NEW DAZA CHELATORS AS LIGANDS IN LIVER IMAGING

Description

Field of the invention

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

[0002] Liver imaging is currently performed primarily with contrast-enhanced CT and MRI (the latter often with liver-specific contrast agent) as well as scintigraphic imaging (SPECT). Various liver-specific MRI contrast agents are known in the state of the art. However, some of the known contrast agents that have been clinically tested, such as Endorem ®< , or that have received approval, such as Resovist ®< , have disadvantages, including toxic side effects. Furthermore, various approaches to liver imaging with PET / CT using 68< Ga tracers exist, all of which, however, have disadvantages. Table 1 shows an overview of contrast agents currently used in various imaging modalities. Table 1: Conventional contrast agents and radiotracers for various imaging techniques method Metal complex for molecular imaging Disadvantages MRI Contrast agent Primovist 9-13< Contraindications: metal implants, claustrophobia, toxicity of contrast media, application of large amounts of substance, intolerances or allergies SPECT or SPECT / CT 99m< Tc-EHIDA 14< Lower spatial and temporal resolution than PET / CT or MRI PET or PET / CT Visualization of the asialoglycoprotein transporter on hepatocytes with 68Ga tracers: 68< Ga-DTPA-GSA 15< Rapid decomposition of the complex in vivo limits the applicability 68< Ga-NOTA-GSA 16< No purification of the product via cartridges possible, use of guaranteed 68< Ge-free eluates or pre-purification of the eluate necessary 68< Ga-NOTA-LSA 17< Differentiation between 68< Ga-transferrin and 68< Ga-NOTA-LSA is difficult because 68< Ga-NOTA-LSA also has a peptide-like structure due to the LSA. Separation using LC methods (radio-HPLC or radio-TLC) is not possible! This also makes it impossible to identify isomers of the tracer (by radio-HPLC). 68< Ga-NODAGA-RGD 18< No increased uptake in HCC compared to the surrounding liver tissue, therefore no tumor imaging possible; enhancement in the bladder, kidney, and other organs, resulting in radiation exposure of surrounding, non-targeted organs, deterioration of image quality due to enhancement in non-hepatobiliary tissue, making diagnosis more difficult PET or PET / CT 68< Ga-Oxine in Lipiodol 19< Complex and time-consuming synthesis of 68< Ga-oxine (e.g. extraction in chloroform), leakage of 68< Ga-oxine from the lipiodol, e.g. due to complex instabilities PET / MRI 68< Ga-siloxane-DO3A-labeled iron nanoparticles 20< Accumulation in the liver and spleen, and to a limited extent in the lungs due to embolization, thereby exposing surrounding, non-targeted organs to radiation

[0003] Due to the disadvantages described above, Primovist ®< is currently the only liver-specific contrast agent commercially available and used. However, the cost per patient dose is high. Additional costs arise from delayed imaging and the resulting long MRI scanner usage time. Furthermore, due to contraindications associated with Primovist ®<, CT or MRI examinations that are actually indicated often cannot be performed or can only be performed after premedication. Furthermore, many MRI examinations cannot be performed in patients with implanted pacemakers or in patients suffering from claustrophobia.

[0004] WO2014198478 A2 discloses bifunctional chelators based on the 1,4-diazepan-6-amine scaffold (DAZA) for noninvasive molecular imaging. The 2-hydroxybenzyl-substituted DAZA unit acts as a coordinating unit for 68< Ga. However, the specific biodistribution properties are only achieved with great effort via specific substituents of DAZA, to which a coupling unit and a targeting unit are attached.

