c=1.0 nm) in DMEM solution (5% BSA) at 37°C for 1 h. The supernatant was then removed and washed once with DMEM solution (5% BSA, 37°C). Then, either A) DMEM solution (5% BSA) alone or B) blocking DMEM solution (5% BSA, 10 μM 2-PMPA) was added as an alternative. The total cell internalization activity at t=0 min was corrected for non-specific binding (10 μM 2-PMPA) and normalized to 100%. All data are expressed as mean ± standard deviation (n=3). [Diagram 3] FIG. 13 shows the biodistribution (in %ID / g) of 2.5-3.0 MBq (0.15-0.25 nmol) of [177Lu]PSMA-66 and [177Lu]PSMA I&T in LNCaP tumor-bearing CB-17 SCID mice (n=4 each). [Figure 4] Maximum intensity projection (MIP) of μPET scan (dynamic scan, total frames 1-1.5 h pi) (top left) following injection of approximately 10.3 MBq (0.19 nmol tracer) of [68Ga]PSMA-36 in LNCaP tumor-bearing CB-17 SCID mice. TAC in %ID / mL of [68Ga]PSMA-36 (log plot) from dynamic PET data (90 min acquisition time, OSEM 3D reconstruction) of blood pool (heart), kidney, tumor, muscle, lacrimal gland and salivary gland in LNCaP tumor-bearing CB-17 SCID mice. [Figure 5-1] Maximum intensity projections (MIPs) of μPET scans (dynamic scans, total frames 1-1.5 hours pi) following injection of approximately 11 and 13 MBq (0.15-0.25 nmol tracer) of 68Ga-labeled PSMA inhibitors, PSMA-62 and PSMA-66, respectively, in LNCaP tumor-bearing CB-17 SCID mice (top left). [Figure 5-2] TAC in %ID / mL of each 68Ga-labeled PSMA inhibitor (logarithmic plot) from dynamic PET data (acquisition time 90 min, OSEM 3D reconstruction) of blood pool (heart), kidney, tumor, and muscle in LNCaP tumor-bearing CB-17 SCID mice for both 68Ga-labeled tracers. [Figure 6] Figure 1 shows the biodistribution (in %ID / g) of 2.5-6.0 MBq (0.15-0.25 nmol) of [177Lu]PSMA-62, [177Lu]PSMA-66, [177Lu]PSMA-71 and [177Lu]PSMA I&T in LNCaP tumor-bearing CB-17 SCID mice (n=4 each). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0252] The examples illustrate the 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 chelator DOTAGA anhydride. 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 synthesis of peptides 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) on Nucleosil 100 Analysis was performed on a C18 column (5 μm, 125 × 4.0 mm, CS GmbH, Langerwehe, Germany). Analysis of peptides was performed by applying different gradients of 0.1% (v / v) trifluoroacetic acid (TFA) in HO (solvent A) and 0.1% TFA (v / v) together 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 for HSA binding was performed using OriginPro 2016G (Northampron, USA). Retention time t R Preparative RP-HPLC of peptides was performed using a Multispher The radioactivity was detected by connecting the UV photometer inlet to a NaI(Tl) well-type scintillation detector from EG&G Ortec (Munich, Germany). 68 Ga and 177 Lu label Compounds were analyzed as previously published [1, 2]. Electrospray ionization mass spectrometry (ESI-MS) spectra were analyzed using the expression LCMS mass spectrometer (Advion Ltd., Harlow, UK) and Varian 500-MS IT mass spectrometer (Agilent Technologies, Santa Clara, USA). For Bradford assay, a V-630 UV-Vis spectrophotometer from JASCO Germany GmbH (Gross-Umstadt, Germany) was used, and centrifugation of the S9 fraction was performed in 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 acquired using an AV 300 (300 MHz) or AV 400 (400 MHz) from Bruker (Billerica, USA) applying 300K. Incubation of S9 fractions for ex vivo metabolite analysis was performed in a Biometra UNO Thermoblock (Biometra, Göttingen, 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 equiv.) in anhydrous dichloromethane (DCM) with N,N-diisopropylethylamine (DIPEA) (4.5 equiv.) at room temperature (RT) for 2 h. The remaining trityl chloride was capped by adding 2 mL / g methanol (MeOH) for 15 min. After this, the resin was filtered and eluted with DCM (2 × ), dimethylformamide (DMF) (2 × ) and MeOH(2 × ) and stored under vacuum overnight. Loading is determined using weight difference.

[0255]

number

[0256] Equation 1. Determining resin loading: m 合計 : mass of loaded resin (Fmoc-AA-OH and HCl); M As : Molar mass of amino acid; M 正味 Weight: Mass of 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 equiv.), N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) (2.0 equiv.), N-hydroxybenzotriazole (HOBt) (2.0 equiv.), and DIPEA (4.5 equiv.) in DMF (8 ml / g resin) was added to the resin-bound free amine peptide, shaken at room temperature for 2 h, and then diluted with DMF (6 × ). Coupling with secondary or aromatic amines was carried out employing a different protocol. Fmoc-AA-OH (3.0 equiv.) 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 hexafluoro-phosphate (HATU) (3.0 equiv.), 1-hydroxy-7-azabenzotriazole (HOAt) (3.0 equiv.) and DIPEA (6.0 equiv.) and stirred for 15 min. The preactivated solution was added to the resin-bound peptide and shaken at room temperature for 2 h. After completion of the reaction, the resin was washed with DMF (6 × ) and washed. Overall, all peptide scaffolds were synthesized as previously described (Weineisen, M.; Schottelius, M.; Simecek, J.; Eiber, M.; Schwaiger, M.; Westerman, M.). 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: On-resin Fmoc deprotection: The resin-bound Fmoc-protected peptide was treated with 20% piperidine (v / v) in DMF for 5 min and a second time for 15 min. The resin was then washed with DMF (8 × ) and washed thoroughly.

