New daza chelators as ligands in liver imaging

Abstract

This invention relates to compounds according to general formula I or pharmaceutically acceptable inorganic or organic acid salts, hydrates, stereoisomers or solvates thereof, wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 The compounds are independently selected from hydrogen and alkoxy groups. Compounds of formula (I) are suitable as ligands for the preparation of radiolabeled compounds. 68 Ga、 64 Cu、 67 Ga、 111 In or 99m Tc complexes. The invention further relates to methods for preparing compounds of formula (I) and radiolabeled compounds, and the use of said radiolabeled compounds in imaging methods such as PET / CT, particularly liver imaging methods.

Description

Technical Field

[0001] This invention relates to novel ligands for PET / CT liver imaging and methods for preparing these compounds. The invention also relates to the use of these ligands in liver imaging methods. Background Technology

[0002] Liver imaging is currently primarily performed using contrast-enhanced CT and MRI (the latter often employing liver-specific contrast agents) and scintillation imaging (SPECT). Various liver-specific MRI contrast agents are known in the existing technology. However, some known contrast agents that have undergone clinical trials (e.g., ) or approved contrast agents (e.g., There are drawbacks, including undesirable toxic effects. Furthermore, PET / CT using Ga tracers has limitations. 68 There are various methods for liver imaging, but all have associated drawbacks. Table 1 shows an overview of the contrast agents currently used in various imaging methods.

[0003] Table 1: Conventional contrast agents and radioactive tracers used in various imaging methods

[0004]

[0005]

[0006] The aforementioned disadvantages mean It is currently the only commercially available and used liver-specific contrast agent. However, the cost of a single patient dose is high. Delayed imaging and the resulting need for prolonged use of an MRI scanner incur additional costs. Furthermore, compared to... The relevant contraindications mean that CT or MRI scans that are practically applicable are usually not possible or may only be performed after preoperative medication. Furthermore, extensive MRI scans are not feasible in patients with implanted pacemakers or those with claustrophobia.

[0007] WO2014198478 A2 discloses a bifunctional chelating agent based on the 1,4-diazacycloheptan-6-amine (DAZA) framework for non-invasive molecular imaging. The 2-hydroxybenzyl-substituted DAZA unit serves as... 68 The coordination unit of Ga. However, the property of specific biodistribution can only be achieved very laboriously through a specific substituent of DAZA that connects the coupling unit and the targeting unit.

[0008] So-called DATA chelating agents are also known from the literature, and non-limiting examples include ligands AAZTA and AAZ3A. 24.25 Characterized by a nitrogen atom and an acetic acid group or a long-chain carboxylic acid (e.g., glutaric acid). 26Functionalization occurs in methyl groups, phosphonates, or coordinating ring systems. 24,25,27-41 Here, 1,4-diazacycloheptan-6-amine is typically obtained through functional groups (e.g., methyl, phenyl). 42 Or a dual-function connector 30,31,33 The ligands extend at the C1 carbon atom of the DAZA ring. Furthermore, a wide range of ligands containing aminophenol salts are known, which can be coupled with open-chain structures (e.g., HBED) via an ortho-hydroxybenzyl unit (e.g., in the form of phenolic or catechol salts). 43 and TREN derivatives 44-48 ) and large rings (such as rings) 49-54 and TACN 55-59 The connections are categorized. These have in most cases been classified as... 68 The ligands of Ga were studied. 43.55.60 Summary of the Invention

[0009] The purpose of this invention is to provide a ligand for PET / CT liver imaging that has improved properties compared to ligands known in the prior art and can be prepared particularly easily with less work involved.

[0010] This objective is achieved by providing compounds corresponding to general formula I, or pharmaceutically acceptable inorganic or organic acid salts, hydrates, stereoisomers, or solvates (including their radiolabeled complexes):

[0011]

[0012] Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 It is independently selected from hydrogen and alkoxy groups.

[0013] In the specification and claims, unless otherwise specified, the term "alkoxy" refers to C 1-12 Alkoxy group, preferably C 1-8 Alkoxy groups, such as C 1-6 alkoxy group or C 1-4Alkoxy group. Alkoxy group can be branched or straight-chain. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy), butoxy (e.g., n-butoxy), pentoxy (e.g., n-pentoxy), hexoxy (e.g., n-hexoxy), heptoxy (e.g., n-heptoxy), and octoxy (e.g., n-octoxy).

[0014] In the context of this invention, "replaced by hydrogen" means "replaced by H".

[0015] Compounds of Formula I are particularly suitable ligands for forming radiolabeled complexes. In a preferred embodiment, the present invention provides a radiolabeled complex consisting of a compound of Formula I and a radioactive isotope selected from the group consisting of: 68 Ga、 64 Cu、 67 Ga、 111 In and 99m Tc. In a preferred embodiment, the radiolabeled complex is a complex corresponding to general formula II:

[0016]

[0017] Or its pharmaceutically acceptable inorganic or organic acid salts, hydrates, stereoisomers or solvates, wherein R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 Defined for compounds of formula 1, and wherein X is selected from... 68 Ga、 67 Ga and 111 In.

[0018] According to the present invention, preferably, each of the hydroxybenzyl groups in the compounds of formula I or II has an alkoxy group as a substituent, while the other three substituents are hydrogen. Therefore, in a preferred embodiment of the present invention:

[0019] Substituent R 1 R 2 R 3 and R 4 One of them is an alkoxy group, while the other three substituents are hydrogen; and

[0020] Substituent R 5 R 6 R7 and R 8 One of them is an alkoxy group, while the other three substituents are hydrogen; and

[0021] Substituent R 9 R 10 R 11 and R 12 One of them is an alkoxy group, while the other three substituents are hydrogen.

[0022] In another preferred embodiment, the alkoxy group in each hydroxybenzyl group of Formula I or Formula II is alkoxy-substituted at the ortho, meta, or para position.

[0023] Therefore, according to the present invention, compounds corresponding to formula I or formula II are particularly preferred, wherein

[0024] R 1 It is an alkoxy group, while R 2 R 3 and R 4 For hydrogen; and

[0025] R 5 It is an alkoxy group, while R 6 R 7 and R 8 For hydrogen; and

[0026] R 9 It is an alkoxy group, while R 10 R 11 and R 12 It is hydrogen;

[0027] or

[0028] R 2 It is an alkoxy group, while R 1 R 3 and R 4 For hydrogen; and

[0029] R 6 It is an alkoxy group, while R 5 R 7 and R 8 For hydrogen; and

[0030] R 10 It is an alkoxy group, while R 9 R 11 and R 12 It is hydrogen;

[0031] or

[0032] R 3 It is an alkoxy group, while R 1 R 2 and R 4 For hydrogen; and

[0033] R 7 It is an alkoxy group, while R 5 R 6 and R 8 For hydrogen; and

[0034] R 11 It is an alkoxy group, while R 9 R 10 and R 12 It is hydrogen;

[0035] or

[0036] R 4 It is an alkoxy group, while R 1 R 2 and R 3 For hydrogen; and

[0037] R 8 It is an alkoxy group, while R 5 R 6 and R 7 For hydrogen; and

[0038] R 12 It is an alkoxy group, while R 9 R 10 and R 11 It is hydrogen.