[0005] Also known from the literature are the so-called DATA chelators, which include, for example, the ligands AAZTA and AAZ3A 24,25<. These are characterized by the functionalization of the nitrogen atoms with acetic acid groups or long-chain carboxylic acid residues (e.g., glutaric acid 26<), methyl groups, phosphonates, or coordinative ring systems. 24,25,27-41<. In these cases, the 1,4-diazepan-6-amine is often extended by a functional group (e.g., methyl, phenyl 42<, or linkers for bifunctional structures 30,31,33<) at the C1 carbon atom of the DAZA ring. Furthermore, a variety of aminophenolate-containing ligands are known, which can be classified by the attachment of ortho-hydroxybenzyl units (e.g. in the form of phenolates or catecholates) to both open-chain structures (e.g. HBED 43< and TREN derivatives 44-48< ) and to macrocycles such as cycles 49-54< and TACN 55-59<.Most of these have already been investigated as ligands for 68< Ga. 43,55,60< . Description of the invention

[0006] The object of the invention was to provide ligands for liver imaging with PET / CT which have improved properties compared to the ligands known from the prior art and, in particular, can be produced easily and with little effort.

[0007] This object is achieved by providing compounds of the general formula I according to claim 1: or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate, including a radiolabeled complex 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< are independently selected from hydrogen and alkoxy.

[0008] Throughout the description and claims, unless specifically limited, the term "alkoxy" refers to a C 1-12 alkoxy group, preferably a C 1-8 alkoxy group, for example, a C 1-6 alkoxy group or a C 1-4 alkoxy group. Alkoxy groups may be straight or branched. Exemplary 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).

[0009] "Substituted by hydrogen" in the sense of the invention means "substituted by H".

[0010] The compounds of formula I are particularly suitable ligands for the formation of radiolabeled complexes. In a preferred embodiment, the invention provides radiolabeled complexes consisting of a compound of formula I and a radioisotope 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 according to general formula II: or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate 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< are as defined for the compound of formula I and wherein X is selected from 68< Ga, 67< Ga and 111< In.

[0011] According to the invention, each of the hydroxybenzyl groups in the compounds of formula I or formula II has an alkoxy group as a substituent and the other three substituents are hydrogen, characterized in that: one of the substituents R 1< , R 2< , R 3< and R 4< is alkoxy and the other three substituents are hydrogen; and one of the substituents R 5< , R 6< , R 7< and R 8< is alkoxy and the other three substituents are hydrogen; and one of the substituents R 9< , R 10< , R 11< and R 12< is alkoxy and the other three substituents are hydrogen.

[0012] In a further preferred embodiment, the alkoxy groups in each of the hydroxybenzyl groups in the compounds of formula I or formula II are all either on the ortho-, meta- or the para-position substituted with alkoxy.

[0013] Particularly preferred according to the invention are therefore compounds according to formula I or formula II, wherein R 1< is alkoxy and R 2< , R 3< and R 4< are hydrogen; and R 5< is alkoxy and R 6< , R 7< and R 8< are hydrogen; and R 9< is alkoxy and R 10< , R 11< and R 12< are hydrogen; or R 2< is alkoxy and R 1< , R 3< and R 4< are hydrogen; and R 6< is alkoxy and R 5< , R 7< and R 8< are hydrogen; and R 10< is alkoxy and R 9< , R 11< and R 12< are hydrogen; or R 3< is alkoxy and R 1< , R 2< and R 4< are hydrogen; and R 7< is alkoxy and R 5< , R 6< and R 8< are hydrogen; and R 11< is alkoxy and R 9< , R 10< and R 12< are hydrogen; or R 4< is alkoxy and R 1< , R 2< and R 3< are hydrogen; and R 8< is alkoxy and R 5< , R 6< and R 7< are hydrogen; and R 12< is alkoxy and R 9< , R 10< and R 11< are hydrogen.

[0014] It is particularly preferred if the alkoxy groups in each of the hydroxybenzyl groups in the compounds of formula I or formula II are all substituted with alkoxy at the meta position. In a particularly preferred embodiment of the invention, therefore: R 2< is alkoxy and R 1< , R 3< and R 4< are hydrogen; and R 6< is alkoxy and R 5< , R 7< and R 8< are hydrogen; and R 10< is alkoxy and R 9< , R 11< and R 12< are hydrogen;

[0015] This structural modification of the three phenolate groups of the modified DAZA makes it possible to achieve the desired specific biodistribution without the need for a targeting unit. This is because the coordinating alkoxyhydroxybenzyl groups, with their additional alkoxy substituents, easily achieve the desired high liver specificity.