[0258] SP-4: On-resin Dde deprotection: N-(1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-ethyl) (Dde) protected peptide (1.0 equiv.) was dissolved in 2.0% hydrazine monohydrate (N2H4·H2O) (v / v) solution in DMF. After 15 min, the deprotected peptide was dissolved in DMF (6 × ) or precipitated in diethyl ether (Et2O) to give the crude product. If Fmoc and Dde protecting groups were present and only Dde deprotection was required, the resin-loaded peptide was treated 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) at room temperature for 3 h. The resin-loaded peptide was then washed with DMF (6 × ) and washed thoroughly.

[0259] SP-5: On-resin allo / allyl deprotection: Allo / allyl protecting groups were removed from the resin-bound peptide using a DCM solution (6.0 mL) containing triisopropylsilane (TIPS) (50.0 equiv.) and (triphenyl)palladium(0) (Pd(PPh3)4) (0.3 equiv.). The resin was treated with this solution for 1.5 h at room temperature. Finally, the resin was washed with DCM (3 × ) to remove Pd(PPh3)4.

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

[0261] SP-7.1:A) Peptide cleavage from resin with preservation of side-chain protecting groups: The fully protected, resin-bound peptide was dissolved in a mixture of DCM / trifluoroethanol (TFE) / acetic acid (AcOH) (6 / 3 / 1; v / v / v) and shaken for 30 min. The solution was filtered off and the resin was dissolved in another cleavage solution for another 30 min. The fractions were combined and the solvent 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 the resin with simultaneous deprotection of all acid-labile protecting groups: The fully protected, resin-bound peptide was dissolved in a mixture of TFA / TIPS / water (95 / 2.5 / 2.5; v / v / v) and shaken for 30 min. The solution was filtered off and the resin was treated in the same way for another 30 min. The fractions were then combined and the solvent was removed in a constant volume. Concentration was performed under a stream of nitrogen. The crude peptide was precipitated in Et2O and left to dry overnight.

[0263] SP-8: Deacetylation of carbohydrate moieties: Deacetylation was accomplished by dissolving the PSMA inhibitor in MeOH containing KCN (0.5 equiv.) overnight at room temperature with simultaneous stirring (Herzig, J., Nudelman, A., Gottlieb, HE, 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 Gallium compounds: nat Ga III For preparation of the complex, 50 μL of a 2.0 mM aqueous (aq.) solution of PSMA inhibitor and 50 μL of a 2.0 mM aq. solution of Ga(NO3)3 were mixed and heated at 40° C. for 30 min. Chelate formation was assessed using RP-HPLC and ESI-MS. The resulting 1.0 mM solution was diluted and analyzed by in vitro IC 50 was used for determination and HSA binding.

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

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

[0267] [ka]

[0268] ((OtBu)KuE(OtBu)2)(1): Synthesis of tert-butyl protected Lys-urea-Glu binding motif (EuK) was synthesized by solution-phase synthesis as previously described [3]. Briefly, a solution of L-di-tert-butyl-glutamate·HCl (2.0 g, 7.71 mmol, 1.0 equiv) in DCM was cooled on ice for 30 min and then treated with trimethylamine (TEA) (2.69 mL, 19.28 mmol, 2.5 equiv) and 4-(dimethylamino)pyridine (DMAP) (3.3 mg, 0.3 mmol, 0.04 equiv). After further stirring for 5.0 min, 1,1'-carbonyldiimidazole (CDI) (1.38 g, 8.84 mmol, 1.1 equiv) was dissolved in DCM and slowly added over a period of 30 min. The reaction mixture was further stirred overnight and allowed to warm to room temperature. Saturated (sat.) NaHCO3 solution (8 mL) was used and Water (2 × ) and Brine (2 × The reaction was quenched with a washing step with 100 mL of ethyl acetate and dried over saturated Na2SO4 solution. The remaining solvent was removed in vacuo and the crude product (S)-di-tert-butyl 2-(1H-imidazole-1-carboxamide)pentanedioate was used without further purification. RP-HPLC (15 min, 10-90% B):t R = 12.2 min; K' = 5.8. Calculated monoisotopic mass (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 equiv.) was dissolved in 1,2-dichloroethane (DCE) and cooled on ice for 30 min. To this solution, TEA (2.15 mL, 15.42 mmol, 2.0 equiv.) and H-Lys(Cbz)-OtBu·HCl (2.87 g, 7.71 mmol, 1.0 equiv.) were added and the solution was stirred at 40 °C overnight. The remaining solvent was evaporated and the crude product was purified using silica gel flash chromatography with an eluent mixture containing ethyl acetate (EtOAc) / hexane / TEA (500 / 500 / 0.8; v / v / v). After removal of the solvent, (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 min, 40-100% B):t R = 14.5 min; K' = 6.25. Calculated monoisotopic mass (C 32 H 51 NO9) = 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 equiv.) was dissolved in ethanol (EtOH) (75 mL) and palladium on activated carbon (0.34 g, 0.57 mmol, 0.1 equiv.) (10%) was added to the solution. The flask containing the reaction mixture was first purged with a stream of hydrogen and the solution was allowed to stir under light hydrogen pressure (balloon) overnight at room temperature. The crude product was purified over Celite and the solvent was evaporated in vacuum. The desired product 1 was obtained as a waxy solid (1.9 g, 3.89 mmol, 71.6% yield). RP-HPLC (15 min, 10–90% B): R = 12.6 min; K' = 6.4. Calculated monoisotopic mass (C 24 H 45 NO) = 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 synthesis of tert-butyl protected Glu-urea-Glu binding motif (EuE) was carried out similarly to that described for 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):t R =11.3 minutes;K '=7.69. Calculated monoisotopic mass (C 23 H 49 NO) = 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 equiv) in DMF was added to HOAt (21.8 mg, 0.16 mmol, 1.5 equiv), HATU (61.0 mg, 161.0 μmol, 1.5 equiv) and DIPEA (73.2 μL, 0.48 mmol, 4.5 equiv). After 15 min of stirring at room temperature, benzyl alcohol (22.2 μL, 0.32 mmol, 3.0 equiv) was further added and the solution was stirred overnight. Finally the solvent was removed in vacuo. The reaction completion of 5 was analyzed by RP-HPLC (15 min, 10-90% B):t R= 17.1 min; K' = 7.55. Calculated monoisotopic mass for 5 (C 34 H 39 NO6): 557.28; Measured value: m / z = 580.7 [M+Na] + .