[0039] Particularly preferred is that the alkoxy group of each hydroxybenzyl group in the compound of formula I or II undergoes alkoxy substitution at the meta position. Therefore, in a particularly preferred embodiment of the invention:

[0040] R 2 It is an alkoxy group, and R 1 R 3 and R 4 For hydrogen; and

[0041] R 6 It is an alkoxy group, and R 5 R 7 and R 8 For hydrogen; and

[0042] R 10 It is an alkoxy group, and R 9 R 11 and R 12 It is hydrogen.

[0043] This structural modification of the three phenolic salt groups of the modified DAZA enables it to achieve the desired specific biodistribution without requiring a target unit to be linked. This is because the alkoxyhydroxybenzyl group achieves the desired high liver specificity in a simple manner through coordination with its additional alkoxy substituent.

[0044] In the compounds according to Formulas I and II, DAZA is substituted only with hydrogen, except for the three hydroxybenzyl groups. In contrast, the DAZA framework of the compounds disclosed in WO2014198478 A2 has substituents other than hydrogen. This means that the specific liver distribution of the substances disclosed in WO2014198478 A2 cannot be guaranteed. The compounds according to Formulas I and II are particularly advantageous because these substances can be obtained via a simple synthetic route starting with DAZA. No additional synthetic steps are required to connect the targeting unit.

[0045] The absence of substituents other than H on DAZA means that no substituents were observed in compounds according to Formula I of the present invention. 68 Ga、 64 Cu、 67 Ga、 111 In and 99m The Tc coordination ability is a drawback; the complex forms within 10 minutes at room temperature (preferably at high temperature) and is stable in vivo.

[0046] When R 2 R 6 and R 10 When substituted with an alkoxy group, the alkoxy substituent is independently, for example, -OC. 1-12 Alkyl group, preferably -OC 1-8 Alkyl, more preferably -OC 1-6 Alkyl or -OC 1-4 Alkyl group, wherein the alkyl group may be unbranched or branched.

[0047] In another preferred embodiment, the alkoxy substituent is independently selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, hexoxy, and octoxy. In particularly preferred compounds of Formula I and Formula II, R 2 R 6 and R 10 It can be independently substituted with methoxy, ethoxy, propoxy, butoxy, pentoxy, heptaoxy, hexoxy, or octoxy, while R 1 R 3 R 4 R 5 R 7 R 8 R 9 R 11 and R 12 Replaced by hydrogen.

[0048] When the hydroxybenzyl groups are respectively replaced by the same alkoxy groups, it is preferable that R 2 R 6 and R 10When substituted with the same alkoxy group, the compounds of formulas I and II achieve a favorable liver distribution. In a preferred embodiment, the hydroxybenzyl group is substituted with an ethoxy group, particularly preferably with R... 2 R 6 and R 10 In another preferred embodiment, the hydroxybenzyl group is substituted with a methoxy group, particularly preferably at the R position. 2 R 6 and R 10 At the position of R. Other substituents of the hydroxybenzyl group are substituted with hydrogen, particularly at R. 1 R 3 R 4 R 5 R 7 R 8 R 9 R 11 and R 12 In position.

[0049] The purpose of this invention is to explain the principle of "liver imaging by injecting a hepatotropic metal complex solution" from the perspective of paramagnetic metals (Gd(III)-MRI) and radioactive metal isotopes as gamma emitters (Gd(III)-MRI). 99m Tc-SPECT has been extended to metal complexes containing gallium(III) or Cu(III), particularly radioactive ones. 68 Ga isotopes and radioactivity 64 Cu isotopes are used as positron emitters in PET / CT imaging. A primary challenge is synthesizing isotopes suitable for use with... 68 Ga、 64 Cu、 67 Ga、 111 In or 99m Tc-labeled ligands are particularly preferred. 68 Ga or 64 Cu-labeled ligands, which also exhibit liver specificity. In conventionally used metal complex solutions... (Gd-EOB-DTPA) and " 99m The ligands EOB-DTPA and EHIDA used in “Tc-EHIDA” cannot form sufficiently stable [agents]. 68 Ga complex 1,21 Conversely, the compound exhibits rapid disintegration under physiological conditions, primarily characterized by demetallization (e.g., via hemoglobin detransferrin). 22 This results in the release of [something] into the body. 68Ga ions (e.g., in colloidal, tetrahydroxyglycine salt, or protein-bound forms) exhibit nonspecific distribution in the blood pool, and insufficient accumulation of radioactive components in the liver hinders their imaging. Therefore, the complex must possess high stability to be usable. By definition, 68 Ga and 64 Suitable ligands for Cu need to be synthesized as efficiently as possible with as few steps as possible, starting from available starting materials. This also allows for simple modifications to the ligand framework, such as in terms of functional groups, lipophilic groups (chain length or the position of the alkoxy group on the benzyl ring), and thus optimizes the tracer structure and its in vivo distribution.

[0050] Compounds according to Formula I of the present invention are generally suitable for use with 68 Ga、 64 Cu、 67 Ga、 111 In or 99m Tc marker, but particularly suitable for use with 68 Ga-labeled. Unlike the aforementioned and known ligands EOB-DTPA and EHIDA, the compounds of formula II... 68 The Ga complex did not exhibit demetallization or decomposition in vivo. This ligand is stable and can be used for... 68 Ga or 64 Cu-labeled precursor storage. Due to the small amount of substance administered, no adverse toxicological effects are expected. The tracer was synthesized according to standard radiopharmaceutical methods. 68 Ga、 64 Cu、 67 Ga、 111 In or 99m The markings for Tc. Access known to those skilled in the art. 68 Ge / 68 Ga generators can ensure, for example, the presence of radioactive nuclides. 68 Ga's availability is virtually unlimited.

[0051] In a particularly preferred embodiment of the invention, the compound of formula I is selected from tri-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine (TEOHB-DAZA) and tri-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine (TMeOHB-DAZA), and the corresponding radiolabeled complex of formula II is selected from:

[0052]

[0053] This invention also provides the following compounds:

[0054]

[0055]

[0056] The accumulation of the compounds according to the invention in the liver can be examined in the so-called ovo test, i.e., in vivo testing in incubated ostrich eggs. 68 Ga-[TEOHB-DAZA] administration showed that it accumulated almost exclusively in the liver of embryonic ostrich eggs.

[0057] Another advantage of the compounds according to the invention is that the ligands TEOHB-DAZA and TMeOHB-DAZA are readily available and can be efficiently synthesized in a one-pot process starting from DAZA, ​​using only NaBH4 as a reducing agent (see below). The starting material DAZA is synthesized according to literature methods. 23

[0058] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula I or II, or a pharmaceutically acceptable inorganic or organic acid salt, hydrate, stereoisomer, or solvate of such a compound. The pharmaceutical composition preferably comprises at least one physiologically tolerable solvent, diluent, adjuvant, and / or excipient.

[0059] In this specification and claims, the terms "inorganic acid" and "organic acid" refer to inorganic acids, including but not limited to acids such as carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, perchloric acid, or sulfuric acid, or their acidic salts (such as potassium hydrogen sulfate), or suitable organic acids, including acids such as aliphatic, cyclic aliphatic, aromatic, aryl aliphatic acids, heterocyclic carboxylic acids, and sulfonic acids. Examples include formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, methanesulfonic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, pyric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid, or sulfanilic acid.