[0016] DAZA in the compounds of formula I and II according to the invention is, except for the three hydroxybenzyl groups, exclusively substituted by hydrogen. In contrast, the DAZA framework of the compounds disclosed in WO2014198478 A2 has additional substituents other than hydrogen. As a result, specific liver distribution for the substances disclosed in WO2014198478 A2 cannot be guaranteed. The compounds of formula I and II according to the invention are also particularly advantageous because the substances are accessible via a simple synthetic route starting from DAZA. Additional synthetic steps for attaching targeting units are eliminated.

[0017] Due to the absence of substituents other than H on DAZA, no disadvantages with regard to the coordination ability of 68< Ga, 64< Cu, 67< Ga, 111< In or 99m< Tc could be observed in the compounds of the formula I according to the invention - the complexes form in less than 10 min at room temperature, preferably at elevated temperature, and are stable in vivo.

[0018] When R 2< , R 6< and R 10< are substituted by alkoxy, alkoxy is, for example, independently of one another -OC 1-12 alkyl, preferably -OC 1-8 alkyl, particularly preferably -OC 1-6 alkyl or -OC 1-4 alkyl, where the alkyl radical may be unbranched or branched.

[0019] In a further preferred embodiment, the alkoxy substituents are 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< are independently substituted by methoxy, ethoxy, propoxy, butoxy, pentoxy, heptoxy, hexoxy or octoxy, and R 1< , R 3< , R 4< , R 5< , R 7< , R 8< , R 9< , R 11< and R 12< are substituted by hydrogen.

[0020] An advantageous liver distribution was achieved with compounds of formula I and formula II when the hydroxybenzyl groups are each substituted by the same alkoxy group, preferably when R 2< , R 6< and R 10< are substituted by the same alkoxy group. In a preferred embodiment, the hydroxybenzyl groups are particularly preferably substituted by ethoxy at positions R 2< , R 6< and R 10<. In a likewise preferred embodiment, the hydroxybenzyl groups are particularly preferably substituted by methoxy at positions R 2< , R 6< and R 10<. The other substituents of the hydroxybenzyl groups, particularly preferably positions R 1< , R 3< , R 4< , R 5< , R 7< , R 8< , R 9< , R 11< and R 12<, are each substituted by hydrogen.

[0021] The aim of the invention was to further develop the principle of "liver imaging by injection of hepatotropic metal complex solutions" from paramagnetic metals (Gd(III) - MRI) and radioactive metal isotopes as gamma emitters (99m<Tc - SPECT) to metal complexes containing gallium(III) or Cu(III), specifically the radioactive 68<Ga isotope and the radioactive 64<Cu isotope, respectively, which are used as positron emitters in PET / CT imaging. The central challenge lay in the synthesis of a ligand suitable for labeling with 68<Ga, 64<Cu, 67<Ga, 111<In or 99m<Tc, particularly preferably with 68<Ga or 64<Cu, respectively, and simultaneously liver-specific. The ligands EOB-DTPA and EHIDA used in the conventionally used metal complex solutions "Primovist ®< " (Gd-EOB-DTPA) and " 99m< Tc-EHIDA" do not form sufficiently stable 68< Ga complexes 1,21< .Rather, the compounds exhibit rapid degradation under physiological conditions, which is primarily characterized by demetallation (e.g., by the blood protein apo-transferrin). 22< That is so. in vivoThe released 68< Ga ion (e.g., in the form of colloids, tetrahydroxogallate, or in protein-bound form) displays a non-specific distribution in the blood pool and insufficient accumulation of the radioactive component in the liver, which hinders imaging of the liver. High complex stability is therefore essential for its applicability. The synthesis of a suitable ligand for 68< Ga or 64< Cu should, of course, be highly efficient, starting from available starting materials, and in as few steps as possible. This would also allow for easily implemented modifications of the ligand framework, e.g., with regard to functional, lipophilic groups (chain length or positioning of the alkoxy groups on the benzyl ring), thus optimizing the tracer structure and its in vivo Distribution.