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

[0274] OBzl-(S)-Fmoc-Asu[(OtBu)KuE(OtBu)2] (7): A solution of 6 (51.8 mg, 10.3 μmol, 1.0 equiv.) in DMF was added to HOBt (20.9 mg, 0.15 mmol, 1.5 equiv.), TBTU (36.3 mg, 15.5 μmol, 1.5 equiv.) and DIPEA (79.4 μL, 59.7 mg, 0.46 mmol, 4.5 equiv.). After stirring for 15 min, 1 (75.6 mg, 15.5 μmol, 1.5 equiv.) was added and further stirred for 20 h at room temperature. The crude product 7 was purified using preparative RP-HPLC (15 min, 70–80% B):t R = 8.9 min; K' = 1.97. The calculated monoisotopic mass 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 equiv.) was dissolved in EtOH (2.0 mL) and palladium on activated charcoal (10%) (5.72 mg, 9.0 μmol, 0.1 equiv.) was added. The flask was pre-purged with a stream of hydrogen and the solution was stirred under light hydrogen pressure (balloon). After stirring for 70 min, the crude product was filtered through Celite, EtOH was evaporated in vacuo, and the product was purified using preparative RP-HPLC (15 min, 70-70.5% B):t R = 6.5 min; K' = 0.54. Calculated monoisotopic mass 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 equiv) in dry DMF was added to DIC (4.77 μL, 1.94 mg, 30.8 μmol, 2.0 equiv) and PfpOH (5.67 mg, 30.8 μmol, 2.0 equiv). After stirring for 5 min, pyridine (2.49 μL, 31.0 μmol, 2.0 equiv) was added and the solution was allowed to stir overnight at room temperature. The reaction completion of 9 was analyzed by RP-HPLC (15 min, 10-90% B):t R = 17.2 min; K' = 7.6. The calculated monoisotopic mass 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) (10.0 mg, 47.1 μmol, 1.0 equiv.) in dry THF was added to N,N'-dicyclohexylcarbodiimide (DCC) (9.7 mg, 47.1 μmol, 1.0 equiv.) and N-hydroxysuccinimide (NHS) (10.8 mg, 94.3 μmol, 2.0 equiv.) and the reaction mixture was allowed to stir overnight. The crude product was purified using RP-HPLC. RP-HPLC (15 min, 10-90% B):t R = 10.21 min; K' = 4.1. Calculated monoisotopic mass (C 11 H7N3O8) = 309.02; Found: 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 accomplished via solid-phase methods as previously described [2, 3]. Briefly, the initial starting point was the loading of 2-CTC resin with Fmoc-D-Lys(Boc)-OH of SP-1. After conjugation of lysine, Fmoc was deprotected by SP-3 and Fmoc-D-phenylalanine was coupled by applying SP-2. The same procedure was used to couple Fmoc-D-Tyr(3-I)-OH. After completion of the reaction, the Fmoc protecting group was cleaved by SP-3 and the resin-bound peptide was condensed with a chelating agent using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.) in DMF. The reaction was allowed to stir at room temperature for 48 hours. Finally, the crude product was cleaved from the resin by SP-7.2, precipitated in Et2O and centrifuged. The supernatant was removed and 30 was purified using RP-HPLC. RP-HPLC (15 min, 10–90% B): R = 6.2 min; K' = 2.1. Calculated monoisotopic mass (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 30 (5.0 mg, 4.8 μmol, 1.0 equiv), 9 (7.5 mg, 7.2 μmol, 1.5 equiv) and DIPEA (3.3 μL, 21.6 μmol, 4.0 equiv) in DMF was added. The reaction solution was allowed to stir at room temperature overnight. After completion of the reaction, the solvent was removed in vacuo and the crude product was treated with a mixture of piperidine (20 / 80; v / v) in DMF for 15 min to achieve Fmoc deprotection. The solvent was reduced to approximately 300 μL via evaporation in vacuo, precipitated in Et2O and centrifuged. The resulting pellet was treated with SP-6 for tBu removal. The final product was purified via RP-HPLC (15 min, 10-90% B):t R = 6.09 min; K' = 2.05. Calculated monoisotopic mass (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 equiv.) in DMF and adding 27 (4.1 mg, 13.2 μmol, 4.0 equiv.) and DIPEA (2.3 μL, 13.2 μmol, 4.0 equiv.). The solution was stirred for 10 h at room temperature and the final product was purified by RP-HPLC (15 min, 10-50% B):t R = 12.12 min; K' = 5.06. Calculated monoisotopic mass (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 min, 10-60%) B):t R = 9.81 min; K' = 3.91. Calculated monoisotopic mass (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 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 Fmoc deprotection by SP-3, 2 (1.5 equiv.) 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 equiv.) and DIPEA (1.5 equiv.) dissolved in DMF. The reaction solution was allowed to stir overnight at room temperature. Then, Fmoc-D-Lys-OtBu·HCl (1.5 equiv.) was coupled by SP-2 and Fmoc deprotected as described in SP-3. Subsequent conjugation with Fmoc-protected amino acids Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-Phe(4-NO2)-OH was performed as described in SP-2. The N-terminal Fmoc-deprotected amino acid was conjugated with a chelator in the final step using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.). The reaction was allowed to stir at room temperature for 48 h. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by 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, 10-60% B):t R = 9.71 min; K' = 3.86. Calculated monoisotopic mass (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. Calculated monoisotopic mass (C 76 H 97 N 14 O29 Calculated: m / z = 1,844.6; Measured: m / z = 1,846.0 [M+H] + 。

[0296] 2,4-DNBA-Dap(DOTAGA)-γ-2-nal-k(Suc-N 5 -orn-C 4 -EuE)(PSMA-53):

[0297]

Chem.