[0060] In another aspect of the invention, a radiopharmaceutical composition is provided, the composition comprising a compound of formula II or a pharmaceutically acceptable inorganic or organic acid salt, hydrate, stereoisomer, or solvate thereof.

[0061] The radiopharmaceutical composition preferably contains at least one physiologically tolerable solvent, diluent, adjuvant, and / or excipient.

[0062] According to the invention, preferably the radiolabeled compounds corresponding to Formula II provided by the invention, they can be contained intravenously in the form of a pharmaceutical composition for intravenous injection in a pharmaceutically acceptable solvent, such as in a conventional medium, like a saline medium or in a plasma medium or serum. Such media may also contain conventional pharmaceutical substances, such as pharmaceutically acceptable salts for osmotic adjustment, buffers, preservatives, etc. Preferred media include physiological saline and human serum. A particularly preferred medium is PBS-buffered saline.

[0063] Those skilled in the art are also aware of other suitable pharmaceutically acceptable solvents, for example, as described in Remington's Practice of Pharmacy, 13th edition and J. of Pharmaceutical Science & Technology, vol. 52, No. 5, Sept-Oct., pp. 238-311.

[0064] According to the invention, the radiolabeled compound of formula II is administered in a single injection dose unit in the form of a neutral composition or a salt having the pharmaceutically acceptable counterion described above. Following radiolabeling, an injection solution for diagnostic imaging of various organs (preferably the liver) can be prepared using any commonly used solvent known to those skilled in the art (e.g., sterile saline or plasma, preferably PBS-buffered saline). The radioactivity range of the unit dose of the diagnostic drug is typically from about 3.7 MBq to about 37 GBq. According to the invention, the radioactivity of the drug / radiopharmaceutical composition is at least 50 MBq. These are particularly suitable for liver imaging methods. The volume of the solution to be injected in a unit dose ranges from about 0.01 ml to about 30 ml. For diagnostic purposes, imaging of the organ or disease can be performed in vivo within minutes after intravenous administration. However, if desired, imaging can occur hours or even longer after injection into the patient. In most cases, a sufficient amount of activity administered will accumulate in the area to be imaged within about 30 minutes, allowing images to be recorded in the imaging method. Any conventional diagnostic imaging method can be used according to the invention. Formula II is preferred. 68 Ga and 64 Cu complexes are used for PET / CT imaging. PET / CT imaging using compounds of Formula II according to the invention is preferably performed for 0.5 to 2 hours per injection (“normal” phase and “late / biliary” phase) or dynamically in a list mode. Similarly, the early phase (arterial spillover) can be recorded by direct administration into the PET / CT scanner (so-called “early dynamic PET”).

[0065] Another advantage of the pharmaceutical / radiopharmaceutical composition according to the invention is its high stability. The composition according to the invention exhibits at least 98% stability in (human serum or PBS-buffered saline) for at least 4 hours. Further preferred is its use in SPECT and SPECT / CT imaging. 67 Ga、 111 In or 99m Tc complex.

[0066] Compounds of Formula II show liver-specific accumulation and are excreted via the intestine and / or gallbladder.

[0067] In another aspect of the invention, a method for preparing compounds of general formula I is provided. In a preferred embodiment, the preparation of compounds of general formula I comprises the following steps:

[0068] a) Synthesizing compound III by reacting compound IV with compound (V) in the presence of a suitable solvent such as methanol.

[0069]

[0070] Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 The definition is as described above;

[0071]

[0072] Where R 9 R 10 R 11 and R 12 The definition is as described above.

[0073] as well as

[0074] b) React the compound of formula III with a suitable reducing agent (such as NaBH4) under reducing conditions in the presence of a suitable solvent.

[0075] When the alkoxy group in the compound of formula I is ethoxy, methanol is preferably used as a solvent in step b) of the preparation method. When the alkoxy group in the compound of formula I is methoxy, a mixture of methanol and chloroform (preferably in a 1:1 ratio) is preferably used as a solvent in step b) of the preparation method.

[0076] The synthesis of TEOHB-DAZA and TMeOHB-DAZA was carried out using bicyclic precursors of Formula III containing N,N'-bridging units provided by acetal amine linkages:

[0077]

[0078] Surprisingly, in step b), under reducing conditions, the triple alkylated product TEOHB-DAZA or TMeOHB-DAZA can be synthesized in good yield from a nitrogen heterocycle functionalized with two 4-alkoxy-2-hydroxybenzyl units (one bonded in the form of an acetalamine and the other in the form of an imine). In a preferred embodiment of the invention, the C=O or C=N component is inserted into one of the two CN bonds of the acetalamine, followed by reduction, for example, by the hydride reagent NaBH4.

[0079] It is known from the literature that acetalamines undergo reducing and cleaving to form the corresponding imines; 61-64 In these known methods, cleavage always occurs between one of the two nitrogen atoms (N) and a carbon bridge. As a result, after reduction of one of the nitrogen atoms (N'), the functional group of the reduced acetal amine functions as the corresponding alkyl substituent, while the second nitrogen atom (N) gains a proton and exists in the form of R₂NH. However, there have been no reports to date of the formation of bis-N,N'-alkylated amine structures from N,N'-bridged acetal amine structures under reducing conditions. This, however, is precisely what occurs according to the method of the invention. The resulting compound of formula I was clearly demonstrated / identified by X-ray structural analysis.

[0080] In a one-pot synthesis beginning with an unprotected 1,4-diazacycloheptane-6-amine, this specific reaction makes it possible to selectively alkylate each of the three nitrogen atoms in a compound of formula I via alkyl groups from the carbonyl component, even if these nitrogen atoms include two secondary amine groups and one primary amine. According to existing techniques, secondary amines are alkylated by condensation with aldehydes and other carbonyl components, especially in the presence of modified, milder reducing agents (such as NaBH(OAc)3 or NaBH3CN), by direct reductive amination alone. 65 Furthermore, attempts to alkylate such nitrogen heterocyclic compounds, especially when selectivity is required, such as the single alkylation of a primary amino group, often result in a mixture of products, particularly in reactions with conventionally used alkyl bromides, or when the use of protecting groups is necessary. 25,34,66,67

[0081] In the reaction according to the invention, tri-N,N',N”-alkylated 1,4-diazacycloheptane-6-amines TEOHB-DAZA and TMeOHB-DAZA are formed in extremely high yields of 80-90% (calculated based on the molar ratio of 4-alkoxy-2-hydroxybenzyl groups in the precursor (=2 units) and product (=3 units). Through this reaction, the inventors have successfully established a novel, highly efficient, unprotected, monoalkylation pathway for all three nitrogen atoms in 1,4-diazacycloheptane-6-amine (DAZA) starting from the corresponding carbonyl group. It has also been found that the structure-related TOHB-DAZA ( Tri-N,N',N”-(2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine and TEOB-DAZA (tri-N,N',N”)-1,4-diazacycloheptane-6-amine) cannot be separated by the same method. In the reduction of the corresponding bridged acetal (III), the formation of a mixture of monoalkylated, dialkylated, and trialkylated DAZA products, as well as (especially TEOB-DAZA) aldehyde (IV) products, increases, making them difficult to separate from each other. Similar to TEOHB-DAZA and TMeOHB-DAZA, ​​selective precipitation of the trialkylated products in methanol does not occur.

[0082] In another aspect, the present invention relates to the use of compounds of formula I as ligands for the preparation of compounds corresponding to formula II. 68 Ga or 64 Cu complexes are also provided. A method for preparing compound II from compound I is also provided.