[0022] The compounds of formula I according to the invention are generally suitable for labeling with 68< Ga, 64< Cu, 67< Ga, 111< In or 99m< Tc, but especially for labeling with 68< Ga. The 68< Ga complexes of the compounds of formula II, in contrast to the above-mentioned and known ligands EOB-DTPA and EHIDA, do not show any demetallation or decomposition. in vivo. The ligands are stable and can be stored as precursors for labeling with 68< Ga or 64< Cu. Due to the small amounts of substance to be administered, no toxicological side effects are to be expected. The labeling of 68< Ga, 64< Cu, 67< Ga, 111< In, or 99m< Tc for tracer synthesis is carried out using standard radiopharmaceutical methods. The availability of 68< Ge / 68< Ga generators, which are familiar to those skilled in the art, ensures the virtually unlimited availability of, for example, the radionuclide 68< Ga.

[0023] In a particularly preferred embodiment of the invention, the compound of formula I is selected from tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine (TEOHB-DAZA) and tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine (TMeOHB-DAZA) and the corresponding radiolabeled complexes of formula II are selected from: Example No. Connection abbreviation 1 68< Ga[Tris-N,N',N"(4-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 68< Ga-[TEOHB-DAZA] 2 68< Ga[Tris-N,N',N"(4-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 68< Ga-[TMeOHB-DAZA] 3 64<Cu[Tris-N,N',N"(4-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 64< Cu-[TEOHB-DAZA] 4 64< CU[Tris-N,N',N"(4-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 64< Cu-[TMeOHB-DAZA] 5 67< Ga[Tris-N,N',N"(4-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 67< Ga-[TEOHB-DAZA] 6 67< Ga[Tris-N,N',N"(4-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 67< Ga-[TMeOHB-DAZA] 7 111< In[Tris-N,N',N"(4-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 111< In-[TEOHB-DAZA] 8 111< In[Tris-N,N',N"(4-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 111< In-[TMeOHB-DAZA] 9 99m< Tc[Tris-N,N',N"(4-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 99m< Tc-[TEOHB-DAZA] 10 99m< Tc[Tris-N,N',N"(4-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 99m< Tc-[TMeOHB-DAZA]

[0024] Furthermore, the invention provides the following compounds: Bsp. Nr. Verbindung 11 68< Ga[Tris-N,N',N"(3-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 12 68< Ga[Tris-N,N',N"(5-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 13 68< Ga[Tris-N,N',N"(6-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 14 68< Ga[Tris-N,N',N"(3-Methoxy-2-hydroxy-benzyl)-14-diazepan-6-amin] 15 68< Ga[Tris-N,N',N"(5-Methoxy-2-hydroxy-benzyl)-14-diazepan-6-amin] 16 68< Ga[Tris-N,N',N"(6-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 17 64< Cu[Tris-N,N',N"(3-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 18 64< Cu[Tris-N,N',N"(5-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 19 64< Cu[Tris-N,N',N"(6-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 20 64< Cu[Tris-N,N',N"(3-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 21 64< Cu[Tris-N,N',N"(5-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 22 64< Cu[Tris-N,N',N"(6-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 23 67< Ga[Tris-N,N',N"(3-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 24 67< Ga[Tris-N,N',N"(5-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 25 67< Ga[Tris-N,N',N"(6-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 26 67< Ga[Tris-N,N',N"(3-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 27 67< Ga[Tris-N,N',N"(5-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 28 67< Ga[Tris-N,N',N"(6-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 29 111< In[Tris-N,N',N"(3-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 30 111< In[Tris-N,N',N"(5-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 31 111< In[Tris-N,N',N"(6-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 32 111< In[Tris-N,N',N"(3-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 33 111< In[Tris-N,N',N"(5-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 34 111< In[Tris-N,N',N"(6-Methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 35 99m< Tc[Tris-N,N',N"(3-Ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amin] 36 99m<Tc[Tris-N,N',N"(5-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 37 99m<Tc[Tris-N,N',N"(6-ethoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 38 99m<Tc[Tris-N,N',N"(3-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 39 99m<Tc[Tris-N,N',N"(5-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine] 40 99m<Tc[Tris-N,N',N"(6-methoxy-2-hydroxy-benzyl)-1,4-diazepan-6-amine]