[0298] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection by SP-3, 2 (1.5 equiv.) 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 equiv.) and DIPEA (1.5 equiv.) dissolved in DMF. The reaction mixture was allowed to stir overnight at room temperature. Then, Fmoc-D-Lys-OtBu·HCl (1.5 equiv.) was coupled by SP-2 and Fmoc deprotected as described in SP-3. Subsequent conjugation with 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. The free amino group was then conjugated to 2,4-dinitrobenzoic acid (2,4-DNBA) using 2,4-DNBA (2.0 eq.), HOBt (2.0 eq.), TBTU (2.0 eq.) and DIPEA (4.0 eq.) in DMF. After completion of the reaction, Dde deprotection was achieved using SP-5. The N-terminal free amino acid L-Dap was conjugated with a chelator in the final step using DOTAGA anhydride (2.0 eq.) and DIPEA (2.0 eq.). The reaction was allowed to stir at room temperature for 48 hours. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by 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, 10-60% B): R = 11.71 min; K' = 4.86. Calculated monoisotopic mass (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. Calculated monoisotopic mass (C 77 H 97 N 16 O 32 Lu) = 1,932.59; Measured value: m / z = 1,933.7 [M+H] + .

[0300] [ka]

[0301] Schematic of the general synthetic procedure for EuE-based PSMA inhibitors PSMA-52 and PSMA-53, 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 equiv.) 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-D-Asp-OAll·HCl (1.5 equiv.) 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 equiv.), HOBt (2.0 equiv.), TBTU (2.0 equiv.) and DIPEA (4.0 equiv.) in DMF. After the reaction was completed, allyl deprotection was performed with SP The conjugation was achieved by SP-5. The next step included repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 equiv.), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-Phe(4-NHBoc)-OH by SP-2. The N-terminal Fmoc-deprotected amino acid L-Phe(4-NHBoc)-OH was conjugated with a chelator in the final step using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.). The reaction was allowed to stir for 48 h at room temperature. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by SP-7.2 and 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 min, 10–90% B): R = 6.40 min; K' = 2.2. Calculated monoisotopic mass (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 minutes; K’ = 3.11. Monoisotopic mass calculated for (C 83 H 102 N 17 O 32 Lu) = 2,023.63; Found: 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]

Chem.

[0307] The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection by SP-3, 2 (1.5 equiv.) 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 Fmoc-D-Asp-OAll·HCl (1.5 equiv.) by SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was Fmoc deprotected by SP-3 and protected with Dde-OH (2.0 equiv.) and DIPEA (4.0 equiv.) in DMF at room temperature. The reaction was allowed to stir overnight. Then, allyl deprotection of D-Asp was achieved by applying SP-5. The next step included repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 eq.), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-Phe(4-NHBoc)-OH by SP-2. To conjugate TMA to D-Asp, selective Dde deprotection was achieved by applying SP-4 to obtain free amino groups. TMA was coupled using TMA (2.0 eq.), HOBt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (10 eq.) in DMF. The reaction was allowed to stir for 8 h at room temperature. After the 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 a chelator in the final step using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.). The reaction was allowed to stir at room temperature for 48 h. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by 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):t R = 7.48 min; K' = 2.74. Calculated monoisotopic mass (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. Calculated monoisotopic mass (C 85 H 104 N 15 O 32 Lu) = 2,021.64; Found: 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 eq.) 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 eq.), HOAt (1.5 eq.), HATU (1.5 eq.) and DIPEA (4.0 eq.) in DMF. The reaction was allowed to stir at room temperature overnight. In the next step, the Abz residue was Fmoc deprotected with SP-3. The next step included repeated conjugation with Fmoc-D-Glu-OtBu, Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-Dap(Dde)-OH by SP-2. After Fmoc deprotection of Fmoc-L-Dap(Dde)-OH by SP-3, 2,4-DNBA was coupled using 2,4-DNBA (1.5 eq.), HOBt (2.0 eq.), TBTU (2.0 eq.) and DIPEA (4.0 eq.) in DMF. After completion of the reaction, the L-Dap(Dde)-residue was Dde-deprotected by SP-4 and conjugated with the chelator using DOTAGA anhydride (2.0 eq.) and DIPEA (2.0 eq.). The reaction was allowed to stir at room temperature for 48 hours. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by SP-7.2 and the crude product was purified by E The final product was purified via RP-HPLC. RP-HPLC (15 min, 10-60% B): R = 10.2 min; K' = 4.1. Calculated monoisotopic mass (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. Calculated monoisotopic mass (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 carried out as described in SP-1. After Fmoc deprotection by SP-3, 2 (1.5 equiv.) 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 Fmoc-D-Asp-OAll·HCl (1.5 equiv.) by SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was Fmoc deprotected by SP-3 and protected with 2.0 equiv. Dde-OH and 4.0 equiv. DIPEA in DMF. The reaction was allowed to stir overnight. Then, allyl deprotection of D-Asp was achieved by applying SP-5. The next step included repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 eq.), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-Dap(Dde)-OH by SP-2. To conjugate TMA to D-Asp and L-Dap, selective Dde deprotection was achieved by applying SP-4 to obtain free amino groups. TMA was coupled using TMA (4.0 eq.), HOBt (3.0 eq.), TBTU (3.0 eq.) and DIPEA (20 eq.) in DMF. The reaction was allowed to stir for 8 h at room temperature. After 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 a chelator in the final step using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.). The reaction was allowed to stir at room temperature for 48 h. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by 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):t R = 7.48 min; K' = 2.74. Calculated monoisotopic mass (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 minutes, 10 - 70% B): t R = 7.46 minutes; K’ = 2.73. Monoisotopic mass calculated for (C 88 H 108 N 15 O 37 Lu) = 2,137.62; found: 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]