[0083] In this method according to the invention, the product is used at room temperature or higher. 68 Ga solution or containing 64 Cu solution treatment of compounds of formula I. This treatment is preferably carried out at a temperature of 50°C or higher, more preferably at 60°C, 70°C, 80°C, 90°C or higher, and particularly preferably at 100°C. The higher the selected temperature, the shorter the reaction time to form the radiolabeled complex, which is particularly advantageous for the performance of the imaging method because the radiolabeled compound of formula II should not be synthesized before administration to the patient as close as possible, and can be provided within a short time if needed, for example, within 5 minutes when the reaction is carried out at 100°C.

[0084] The yields of the obtainable compound of formula II are also pH-dependent. If we want to... 68 Ga is incorporated into the ligand of formula I, using a mixture containing... 68 Solution treatment of Ga ligands of formula I is preferably carried out at pH 5.0 or lower, more preferably in the range of 3.7-5.0, and particularly preferably in the range of 4.0-4.5. If it is to...64 Cu is incorporated into the ligand of formula I, using a mixture containing... 64 The solution treatment of Cu ligands of Formula I is preferably carried out at pH 4.0 or higher, more preferably in the range of 4.0-8.0, and particularly preferably in the range of 6.0-7.0.

[0085] The present invention also provides a kit for preparing radiopharmaceutical formulations, wherein the kit comprises a sealed ampoule containing a predetermined amount of the ligand corresponding to Formula I or the compound of Formula II of the present invention, and optionally instructions for using the kit components. The present invention also provides a kit for disease imaging.

[0086] In another aspect, the present invention provides compounds of Formula II or (radioactive) pharmaceutical compositions comprising compounds of Formula II, which are used in diagnostic methods such as PET / CT imaging.

[0087] This invention also relates to the use of compounds of Formula II in the preparation of (radioactive) pharmaceutical compositions for diagnostic purposes (e.g., for imaging methods such as PET / CT). Specifically, the compounds of this invention can be used for imaging of liver diseases, including but not limited to chronic liver diseases and tumors. Compounds of Formula II allow, for example, imaging of liver diseases selected from liver inflammation (hepatitis), cirrhosis (liver shrinkage), fatty liver, autoimmune liver diseases such as autoimmune hepatitis (AIH), primarily sclerosing cholangitis (PSC) and primarily biliary cirrhosis (PBC), and iron storage diseases (hemochromatosis).

[0088] Compounds of Formula II allow imaging of all primary and secondary tumors of the liver and bile ducts, such as hemangiomas, hepatocellular adenomas, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), cholangiocarcinomas; hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, angiosarcoma and hepatoblastoma, metastatic tumors of other tumors (such as colorectal cancer); appendiceal carcinoids; breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, etc.

[0089] In another aspect, the present invention relates to a treatment or diagnostic method comprising administering a compound of formula II or a (radioactive) pharmaceutical composition comprising a compound of formula II to an individual in a therapeutically active amount or an amount sufficient to perform a diagnostic method. For example, the individual is an animal, preferably a mammal, or more preferably a human.

[0090] According to the present invention, it is preferred to use or administer a compound of formula II or a (radioactive) pharmaceutical composition containing a compound of formula II for liver PET / CT imaging.

[0091] In a particularly preferred embodiment of the present invention, a method for obtaining an image of an animal or human liver is provided, wherein the method includes the following steps:

[0092] (a) Administering to an animal or human a pharmaceutical composition comprising a compound of formula II as described in any of claims 2-9 or 11,

[0093] (b) Perform PET or PET / CT scans on the treated animals or humans;

[0094] (c) A measurable emission signal induced by the compound of formula II is detected in the relevant animal or human; and

[0095] (d) Generate an image from the detectable signal to obtain an image of the liver of an animal or human.

[0096] Exemplary Implementation

[0097] 1. Composition Description

[0098] The synthesis of compound I is shown in synthetic route 1.

[0099]

[0100] Synthetic Route 1: Synthesis of Compound I

[0101] Synthesis of precursors / Synthesis of 1

[0102] In a round-bottom flask, 1,4-diazacycloheptan-6-amine (65 mg, 0.57 mmol) and 4-methoxy-2-hydroxybenzaldehyde (172 mg, 1.13 mmol) were mixed in 15 mL of methanol, and the resulting yellow suspension was stirred at room temperature for one hour. The solid was filtered, washed with methanol, and dried under reduced pressure (205 mg, 0.54 mmol, 94%).

[0103] 1 H-NMR (400.1MHz, CDCl3): δ = 13.17 (s, broad, 1H), 11.85 (s, broad, 1H), 8.28 (s, 2H), 7.26-7.23 (m, 1H), 7.12 (d, 3 J H,H =8.4Hz,1H),6.45-6.36(m,HH),5.21(s,1H),3.81(s,3H),3.76(s,3H),3.71-3.64(m,1H),3.37-2.90(m,8H).

[0104] 13C-NMR (100.6MHz, CDCl3): δ=165.0,163.7,163.5,161.2,158.5,132.7,128 .0,112.5,106.9,105.5,101.8,101.2,87.4,60.6,59.1,55.6,55.3,50.6.

[0105] MS(ESI pos.,CH3OH):m / z=383([M] + ,100%.

[0106] EA[%](C 21 H 25 N3O4):C 65.46(65.78),H 6.72(6.57),N 11.07(10.96).

[0107] Synthesis of precursors / 2

[0108] In a round-bottom flask, 1,4-diazacycloheptan-6-amine (30 mg, 0.26 mmol) and 4-ethoxy-2-hydroxybenzaldehyde (86 mg, 0.52 mmol) were mixed in 10 mL of methanol, and the resulting yellow suspension was stirred at room temperature for one hour. The solid was filtered, washed with methanol, and dried under reduced pressure (100 mg, 0.24 mmol, 94%).

[0109] 1 H-NMR (400.1MHz, CDCl3): δ = 13.16 (s, 1H), 8.27 (s, 2H), 7.24-7.22 (m, 2H), 7.12-7.09 (m, 2H), 6.45-6.41 (m, 2H), 6. 38-6.35(m,4H),5.60(s),5.21(s,1H),4.07-3.96(m,4H),3.72-3.64(m,1H),3.49-2.90(m,8H),1.43-1.36(m,6H).

[0110] 13 C-NMR (62.9MHz, CDCl3): δ=165.0,163.4,163.0,160.5,158.5,132.7,128.0,11 2.3,107.4,106.1,102.3,101.6,87.4,63.8,63.5,60.6,59.1,50.6,15.0,14.8.

[0111] MS(ESI pos.,CH3OH):m / z=434([M+Na] + ,100%),412([M+H]+ 45%.

[0112] EA[%](C 23 H 29 N3O4):C 66.90(67.13),H 7.13(7.10),N 10.26(10.21).

[0113] Synthesis of ligand TMeOHB-DAZA

[0114] Add 71 mg (1.89 mmol) of NaBH4 in several portions to a solution of 1 (200 mg, 0.52 mmol) in 10 mL of a 1:1 mixture of methanol and chloroform, and then decolorize the solution. Stir the reaction solution for one hour. Then remove the solvent under reduced pressure, and resuspend the residue in methanol. Filter the solid, wash with methanol, and dry under reduced pressure (163 mg, 0.31 mmol, 60%).