[0025] The accumulation of the compounds according to the invention in the liver can be determined in a so-called ovo test, ie in vivo in the incubated ostrich egg. The application of 68< Ga-[TEOHB-DAZA], for example, showed almost exclusive accumulation in the liver of the embryonated ostrich egg.

[0026] The easy accessibility of the ligands TEOHB-DAZA and TMeOHB-DAZA starting from DAZA via an efficient one-pot synthesis (see below), in which only NaBH 4 is used as the reducing agent, is a further advantage of the compounds of the invention. The starting material DAZA is synthesized according to a literature procedure. 23

[0027] In a further aspect, the invention provides pharmaceutical compositions containing a compound of formula I or formula II or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer, or a solvate of such a compound. Preferably, the pharmaceutical composition comprises at least one physiologically acceptable carrier, diluent, adjuvant, and / or excipient.

[0028] As used in the description of the invention and in the claims, the terms "inorganic acid" and "organic acid" refer to mineral acids, including, but not limited to, acids such as carbonic, nitric, hydrochloric, hydrobromic, hydroiodic, phosphoric, perchloric, or sulfuric acid or their acid salts, such as potassium hydrogen sulfate, or suitable organic acids, including acids such as aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic carboxylic acids, and sulfonic acids. Examples include formic, acetic, trifluoroacetic, propionic, succinic, glycolic, gluconic, lactic, malic, fumaric, pyruvic, benzoic, anthranilic, mesylic, fumaric, salicylic, phenylacetic, mandelic, embonic, and methanesulfonic acids.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.

[0029] In a further aspect of the invention, there is provided a radiopharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate of such a compound.

[0030] Preferably, the radiopharmaceutical composition comprises at least one physiologically acceptable carrier, diluent, adjuvant and / or excipient.

[0031] The compounds according to the present invention, preferably the radiolabeled compounds according to formula II provided by the invention, can be administered intravenously in a pharmaceutically acceptable carrier, e.g., in a conventional medium such as an aqueous saline medium or in blood plasma medium or serum as a pharmaceutical composition for intravenous injection. Such a medium may also contain conventional pharmaceutical substances, such as, for example, pharmaceutically acceptable salts for adjusting osmotic pressure, buffers, preservatives, and the like. Preferred media include physiological saline and human serum. A particularly preferred medium is PBS-buffered saline.

[0032] Other suitable pharmaceutically acceptable carriers are known to the person skilled in the art, for example, from Remington's Practice of Pharmacy, 13th Edition and J. of. Pharmaceutical Science & Technology, Vol. 52, No. 5, Sept.-Oct., pp. 238-311.