Chemical Structure

[0318] ​The initial resin loading of Fmoc-D-Orn(NHDde)-OH was performed as described in SP-1. After Fmoc deprotection by SP-3, 2 (1.5 equiv.) 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 Fmoc-D-Asp-OAll·HCl (1.5 equiv.) by SP-2. The amino group of Fmoc-D-Asp-OAll·HCl was Fmoc deprotected by SP-3 and protected with Dde-OH (2.0 equiv.) and DIPEA (4.0 equiv.) in DMF at room temperature. The reaction was allowed to stir overnight. Then, allyl deprotection of D-Asp was achieved by applying SP-5. The next step included repeated conjugation with Fmoc-D-Lys-OtBu·HCl (1.5 eq.), Fmoc-D-2-Nal-OH, Fmoc-D-Tyr(OtBu)-OH and Fmoc-L-2-Nal-OH by SP-2. To conjugate TMA to D-Asp, selective Dde deprotection was achieved by applying SP-4 to obtain free amino groups. TMA was coupled using TMA (2.0 eq.), HOBt (1.5 eq.), TBTU (1.5 eq.) and DIPEA (10 eq.) in DMF. The reaction was allowed to stir for 8 h at room temperature. After 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 a chelator in the final step using DOTAGA anhydride (2.0 equiv.) and DIPEA (2.0 equiv.). The reaction was allowed to stir at room temperature for 48 h. After completion of the reaction with DOTAGA anhydride, the peptide was cleaved from the resin by 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, 10-80% B):t R = 7.57 min; K' = 2.79. Calculated monoisotopic mass (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. Calculated monoisotopic mass (C 89 H 105 N 14 O 32 Lu) = 2,056.64; Measured value: m / z = 1, 029.7[M+2H] 2+ . 7. Radiolabeling 68 Ga label: 68 Ge / 68 The Ga-generating material was eluted in aq. HCl (1.0 M) from which 1.25 mL fractions containing approximately 80% activity (600-800 MBq) were transferred into reaction vials (ALLTECH, 5 mL). The vials were preloaded with the respective compounds (5.0 nmol) and aq. 2-(4-(2-hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid (HEPES) solution (950 μL, 2.7 M). The reaction vials were heated at 95 °C for 5 min, followed by immobilization of the radiolabeled compounds on preconditioned SPE cartridges (C8 light, SepPak). After prior purging of the cartridges with water (10 mL), elution of the radiolabeled PSMA inhibitors from the cartridges was achieved with a mixture of EtOH and water (1 / 1; v / v), phosphate buffered saline (PBS) (1.0 mL) and again water (1.0 mL). After completion of the radiolabeling, EtOH was evaporated in vacuum and the tracer was used without any further purification. Radiochemical purity was controlled 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 as previously described [5] with minor modifications and used without further purification. Briefly, NHOAc buffer (10 μL, 1.0 M, pH = 5.9) was mixed with the respective tracer (0.75–1.0 nmol, 7.5–10 μL), 177 LuCl3 (10-40MBq; A S >3000 GBq / mg, 740 MBq / mL, 0.04 M HCl, ITG, Garching, Germany) was added and finally filled with a trace of pure water (up to 100 μL) (Merck, Darmstadt, Germany). The reaction mixture was heated at 95° C. for 40 min and the radiochemical purity was determined using radio-TLC.

[0321] 125 I-labeling: Briefly, the stannylated precursor (SnBu3-BA)(OtBu)KuE(OtBu)2(PSMA-45) (approximately 0.1 mg) was dissolved in 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) was dissolved in a solution containing MeCN (20 μL) and AcOH (10 μL). The reaction solution was incubated at room temperature for 10 min, loaded onto a cartridge (C18 Sep Pak Plus, preconditioned with 10 mL MeOH and 10 mL water) and rinsed with water (10 mL). After elution with a 1 / 1 mix (v / v) of EtOH and MeCN (2.0 mL), the solution was evaporated to dryness under a gentle stream of nitrogen and treated with TFA (200 μL) for 30 min, followed by evaporation of the TFA. ([ 125 The crude product of [I]I-BA)KuE was purified by radio RP-HPLC (20 min, 20-40% B):t R =13.0 min; K'=6.2. 8. Determination of HSA Binding HSA binding experiments were performed as described previously [6]. The mobile phase consisted of a binary gradient with a constant total flow rate of 0.5 mL / min. Mobile phase A was a 50 mm pH 6.9 NHOAc solution and mobile phase B was 2-propanol (RP-HPLC grade, VWR, Germany). The gradient of mobile phase A was 100% from 0 to 3 min, and from 3 min to the end of each experiment, mobile phase B was set to 20%. On each experimental day, the column was calibrated with nine reference substances to check the performance and establish the nonlinear regression. PSMA inhibitors were dissolved at a concentration of 0.5 mg / mL in a mixture of 2-propanol and NHOAc 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 for HSA binding [%] was obtained from Valko et al. or Yamazaki et al. [6, 7]. Nonlinear regression was established using OriginPro 2016G.

[0322] 9. Lipophilicity Determination Lipophilic: Radiolabeled PSMA inhibitors (0.5–1.0 MBq) dissolved in PBS (500 μL, pH = 7.4) were added to n-octanol (500 μL) in reaction vials (1.5 mL) and vortexed rigorously for 3 min (n = 6). For separation of the quantitative phases, the mixture was centrifuged at 6,000 g for 5 min (Biofuge 15, Heraus Sepatech, Osterode, Germany). Activity from samples (100 μL) of each phase was measured in a γ-counter and expressed as logP (o / w) Got the value.

[0323] 10. Cell Experiments Cell culture: PSMA-positive LNCAP cells (300265; Cell Lines Service GmbH) were cultured in Dulbecco's modified Eagle's medium / nutrient mixture F-12 (1 / 1) (DMEM-F12, Biochrom) supplemented with fetal calf serum (FCS) (10%, Biochrom) and maintained at 37°C in a humidified CO2 atmosphere (5%). One day (24h ± 2h) before all experiments with LNCaP cells, cultured cells were harvested 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. The cells were then counted using a hemocytometer (Neubauer) and seeded in 24-well plates. IC 50 Values ​​were determined by transferring 150,000 cells / mL per well into 24-well plates, while internalization rates were obtained by transferring 125,000 cells / mL per well into 24-well PLL-coated plates.