[0115] 1 H-NMR (400.1MHz, CDCl3): δ = 10.45 (s, broad, 1H), 6.88 (d, 3 J H,H =8.1Hz,2H),6.52(d, 3 J H,H =8.4Hz,1H),6.41-6.35(m,5H),6.27(dd, 3 J H,H =8.3Hz, 2 J H,H =2.5Hz, 1H), 3.82(d, 2 J H,H =13.4Hz,2H),3.75(s,6H),3.74(s,3H),3.67(d, 2 J H,H =13.4Hz,2H),3.37(s,2H),2.98-2.72(m,9H).

[0116] 13 C-NMR (100.6MHz, CDCl3): δ=161.1,160.6,159.2,158.7,129.7,129.2,114.4 ,114.0,105.9,105.2,102.1,102.0,62.5,58.3,57.9,55.4,54.7,51.0,49.4.

[0117] MS(ESI pos.,CH3OH):m / z=546([M+Na] + ,45%),524([M+H]+ ,100%.

[0118] EA[%](C 32 H 45 N3O7·0.5MeOH):C 65.58(65.66),H 7.07(7.28),N 7.89(7.79).

[0119] Synthesis of ligand TEOHB-DAZA

[0120] 22 mg (0.58 mmol) of NaBH4 was added in portions to a suspension of 2 (120 mg, 0.29 mmol) in 10 mL of methanol, and the yellow suspension was decolorized within 10 minutes. The resulting solution was stirred for one hour, and then the solvent was concentrated to 5 mL. A white solid precipitated from the methanol solution overnight, filtered, washed with methanol, and then dried under reduced pressure (85 mg, 0.15 mmol, 52%).

[0121] 1 H-NMR (400.1MHz, CDCl3): δ = 6.86 (d, 3 J H,H =8.1Hz,2H),6.51(d, 3 J H,H =8.3Hz,1H),6.40-6.33(m,5H),6.25(dd, 3 J H,H =8.3Hz, 2 J H,H =2.5Hz, 1H), 3.96(q, 3 J H,H =7.0Hz, 6H), 3.82(d, 2 J H,H =13.4Hz, 2H), 3.66(d, 2 J H,H =13.4Hz,2H),3.35(s,2H),2.98-2.71(m,9H),1.41-1.36(m,6H).

[0122] 13 C-NMR (100.6MHz, CDCl3): δ=160.4,159.9,159.2,158.6,129.7,129.2,114.3,11 3.9,106.4,105.6,102.6,102.6,63.5,63.4,62.5,58.3,57.9,54.6,49.4,15.0.

[0123] MS(ESI pos.,CH3OH):m / z=588([M+Na] + ,100%),566([M+H] + ,62%),438([M-(CH2-C6H4O-OC2H5)+Na] + ,25%),416([M-(CH2-C6H4O-OC2H5)+H] + 46%.

[0124] EA[%](C 32 H 45 N3O7·H2O):C 65.49(65.84),H 7.43(7.77),N 7.27(7.20).

[0125] 68 Radiolabeling of Ga

[0126] Use 70 μL of TMeOHB-DAZA or TEOHB-DAZA (1 mg / ml). Treatment with an aqueous solution / HCl (1M) / ethanol (3:1:1) and 2 ml acetate buffer 68 Ge / 68 Cationic purified Ga in a Ga generator (TiO2, eluted with 0.6M hydrochloric acid) 68 Ga eluent (approximately 1600 MBq). Heat the solution to pH 3.8–4.0 at 100°C for 5 minutes. Then load the solution onto a pretreated C8 reversed-phase extraction column. C8Plus was washed with 2 ml of water (water for injection) and eluted with 1 ml of ethanol (50%). 68 Ga tracer. Radiochemical yield 65-80% (decay corrected). Dilute the sample with PBS (10 ml). Determine radiochemical purity by radioactive TLC and radioactive HPLC, and it is ≥99.6%. Assess its activity in a calibrated activity meter.

[0127] X( 64 Cu、 67 Ga、 111 In、 99m Radiolabeling of Tc

[0128] Using radioactive metal X with an activity of 1 MBq-100 GBq ( 64 Cu、 67 Ga、 111 In、 99mAn aqueous solution of compound I is treated with an aqueous solution of Tc, the latter containing suitable additives or excipients, such as buffers, reducing agents (e.g., SnCl2), stabilizers, emulsifiers, etc., and with a pH in the range of 2-12. Labeling is optionally performed by heating to a temperature up to 100°C for 1 minute to 12 hours. The solution is then purified, concentrated, buffered, or diluted to suit the composition for intravenous administration.

[0129] 2. Ostrich egg administration and PET / CT scan

[0130] To perform intravascular injection into the ovum, the amniotic vessels must first be located. This is done using a Schier lamp (Tempo No. 119, Brecker Ltd. & Co. KG, Ruethen, Germany or Powerlux Eggtester 4.5VDC, Lyon Technologies Inc., Chula Vista, CA, USA), illuminating the egg through the shell in a manner similar to transillumination. After locating a large-diameter container, a rectangular sheet approximately 2.5 x 5 cm is processed from the approximately 2 mm thick eggshell. 3000, Dremel Europe-Bosch Powertools BV, Breda, the Netherlands). Special care must be taken to maintain the integrity of the inner shell membrane, which corresponds to the chorioallantoic membrane (CAM).

[0131] After removing the eggshell cap (using a Schier lamp again), the yolk container was pierced with a narrow 27G cannula and secured to the eggshell with adhesive strips. The created channel now allows passage through shorter lengths of plastic tubing (Smiths Medical). TM 800 / 100 / 100 Smiths, Smiths Medical International Ltd, Ashford, Great Britain) CT contrast agent and radiopharmaceutical were injected. To ensure no blockage by backflow and clotted blood, the area was flushed with heparin.

[0132] In each case, the tracer produced according to the method is delivered via a pathway. 68 Ga[TMeOHB-DAZA] and 68 Ga[TEOHB-DAZA] was injected into PBS solution (10 MBq per 0.3–0.8 ml), followed immediately by rinsing with 1 ml of isotonic saline (0.9%). Dosing was administered in a list mode at the start of the PET imaging procedure.

[0133] Summary of results from exemplary implementation schemes

[0134] Compounds TEOHB-DAZA and TMeOHB-DAZA of Formula I represent compounds suitable for use with 68 Ga and 64 Cu-labeled ligands. Unlike the known ligands EOB-DTPA and EHIDA, 68 The Ga complex did not exhibit demetallization or decomposition in vivo. This ligand is stable and can be used as... 68 Ga or 64 Cu-labeled precursor preservation. Due to the small amount of substance administered, no adverse toxicological effects are expected. The synthesis of this complex was performed according to standard radiopharmaceutical methods. 68 Ga or 64 The marking of Cu. 68 Ga-[TEOHB-DAZA] administration showed that it accumulated almost exclusively in the liver of embryonic ostrich eggs. Another advantage is the availability of the ligands TEOHB-DAZA and TMeOHB-DAZA, ​​which are efficiently synthesized in a one-pot process starting from DAZA, ​​using only NaBH4 as a reducing agent.

[0135] literature

[0136] 1.Greiser,J.,Niksch,T.,Freesmeyer,M.&Weigand,W.Investigations on theGa(III)Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue.J Vis Exp(2016).