[0033] According to the invention, the radiolabeled compounds of general formula II are administered either as a neutral composition or as a salt with a pharmaceutically acceptable counterion, as described above, in a single injectable dosage unit. Any of the conventional carriers known to those skilled in the art, such as sterile saline or plasma, preferably PBS-buffered saline, can be used after radiolabeling to prepare the injectable solution for diagnostic imaging of various organs, preferably the liver. Typically, the unit dose to be administered for a diagnostic agent has a radioactivity of about 3.7 MBq to about 37 GBq. According to the invention, the pharmaceutical or radiopharmaceutical compositions have a radioactivity of at least 50 MBq. These are particularly suitable for liver imaging.The volume of solution to be injected at the unit dose ranges from approximately 0.01 ml to approximately 30 ml. For diagnostic purposes following intravenous administration, imaging of the organ or disease may be required. in vivowithin a few minutes. However, if desired, imaging can be performed within hours or even longer after injection into patients. In most cases, a sufficient amount of the administered activity will accumulate in the area to be imaged within about 30 minutes to enable the acquisition of images in imaging procedures. Any conventional imaging procedure for diagnostic purposes can be used according to this invention. The use of the 68<Ga and 64<Cu complexes of formula II in PET / CT imaging is preferred. PET / CT imaging with the 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 list mode. Recording of the early phase (arterial inundation) by application directly to the PET / CT scanner (so-called "early-dynamic PET") is also possible.

[0034] The pharmaceutical or radiopharmaceutical composition according to the invention has a further advantage of high stability. The compositions according to the invention exhibit a stability of at least 98% in human serum or PBS-buffered saline for at least 4 hours. Furthermore, the use of the 67<Ga, 111<In, or 99m<Tc complexes of formula II in imaging by SPECT or SPECT / CT is preferred.

[0035] The compounds of formula II show liver-specific accumulation and are excreted via the intestine and / or gallbladder.

[0036] In a further aspect of the invention, a process for preparing a compound of general formula I is provided. In a preferred embodiment, the process for preparing a compound of general formula I comprises the steps: a) Synthesis of a compound of formula III where R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 7< and R 8< are as defined above; by reaction of a compound of formula IV where R 9< , R 10< , R 11< and R 12< are as defined above, with a compound of formula (V): in the presence of a suitable solvent, such as methanol; and b) reacting the compound of formula III under reductive conditions with a suitable reducing agent, such as NaBH 4 , in the presence of a suitable solvent.

[0037] If alkoxy in the compound of formula I is ethoxy, methanol is preferably used as the solvent in step b) of the preparation process. If alkoxy in the compound of formula I is methoxy, a mixture of methanol and chloroform, preferably in a 1:1 ratio, is preferably used as the solvent in step b) of the preparation process.

[0038] The synthesis of TEOHB-DAZA and TMeOHB-DAZA proceeds via an aminal N,N'-bridged bicyclic precursor of formula III:

[0039] Surprisingly, it was found that in step b) under reductive conditions, the trialkylated product TEOHB-DAZA or TMeOHB-DAZA can be prepared in very good yields from the azacycle functionalized with two 4-alkoxy-2-hydroxybenzyl units (one bound as an aminal, one as an imine). In a preferred embodiment of the invention, the insertion of a C=O or C=N component into one of the two CN bonds of the aminal is carried out, followed by reduction, for example, with the hydride reagent NaBH 4 .

[0040] The reductive cleavage of aminals to the corresponding amines is known in the literature 61-64< , whereby in the known processes the cleavage always occurs between one of the two nitrogen atoms N and the carbon bridge, so that after the reduction of one of the nitrogen atoms N' carries the functional residue of the reduced aminal as the corresponding alkyl substituent, while the second nitrogen atom N adds a proton and is present as R 2 NH. However, it has not yet been reported that a bis-N,N'-alkylated amine structure arises from an N,N'-bridged aminal structure under reductive conditions. This is precisely the case, however, with the process according to the invention. The resulting compounds of formula I were unequivocally proven or identified by means of X-ray crystallography.