[0324] 11. Affinity (IC 50 ) After removal of the culture medium, cells were treated once with HBSS (500 μL, Hanks' Balanced Salt Solution, Biochrom, Berlin, Germany, supplemented with 1% BSA) and left on ice for 15 min to equilibrate in HBSS (200 μL, 1% BSA). Then, cells were incubated with either HBSS (1% BSA, control) or increasing concentrations of the respective ligand (10 -10 ~10 -4 A solution (25 μL per well) containing either ([ 125[I]I-BA)KuE (25 μL, 2.0 nM) was added. All experiments were performed at least three times for each concentration. After 60 min incubation on ice, the experiment was terminated by removing the medium, followed by rinsing with HBSS (200 μL). The medium from both steps was combined into one fraction to represent the amount of free radioligand. Cells were then dissolved in NaOH (250 μL, 1.0 m) and combined with HBSS (200 μL) from the subsequent washing step. Quantification of bound and free radioligand was completed in a gamma counter.

[0325] 12. Internalization Following removal of the culture medium, the cells were washed once with DMEM-F12 solution (500 μL, 5% BSA) and left to equilibrate 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 blocking. 68 Ga or 177 Lu-labeled PSMA inhibitors (25 μL; 2.0 nm and 10 nm, respectively) were added and the cells were incubated at 37° C. for 5, 15, 30 and 60 min, respectively. The experiment was terminated by placing the 24-well plate on ice for 3 min, 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-bound activity was accomplished by incubation of the cells with ice-cold 2-PMPA solution (250 μL, 10 μm in PBS) for 5 min, followed by rinsing with ice-cold PBS (250 μL). Internalization activity was determined through incubation of the cells in NaOH (250 μL, 1.0 m) and combination of the fractions in a subsequent washing step, again with NaOH (250 μL, 1.0 m). For each experiment (pairs) Illumination and blocking (illumination and blocking) were performed in triplicate for each time point. Free, surface-bound and internalized activity were quantified in a gamma counter.

[0326] 13. External Migration The externalization kinetics of radiolabeled PSMA inhibitors were determined using LNCaP cells prepared similarly to those described for the internalization assay. After an initial step of washing the cells with DMEM-F12 solution (5% BSA), the cells were left to recondition at 37°C for at least 15 min. LNCaP cells were then incubated with the respective radiolabeled peptide (25 μL, 10.0 nm) in a total volume of 250 μL in each well for 60 min at 37°C. After 60 min, the supernatant with the unbound free fraction was removed and measured in a gamma counter for calculation of the total radioactivity added. An acid wash step was avoided to ensure the integrity of the enzyme during the subsequent externalization and recycling tests. To determine the recycling rate, the cells were given fresh DMEM-F12 solution (250 μL, 5% BSA) 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 of 100 μM 2-PMPA solution (PBS)). The cells were then incubated at 37° C. for 0, 20, 40 and 60 min. The supernatant was subsequently removed and the cells were washed with ice-cold HBSS (250 μL). The combined volume of the supernatant and the associated washing step with HBSS (200 μL) represents the externalized radioligand at the investigated time point. Furthermore, the cells were then 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 internalized fraction was achieved by lysis as described for the internalization assay with NaOH (250 μL, 1.0 m). Free, externalized, membrane-bound and internalized radioligand activity was quantified in a gamma counter.

[0327] 14. Animal testing All animal experiments were performed in accordance with the prevailing animal welfare laws in Germany (Deutsches Tierschutzgesetz, approval number 55.2-1-54-2532-71-13). For the tumor model, 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- to 8-week-old CB-17 SCID mice (Charles River Laboratories, Sulzfeld, Germany). Animals were used for experiments after tumor size reached 4-8 mm in diameter. 15.PET Imaging experiments were performed using a Siemens Inveon small animal PET and data were analyzed with associated Inveon Research Workplace software. Mice were anesthetized with isoflurane and injected with approximately 4.0-17 MBq of 68 Ga-labeled compounds were injected via the tail vein (approximately 150-300 μL). Dynamic imaging was performed 90 min after injection on the bed. Static block images were obtained 1 h pi with an acquisition time of 15 min. PSMA block was achieved by co-injection of 8 mg / kg 2-PMPA-solution (PBS). All images were reconstructed without scanner and attenuation correction using the OSEM3D algorithm.

[0328] 16. Biodistribution 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 LNCaP tumor-bearing male CB-17 SCID mice, and the mice were sacrificed after a specific time frame (n=4 each). Selected organs were removed, weighed, and measured in 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. Effect of introduction of 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 internalization. 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 showed higher It showed internalization and exhibited improved affinity. Thus, based on the structure of PSMA-46, electron-deficient aromatic residues were introduced in a further 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 the affinity remained similar, introduction of 4-nitrophenylalanine slightly increased internalization, but introduction of an additional nitro group through 2,4-DNBA was able to significantly increase internalization.

[0340] For increased internalization, two electron-withdrawing groups are preferred. 4. Introduction of 4-amino-phenylalanine

[0341] [ka]

[0342] [Table 6]

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

[0344] [ka]

[0345] [Table 7]

[0346] The electron-deficient aromatic modification 2,4-DNBA allowed for increased internalization. 6. Trimesic acid was incorporated into the linker and peptide spacer of PSMA inhibitors.

[0347] [ka]

[0348] [Table 8]

[0349] Replacement of 4-amino-phenylalanine with Dap(TMA) resulted in similar affinity but slightly reduced internalization capacity. As both ligands appeared to be very promising, both tracers were evaluated in further experiments.

[0350] The conclusion of these experiments is that electron-deficient aromatic residues can be transferred and increase internalization while maintaining high affinity. 7. In vitro effects of internalization on cell retention, [ 177 Lu]PSMA I&T and [ 177 Compared with [Lu]PSMA-617, compound [ 177 Lu]PSMA-62 and [ 177Lu]PSMA-66 was evaluated.