[0137] 2.Greiser,J.et al.Synthesis and Characterization of GaIII,InIII andLuIII Complexes of a Set of dtpa Bis-Amide Ligands.Eur.J.Inorg.Chem.2015,4125-4137,doi:10.1002 / ejic.201500436(2015).

[0138] 3. Price, EW & Orvig, C. Matching chelators to radiometals for radiopharmaceuticals. Chem. Soc. Rev. 43, 260-290, doi: 10.1039 / C3CS60304K (2014).

[0139] 4.Price,T.W.,Greenman,J.&Stasiuk,G.J.Current advances in liganddesign for inorganic positron emission tomography tracers 68Ga,64Cu,89Zr and44Sc.Dalton Trans.,Ahead of Print,doi:10.1039 / C5DT04706D(2016).

[0140] 5.Wadas,T.J.,Wong,E.H.,Weisman,G.R.&Anderson,C.CoordinatingRadiometals of Copper,Gallium,Indium,Yttrium,and Zirconium for PET and SPECTImaging of Disease.J.Chem.Rev.110,2858-2902 doi:10.1021 / cr900325h.(2010).

[0141] 6.Bartholoma,M.D.,Louie,A.S.,Valliant,J.F.&Zubieta,J.Technetium andGallium Derived Radiopharmaceuticals:Comparing and Contrasting the Chemistryof Two Important Radiometals for the Molecular Imaging Era.Chem.Rev.(Washington,DC,U.S.)110,2903-2920,doi:10.1021 / cr1000755(2010).

[0142] 7.Clevette,D.J.&Orvig,C.Comparison of ligands of differing denticityand basicity for the in vivo chelation of aluminum and gallium.Polyhedron 9,151-161,doi:10.1016 / S0277-5387(00)80564-1(1990).

[0143] 8.Mathias,C.J.et al.Targeting radiopharmaceuticals:comparativebiodistribution studies of gallium and indium complexes of multidentateligands.Nucl.Med.Biol.15,69-81,doi:10.1016 / 0883-2897(88)90163-8(1988).

[0144] 9.Stroszczynski,C.et al.Current Status of MRI Diagnostics With Liver-Specific Contrast Agents.Radiologe 44,1185,doi:10.1007 / s00117-004-1134-5(2004).

[0145] 10.Vogl,T.J.et al.Liver tumors:comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA.Radiology 200,59-67,doi:10.1148 / radiology.200.1.8657946(1996).

[0146] 11.Weinmann,H.J.et al.A new lipophilic gadolinium chelate as atissue-specific contrast medium for MRI.Magn.Reson.Med.22,233-237,doi:10.1002 / mrm.1910220214(1991).

[0147] 12.Ba-Ssalamah,A.et al.MRT of the liver.Radiologe 44,1170-1184,doi:10.1007 / s00117-004-1142-5(2004).

[0148] 13.Reimer,P.et al.Phase II clinical evaluation of Gd-EOB-DTPA:dose,safety aspects,and pulse sequence.Radiology 199,177-183,doi:10.1148 / radiology.199.1.8633143(1996).

[0149] 14.Fritzberg,A.R.&Klingensmith,W.C.,III.Quest for the perfecthepatobiliary radiopharmaceutical.J.Nucl.Med.23,543-546(1982).

[0150] 15.Haubner,R.et al.Development of(68)Ga-labelled DTPA galactosylhuman serum albumin for liver function imaging.Eur.J.Nucl.Med.Mol.Imaging 40,1245-1255(2013).

[0151] 16.Haubner,R.et al.[68Ga]NOTA-Galactosyl Human Serum Albumin:a Tracerfor Liver Function Imaging with Improved Stability.Mol.Imaging Biol.,Ahead ofPrint,doi:10.1007 / s11307-017-1046-1(2017).

[0152] 17.Choi,J.et al.Ga-68-labeled neolactosylated human serum albumin(LSA)for PET imaging of hepatic asialoglycoprotein receptor.Nucl.Med.Biol.,Ahead of Print,doi:10.1016 / j.nucmedbio.2014.08.009(2014).

[0153] 18.Haubner,R.et al.[68Ga]NODAGA-RGD-Metabolic stability,biodistribution,and dosimetry data from patients with hepatocellularcarcinoma and liver cirrhosis.Eur.J.Nucl.Med.Mol.Imaging,Ahead of Print,doi:10.1007 / s00259-016-3396-3(2016).

[0154] 19.Ghosh,S.,Das,T.,Sarma,H.D.&Banerjee,S.Preparation and preliminarybioevaluation of 68Ga-oxine in lipiodol as a potential liver imagingagent.J.Radioanal.Nucl.Chem.,Ahead of Print,doi:10.1007 / s10967-016-4985-0(2016).

[0155] 20.Burke,B.P.et al.Final step gallium-68 radiolabelling of silica-coated iron oxide nanorods as potential PET / MR multimodal imagingagents.Faraday Discuss.175,59-71,doi:10.1039 / C4FD00137K(2014).

[0156] 21.Pfeifer-Leeg,M.et al.Synthesis and Characterization of GaIII,YIII,and LuIII Complexes with Etifenin and Analogues.Z.Anorg.Allg.Chem.642,486-491,doi:10.1002 / zaac.201600016(2016).

[0157] 22.Jurisson,S.,Berning,D.,Jia,W.&Ma,D.Coordination compounds innuclear medicine.Chem.Rev.93,1137-1156,doi:10.1021 / cr00019a013(1993).

[0158] 23.Romba,J.et al.The coordination chemistry of 1,4-diazepan-6-amine.Eur.J.Inorg.Chem.,314-328,doi:10.1002 / ejic.200500690(2006).

[0159] 24.Roesch,F.,Waldron,B.P.&Parker,D.Bifunctional chelating agentsbased on the 1,4-diazepine scaffold(DAZA)for non-invasive molecularimaging.WO2014198478A2(2014).

[0160] 25.Tei,L.,Gugliotta,G.,Fekete,M.,Kalman,F.K.&Botta,M.Mn(II)complexesof novel hexadentate AAZTA-like chelators:a solution thermodynamics andrelaxometric study.Dalton Trans.40,2025-2032,doi:10.1039 / c0dt01114b(2011).

[0161] 26.Elemento,E.M.,Parker,D.,Aime,S.,Gianolio,E.&Lattuada,L.Variationof water exchange dynamics with ligand structure and stereochemistry inlanthanide complexes based on 1,4-diazepine derivatives.Org.Biomol.Chem.7,1120-1131,doi:10.1039 / b818445c(2009).

[0162] 27.Aime,S.et al.[Gd-AAZTA]-:A New Structural Entry for an ImprovedGeneration of MRI Contrast Agents.Inorg.Chem.43,7588-7590,doi:10.1021 / ic0489692(2004).

[0163] 28.Baranyai,Z.et al.Equilibrium,Kinetic and Structural Studies ofAAZTA Complexes with Ga3+,In3+and Cu2+.Eur.J.Inorg.Chem.2013,147-162,doi:10.1002 / ejic.201201108(2013).

[0164] 29.Baranyai,Z.et al.Equilibrium and kinetic properties of thelanthanoids(III)and various divalent metal complexes of the heptadentateligand AAZTA.Chem.-Eur.J.15,1696-1705,doi:10.1002 / chem.200801803(2009).

[0165] 30.Parker,D.,Waldron,B.P.&Yufit,D.S.Crystallographic and solution NMRstructural analyses of four hexacoordinated gallium(III)complexes based onligands derived from 6-amino-perhydro-1,4-diazepine.Dalton Trans.42,8001-8008,doi:10.1039 / c3dt50287b(2013).

[0166] 31.Farkas,E.et al.Equilibrium,kinetic and structural properties ofgallium(III)-and some divalent metal complexes formed with the new DATAm andDATA5m ligands.Chemistry(2017).

[0167] 32.Vologdin,N.,Rolla,G.A.,Botta,M.&Tei,L.Orthogonal synthesis of aheterodimeric ligand for the development of the GdIII-GaIII ditopic complexas a potential pH-sensitive MRI / PET probe.Org.Biomol.Chem.11,1683-1690,doi:10.1039 / c2ob27200h(2013).

[0168] 33.Gugliotta,G.,Botta,M.&Tei,L.AAZTA-based bifunctional chelatingagents for the synthesis of multimeric / dendrimeric MRI contrastagents.Org.Biomol.Chem.8,4569-4574,doi:10.1039 / c0ob00096e(2010).

[0169] 34.Waldron,B.P.et al.Structure and stability of hexadentate complexesof ligands based on AAZTA for efficient PET labelling with gallium-68.Chem.Commun.(Cambridge,UK)49,579-581,doi:10.1039 / C2CC37544C(2013).

[0170] 35.Seemann,J.&al.,e.Novel Ga-68-labeled folic acidderivatives.Journal of Labelled Compounds and Radiopharmaceuticals 56,351(2013).

[0171] 36.Parker,D.&Waldron,B.P.Conformational analysis and syntheticapproaches to polydentate perhydro-diazepine ligands for the complexation ofgallium(III).Org.Biomol.Chem.11,2827-2838,doi:10.1039 / c3ob40287h(2013).

[0172] 37.Manzoni,L.et al.Synthesis of Gd and 68Ga Complexes in Conjugationwith a Conformationally Optimized RGD Sequence as Potential MRI and PETTumor-Imaging Probes.ChemMedChem 7,1084-1093,doi:10.1002 / cmdc.201200043(2012).

[0173] 38.Giovenzana,G.B.et al.Multidentate aza ligands able to complexmetal ions and the their use in diagnostics and therapy.US20060034773A1(2006).

[0174] 39.Maiocchi,A.,Visigalli,M.,Beltrami,L.,Sini,L.&Lattuada,L.A newclass of diazepine derivative chelating agents and complexes withparamagnetic metals as MRI contrast agents.WO2013135750A1(2013).

[0175] 40.Giovenzana,G.B.et al.Multidentate aza ligands able to complexmetal ions and the their use in diagnostics and therapy.WO2003008390A1(2003).

[0176] 41.Aime,S.et al.Contrast agents endowed with highrelaxivity.WO2006002873A2(2006).

[0177] 42.Seemann,J.,Waldron,B.P.,Roesch,F.&Parker,D.Approaching'Kit-Type'Labelling with 68Ga:The DATA Chelators.ChemMedChem 10,1019-1026,doi:10.1002 / cmdc.201500092(2015).

[0178] 43.Madsen,S.L.,Welch,M.J.,Motekaitis,R.J.&Martell,A.E.Gallium-68-THM2BED:a potential generator-produced tracer of myocardial perfusion forpositron emission tomography.Nucl.Med.Biol.19,431-444,doi:10.1016 / 0883-2897(92)90158-U(1992).

[0179] 44.Silva,F.et al.Chemical,radiochemical and biological studies of newgallium(III)complexes with hexadentate chelators.Dalton Trans.44,3342-3355,doi:10.1039 / C4DT02274B(2015).

[0180] 45.Sahoo,S.K.,Kanungo,B.K.&Baral,M.Complexation of a tripodal amine-catechol ligand tris((2,3-dihydroxybenzylamino)ethyl)amine towards Al(III),Ga(III),and In(III).Monatsh.Chem.140,139-145,doi:10.1007 / s00706-008-0068-4(2009).

[0181] 46.Liu,S.,Rettig,S.J.&Orvig,C.Polydentate ligand chemistry of Group13 metals:effects of the size and donor selectivity of metal ions on thestructures and properties of aluminum,gallium,and indium complexes withpotentially heptadentate(N4O3)amine phenol ligands.Inorg.Chem.31,5400-5407,doi:10.1021 / ic00052a015(1992).

[0182] 47.Caravan,P.&Orvig,C.Tripodal Aminophenolate Ligand Complexes ofAluminum(III),Gallium(III),and Indium(III)in Water.Inorg.Chem.36,236-248,doi:10.1021 / IC961222U(1997).

[0183] 48.Higham,C.S.et al.Multidentate aminophenol ligands prepared withMannich condensations.Tetrahedron Lett.47,4419-4423,doi:10.1016 / j.tetlet.2006.04.077(2006).

[0184] 49.Huemmer,J.,Heinemann,F.W.&Meyer,K.Uranium Tetrakis-AryloxideDerivatives Supported by Tetraazacyclododecane:Synthesis of Air-Stable,Coordinatively-Unsaturated U(IV)and U(V)Complexes.Inorg.Chem.,Ahead of Print,doi:10.1021 / acs.inorgchem.6b02123(2016).

[0185] 50.Wei,Y.,Wang,G.&Wu,K.First Eu(II) / Ln(III)Mixed Complex with HighOxidative Stability.Cryst.Growth Des.15,5288-5292,doi:10.1021 / acs.cgd.5b00804(2015).

[0186] 51.Wang,G.,Wei,Y.&Wu,K.Goblet-shaped pentanuclear lanthanide clustersassembled with a cyclen derivative ligand exhibiting slow magneticrelaxation.Dalton Trans.45,12734-12738,doi:10.1039 / C6DT02062C(2016).

[0187] 52.Nakai,H.et al.Control of Lanthanide Coordination Environment:Synthesis,Structure,and Oxygen-Sensitive Luminescence Properties of an Eight-Coordinate Tb(III)Complex.Inorg.Chem.55,6609-6615,doi:10.1021 / acs.inorgchem.6b00800(2016).

[0188] 53.Nakai,H.et al.A macrocyclic tetraamine bearing four phenol groups:a new class of heptadentate ligands to provide an oxygen-sensitiveluminescent Tb(III)complex with an extendable phenol pendant arm.DaltonTrans.44,10923-10927,doi:10.1039 / C5DT00816F(2015).

[0189] 54.Bender,M.et al.Theoretically Predicted and Experimentally ObservedRelaxation Pathways of two Heterodinuclear 3d-4fComplexes.Z.Anorg.Allg.Chem.641,2291-2299,doi:10.1002 / zaac.201500595(2015).

[0190] 55.Moore,D.A.,Fanwick,P.E.&Welch,M.J.Synthesis,characterization,andsolid-state structure of a new hexachelating ligand and its complex withgallium(III).Inorg.Chem.28,1504-1506,doi:10.1021 / ic00307a016(1989).

[0191] 56.Schnepf,R.et al.Resonance Raman Spectroscopic Study of PhenoxylRadical Complexes.J.Am.Chem.Soc.120,2352-2364,doi:10.1021 / JA972269X(1998).