[0351] [ 177 Lu]PSMA-66 showed the highest intracellular activity in tumor cells at 1 hour, followed by [ 177 Lu]PSMA-62 followed, but [ 177 Internalization of [Lu]PSMA-62 177 Lu]PSMA-66 (343.9% vs. 297.8%, respectively). Interestingly, even when re-internalization was blocked with a 100 μM 2-PMPA solution, the [ 177 The intracellular clearance of [Lu]PSMA-66 was lower than that of all other compounds investigated. When re-internalization was blocked, ref. [ 177 The difference compared with [Lu]PSMA I&T was more than two-fold.

[0352] [ 177 [Lu]PSMA-66 has nine free carboxyl groups, which equates to nine negative charges in vivo (pH = 7.4). The extensively charged nature of this compound may be a possible explanation for its extended intracellular retention due to electrostatic repulsion from negatively charged cell membranes.

[0353] 8. In vivo experiments: Biodistribution

[0354] [Table 9]

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

[0356] [ 177 [Lu]Incorporation of trimesic acid into the linker of PSMA-62 resulted in decreased kidney uptake compared to the reference (106.45±17.18% vs. 162.96±23.20%, respectively) and slightly reduced tumor uptake. 177 The internalization of PSMA-62 is 177 The reduction in tumor uptake was unexpected because the affinity of [Lu]PSMA-49 was higher in a direct comparison. It is unclear to what extent internalization contributes to tumor uptake and whether it is less important than affinity. 177 Lu]PSMA-49 is more affine to PSMA (2.5 ± 0.6 nM vs. 4.0 ± 0.2 nM, respectively), 177 Lu]PSMA-49 and [ 177 Direct comparison with [Lu]PSMA-62 indicates that the affinity is more definitive.

[0357] [Table 10]

[0358] The results in Table 10 show that the tracers evaluated [ 177 Lu]PSMA-62,[ 177 Lu]PSMA-66 and [ 177 With regard to renal clearance, it was evident that for all ligands, a reduction in renal uptake was observed compared to 1 hour pi (Table 9). 177 Lu]PSMA I&T showed the highest renal uptake at 24 hours pi, whereas [ 177 [Lu]PSMA-62 showed the lowest renal uptake, consistent with the renal clearance observed in the PET study. 177 Tumor uptake of Lu]PSMA-61 remained fairly stable over 23 h (8.00 ± 0.75 vs. 7.70 ± 1.35%ID / g, 1 h pi and 24 h pi, respectively). 177Lu]PSMA-62 and [ 177 Lu]PSMA-66 showed similar in vitro parameters for internalization and affinity, whereas [ 177 Tumor uptake of PSMA-66 was 177 Lu]PSMA-62 was significantly reduced from 1 to 24 hours pi (10.00 ± 0.44 vs. 5.73 ± 1.39%ID / g, respectively). The stronger tumor retention, together with more favorable tumor-to-liver and tumor-to-muscle ratios, was 177 Lu] compared to PSMA-66 177 Lu]PSMA-62 was superior to PSMA-71. The highest tumor uptake was observed for PSMA-71, which also exhibited the highest HSA binding values. Kidney uptake at 24 hours pi was [ 177 Lu]PSMA I&T, whereas tumor uptake was [ 177 Lu]PSMA-71 was more than three-fold 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 may be considered a particularly valuable tracer for internal radiotherapy applications and a candidate for clinical applications. 9. In Vivo PET Imaging Effect of 2,4-dinitrobenzoic acid linker substitution on EuK-based inhibitors The EuK-based inhibitor PSMA-36 was evaluated in small animal PET scans to examine the effect of 2,4-dinitrobenzoic acid in the linker on in vivo distribution.

[0360] The logarithmic TAC plot is 68Specific kidney and tumor uptake of [Ga]PSMA-36 is shown. The linear decline in blood pool activity and in the muscle region suggests nonspecific binding and rapid excretion. Accumulation in the tumor remained stable over the observation period. 177 Lu]PSMA-36 is 177 Lu]PSMA I&T showed >3-fold higher internalization rate, but tumor uptake was only moderate at 3.5% ID / mL at 85 min 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. 68 Since the only structural difference from [Ga]PSMA I&T is the introduction of 2,4-dinitrobenzoic acid, the linker modification must be the reason for this enhanced uptake, but further studies are needed to confirm this effect.

[0361] Interestingly, clearance in these regions was slower compared to the blood pool and muscle, implying the involvement of distinct retention mechanisms. PSMA has been reported to be involved in angiogenesis during ocular neovascularization in mice, and thus [ 68 This may explain the uptake of [Ga]PSMA-36 [1]. Tracer accumulation in the salivary glands may be due to 177 This is a common problem during clinical treatment approaches using Lu-labeled PSMA inhibitors [2]. Drug uptake into the salivary glands depends on intracellular or extracellular routes and, most commonly, on simple diffusion in the phospholipid bilayer of the acinar cells. Salivary drug concentrations, in terms of passive diffusion, are mainly reflected by the free, non-ionized fraction in plasma [3-5]. In this respect, passive diffusion is highly unlikely to be responsible for salivary gland uptake. As EuK-based PSMA inhibitors are highly charged in vivo and thus highly polar, other mechanisms must be involved. Moreover, passive diffusion would be visible during PET scans as high background activity in all regions, whereas visualization does not occur for the majority of PSMA ligands, as rapid clearance removes the tracer from the blood pool.