[0192] 57.Lam,O.P.,Heinemann,F.W.&Meyer,K.A new diamantane functionalizedtris(aryloxide)ligand system for small molecule activation chemistry atreactive uranium complexes.C.R.Chim.13,803-811,doi:10.1016 / j.crci.2010.03.004(2010).

[0193] 58.Murphy,B.P.et al.Lanthanide complexes of new ditopic,tripodalmacrocycles:synthetic,structural,stability and luminescencestudies.Inorg.Chem.Commun.5,577-580,doi:10.1016 / S1387-7003(02)00486-0(2002).

[0194] 59.Schmidt,A.-C.,Nizovtsev,A.V.,Scheurer,A.,Heinemann,F.W.&Meyer,K.Uranium-mediated reductive conversion of CO2 to CO and carbonate in asingle-vessel,closed synthetic cycle.Chem.Commun.(Cambridge,UK)48,8634-8636,doi:10.1039 / c2cc34150f(2012).

[0195] 60.Adam,B.et al.Phenoxyl radical complexes of gallium,scandium,ironand manganese.Chem.-Eur.J.3,308-319,doi:10.1002 / chem.19970030221(1997).

[0196] 61.Denat,F.,Tripier,R.,Boschetti,F.,Espinosa,E.&Guilard,R.Reaction ofpolyamines with diethyloxalate:a convenient route for the synthesis oftetraazacycloalkanes.ARKIVOC(Gainesville,FL,US),212-233,doi:10.3998 / ark.5550190.0007.415(2006).

[0197] 62.Boyd,E.et al.Synthesis and derivatization of N,N'-trisubstituted1,2-diamines derived from(1R,2R)-1,2-diaminocyclohexane.Tetrahedron Lett.46,3479-3484,doi:10.1016 / j.tetlet.2005.03.129(2005).

[0198] 63.Zhang,Y.et al.Substituent-directed reduction of cyclic aminalsleading to two different heterocycles selectively:syntheses of functionalizednicotines and pyrido[2,3-b]azepines.Tetrahedron 71,1930-1939,doi:10.1016 / j.tet.2015.02.025(2015).

[0199] 64.Yamamoto,H.&Maruoka,K.Regioselective carbonyl amination usingdiisobutylaluminum hydride.J.Am.Chem.Soc.103,4186-4194,doi:10.1021 / ja00404a035(1981).

[0200] 65.Abdel-Magid,A.F.,Carson,K.G.,Harris,B.D.,Maryanoff,C.A.&Shah,R.D.Reductive Amination of Aldehydes and Ketones with SodiumTriacetoxyborohydride.Studies on Direct and Indirect Reductive AminationProcedures.J.Org.Chem.61,3849-3862,doi:10.1021 / JO960057X(1996).

[0201] 66.Mamedov,I.,Engelmann,J.,Eschenko,O.,Beyerlein,M.&Logothetis,N.K.Dual-functional probes towards in vivo studies of brain connectivity andplasticity.Chem.Commun.(Cambridge,UK)48,2755-2757,doi:10.1039 / C1CC15991G(2012).

[0202] 67.Guanci,C.et al.Synthesis of phosphonic analogues of AAZTA=6-Amino-6-methylperhydro-1,4-diazepine-N,N',N”,N”-tetraacetic acid andrelaxometric evaluation of the corresponding Gd(III)complexes as potentialMRI contrast agents.Tetrahedron Lett.56,1994-1997,doi:10.1016 / j.tetlet.2015.02.118(2015).

Claims

1. Compounds of general formula (I): (I) Or its pharmaceutically acceptable inorganic or organic acid salts, Where R 2 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 1 R 3 and R 4 For hydrogen; and R 6 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 5 R 7 and R 8 For hydrogen; and R 10 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 9 R 11 and R 12 It is hydrogen.

2. The compound of claim 1, wherein R 2 R 6 and R 10 It is independently selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, hexoxy, and octoxy.

3. The compound of claim 2, wherein R 2 R 6 and R 10 It is an ethoxylated compound.

4. The compound of claim 2, wherein R 2 R 6 and R 10 It is a methoxy group.

5. The compound of claim 1, wherein the compound is selected from tri-N,N',N''(4-ethoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine and tri-N,N',N''(4-methoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine.

6. Complexes of general formula (II): (II) Or its pharmaceutically acceptable inorganic or organic acid salts, Where R 2 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 1 R 3 and R 4 For hydrogen; and R 6 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 5 R 7 and R 8 For hydrogen; and R 10 -OC 1-12 Alkyl group, wherein the alkyl group may be unbranched or branched, and R 9 R 11 and R 12 For hydrogen, and Where X is selected from 68 Ga、 67 Ga and 111 In.

7. The complex of claim 6, wherein R 2 R 6 and R 10 It is independently selected from methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, hexoxy, and octoxy.

8. The complex of claim 7, wherein R 2 R 6 and R 10 It is an ethoxylated compound.

9. The complex of claim 7, wherein R 2 R 6 and R 10 It is a methoxy group.

10. The complex of claim 6, wherein the complex is selected from: 68 Ga[tri-N,N',N''(4-ethoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine], and 68 Ga[tri-N,N',N''(4-methoxy-2-hydroxybenzyl)-1,4-diazacycloheptane-6-amine].

11. A radiopharmaceutical composition comprising a complex of general formula (II) as described in any one of claims 6-10, said complex optionally in combination with one or more pharmaceutically acceptable diluents or carriers.

12. The radiopharmaceutical composition of claim 11, wherein it comprises PBS-buffered saline.

13. The radiopharmaceutical composition of claim 11, wherein the composition has an activity of at least 50 MBq.

14. The radiopharmaceutical composition of claim 11, wherein the composition has at least 98% stability in human serum and PBS buffered saline for at least 4 hours.

15. Use of the compound of any one of claims 1-5 as a ligand for preparing the complex of any one of claims 6-10.

16. A kit for preparing a radiopharmaceutical formulation, wherein the kit comprises a sealed ampoule containing a predetermined amount of a complex of general formula (II) as described in any one of claims 6-10, and optionally, instructions for using the kit.

17. A method for preparing a compound of general formula (I) as described in any one of claims 1-5, comprising the following steps: a) To synthesize compound (III) by reacting compound (IV) with compound (V) in the presence of a solvent. (III), Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 and R 8 As defined in any one of claims 1-5; (IV) Where R 9 R 10 R 11 and R 12 As defined in any one of claims 1-5; (V); and b) React the compound of formula (III) with a reducing agent in the presence of a solvent and under reducing conditions.

18. The method of claim 17, wherein the solvent used in step a) is methanol.

19. The method of claim 17, wherein the reducing agent in step b) is NaBH4.

20. Preparation of a product according to any one of claims 6-10, wherein X is... 68 A method for obtaining a complex of Ga of general formula (II), comprising using a solution containing Ga at a pH of 5.0 or lower. 68 Solution treatment of Ga of compounds of general formula (I) as described in any one of claims 1-5.

21. The method of claim 20, wherein the method is performed at a temperature of 50°C or higher.

22. The method of claim 20, wherein the method is performed at a temperature of 80°C or higher.

23. The method of claim 20, wherein the method is performed at a temperature of 100°C.

24. Use of the complex of general formula (II) as described in any one of claims 6-10 in the preparation of a pharmaceutical composition for obtaining images of the liver of an animal or human.

Images