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

[0363] Both tracers exhibited excellent tracer kinetics with respect to kidney, muscle and blood pool uptake. Specific uptake in the kidney was [ 68 Ga]PSMA-62 compared to [ 68 Ga]PSMA-66 was slightly higher (45.3% ID / mL vs. 3 4.8% ID / mL). 68 Ga]PSMA-62, 68 The higher kidney accumulation in PET scans of [Ga]PSMA-66 correlated well with the biodistribution experiments. 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. A compound of formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula, m is an integer from 2 to 6; n is an integer from 2 to 6; R １Ｌ is CH ２ , NH or O; R ２Ｌ is C or P(OH); R ３Ｌ is CH ２ , NH or O; X １ 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; L １ 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); The linking group can have an EDS group; 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; R ２ is an optionally substituted aryl group or an optionally substituted aralkyl group, the aryl group or the aralkyl group being optionally 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 the aralkyl group being optionally substituted on its aromatic ring with one or more substituents selected from halogen and -OH; r is 0 or 1; p is 0 or 1; q is 0 or 1; R ４ is selected from optionally substituted aryl groups and EDS groups, the aryl group containing halogen, —OH and —NH on its aromatic ring. ２ may be substituted with one or more substituents selected from X ３ is an amide bond, an ether bond, a thioether bond, an ester bond, a thioester bond, a urea bridge, an amine bond, and a 【Chemistry 2】 wherein the bond marked with a carbonyl group is selected from the group ３ R Ｍ The other marked bonds are attached to X ３ to the remainder of the compound of formula (I); R Ｍ is a labeling group comprising a chelating group optionally containing a chelated non-radioactive or radioactive cation; and wherein the EDS group is contained at least once in the compound of formula (I), (E-1A), (E-1B), (E-2A) and (E-2B): 【Chemistry 3】 having a structure selected from During the ceremony, 【Chemistry 4】 marks the bond attaching 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 is independently, for each occurrence, where s>1, preferably -NO ２ and -COOH, more preferably -COOH; R ５Ａ The bond between and the phenyl ring is ５Ａ represents a group replacing s hydrogen atoms at any position on the phenyl ring; R ５Ｂ is independently, for each occurrence where s>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably -OH and -NH ２ More preferably, it is selected from the group consisting of —NH ２ and R ５Ｂ The bond between and the phenyl ring is ５Ｂ represents a group replacing s hydrogen atoms at any position on the phenyl ring; R ６Ａ is independently, for each occurrence for t>1, preferably -NO ２ and -COOH, more preferably -COOH; R ６Ａ The bond between and the phenyl ring is ６Ａ represents a group replacing t hydrogen atoms at any position on the phenyl ring; and R ６Ｂ is independently, for each occurrence for t>1, a substituent having a lone pair at the atom directly attached to the phenyl ring shown in formula (E-1B), the substituent being preferably -OH and -NH ２ is selected from, more preferably -OH, and R ６Ｂ The bond between and the phenyl ring is ６Ｂ represents that the group replaces t hydrogen atoms at any position on the phenyl ring.

2. m is 2, n is 2 or 4, R １Ｌ is NH, R ２Ｌ is C, and R ３Ｌ The compound or salt of claim 1 , wherein is NH.

3. L １ is a divalent linking group having 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, and the linking group may have an EDS group.

4. The moiety -X in formula (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) (L-2)、および *-C(O)-NH-R ９Ｂ -C(O)-NH-R １０Ｂ -C(O)-NH-R １１Ｂ -NH-C(O)- (L-2B) The compound or salt of any one of claims 1 to 3, having a structure selected from (wherein the amide bond marked with * represents R ２ is attached to a carbon atom having R ７ , R ８ , R ９Ａ , R ９Ｂ , R １１Ａ and R １１Ｂ are independently selected from optionally substituted C2-C10 alkanediyl, each alkanediyl group being independently selected from -OH, -OCH ３ , -COOH, -COOCH ３ , -NH ２ , -NHC(NH)NH ２ and EDS groups, and R １０Ａ and R １０Ｂ is selected from optionally substituted C2-C10 alkanediyl, and optionally substituted C6-C10 arenediyl, the alkanediyl and arenediyl groups each independently being —OH, —OCH ３ , -COOH, -COOCH ３ , -NH ２ , -NHC(NH)NH ２ and EDS groups).

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) The compound or salt of claim 4 having a structure selected from (wherein the bond marked with * represents R in formula (I) ２ is attached to a carbon atom having R １２ and R １４ is independently selected from linear C2-C6 alkanediyl; R １３ is a straight chain C2-C10 alkanediyl, R １５ and R １６ is independently selected from linear C2-C6 alkanediyl; R １３ and R １５ each having one EDS group as a substituent; R １７ is a straight chain C2-C6 alkanediyl, R １８ is a phenylene group, and R １９ is a straight-chain C2-C6 alkanediyl.

6. R ２ is an optionally substituted —CH ２ -phenyl and optionally substituted -CH ２ -naphthyl, wherein the phenyl and naphthyl groups are optionally substituted with substituents selected from halogen, preferably I and -OH.

7. R ３ is an optionally substituted —CH ２ -phenyl and optionally substituted -CH ２ -naphthyl, wherein the phenyl and naphthyl groups are optionally substituted with substituents selected from halogen and -OH.

8. r is 1, R ４ is selected from optionally substituted phenyl, optionally substituted naphthyl and EDS groups, the phenyl and naphthyl groups being selected from halogen, -OH and -NH ２ 8. The compound or salt of claim 1, optionally substituted with a substituent selected from:

9. X ３ is an amide bond or a compound of the formula 【Chemistry 5】 9. The compound or salt according to claim 1, which is a group (wherein the bond marked with a carbonyl group is X ３ R Ｍ The other marked bonds are attached to X ３ to the rest of the molecule).

10. R Ｍ 10. The compound or salt according to any one of claims 1 to 9, wherein is a chelating group optionally containing a chelated non-radioactive or radioactive cation.

11. The compound of formula (I) comprises a linking group L １ or one EDS group having R ４ One is represented by L １ 11. The compound or salt according to claim 1, wherein

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

13. The following formula: 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 13. The compound or salt according to any one of claims 1 to 12, having one of the following formulas:

14. 14. A pharmaceutical or diagnostic composition comprising or consisting of one or more compounds or salts according to any one of claims 1 to 13.

15. (a) cancer, including prostate cancer; or (b) Angiogenesis / angiogenesis 14. A compound according to any one of claims 1 to 13 or a salt thereof for use in a method for the diagnosis and / or treatment of

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