[0041] This specific reaction enables, starting with the unprotected 1,4-diazepan-6-amine, the selective alkylation of each of the three nitrogen atoms in the compound of formula I with an alkyl radical via the carbonyl component in a one-pot synthesis, even though two secondary and one primary amino groups are involved. In particular, the alkylation of secondary amines by condensation with aldehydes and other carbonyl components currently only takes place by direct reductive amination in the presence of modified, milder reducing agents such as NaBH(OAc) 3 or NaBH 3 CN. 65< Furthermore, alkylation attempts on such an azacycle, especially when selectivity is desired, such as the monoalkylation of the primary amino group, frequently lead to product mixtures, especially when reacting with standard alkyl bromides, or require the use of protecting groups. 25, 34, 66, 67<

[0042] The tris-N,N',N"-alkylated 1,4-diazepan-6-amines TEOHB-DAZA and TMeOHB-DAZA are formed in the reaction according to the invention in very high yields of 80-90% (calculated with the molar ratio of the 4-alkoxy-2-hydroxybenzyl groups in the precursor - 2 units - and in the product - 3 units). The inventors have succeeded in establishing a new reaction pathway for the efficient, protecting group-free, simple alkylation of all three nitrogen atoms in 1,4-diazepan-6-amine (DAZA), starting from the corresponding carbonyl component. It was also found that the structurally related TOHB-DAZA (tris-N,N',N"-(2-hydroxybenzyl)-1,4-diazepan-6-amine) and TEOHB-DAZA (Tris-N,N',N"-(4-ethoxybenzyl)-1,4-diazepan-6-amine) cannot be isolated using the same method.During the reduction of the corresponding bridged aminals (III), product mixtures of mono-, di-, and trialkylated DAZA and (especially in the case of TEOB-DAZA) aldehyde (IV) are increasingly formed, which are difficult to separate. Selective precipitation of the trialkylated products from methanol, as in the case of TEOHB-DAZA and TMeOHB-DAZA, does not occur.

[0043] In a further aspect, the invention relates to the use of a compound of formula I as a ligand for preparing a 68<Ga or 64<Cu complex according to formula II. Also provided is a process for preparing a compound of formula II from a compound of formula I.

[0044] For this purpose, according to the invention, a compound of formula I is treated with a 68< Ga-containing or a 64< Cu-containing solution at room temperature or higher. The treatment is preferably carried out at 50°C or higher, particularly preferably at 60°C, 70°C, 80°C, 90°C or higher, especially preferably at 100°C. The higher the temperature selected, the shorter the reaction times until the formation of the radioactively labeled complexes, which is particularly advantageous for carrying out imaging procedures, since the radioactively labeled compounds of formula II should be synthesized as shortly as possible before administration to the patient or, if required at short notice, can be provided within a few minutes, for example within 5 minutes, if the reaction is carried out at 100°C.

[0045] The achievable yields of the compounds of formula II also depend on the pH. If 68< Ga is to be incorporated into a ligand of formula I, the treatment of the ligand of formula I with a 68< Ga-containing solution is preferably carried out at a pH of 5.0 or less, more preferably in the range from 3.7 to 5.0, especially preferably in the range from 4.0 to 4.5. If 64< Cu is to be incorporated into a ligand of formula I, the treatment of the ligand of formula I with a 64< Cu-containing solution is preferably carried out at a pH of 4.0 or higher, more preferably in the range from 4.0 to 8.0, especially preferably in the range from 6.0 to 7.0.

[0046] The invention also provides a kit for preparing a radiopharmaceutical preparation, the kit comprising a sealed ampoule containing a predetermined amount of a ligand of the invention according to formula I or a compound of formula II and optionally instructions for using the components of the kit. The present invention also provides a kit for imaging diseases.

[0047] In a further aspect, the invention provides the compounds of formula II or (radio)pharmaceutical compositions comprising a compound of formula II for use in diagnostic methods such as PET / CT imaging.

[0048] The invention further relates to the use of the compounds of formula II for the preparation of a (radio)pharmaceutical composition for diagnostic purposes, for example for imaging methods such as PET / CT. In particular, the compounds of this invention are useful for imaging liver diseases, including but not limited to chronic diseases and tumors of the liver. The compounds of formula II can be used, for example, to image liver diseases selected from liver inflammation (hepatitis), liver cirrhosis (shrunken liver), fatty liver, autoimmune liver diseases such as autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and iron storage disease (hemochromatosis).

[0049] All primary and secondary tumors of the liver and bile ducts can be visualized with the compounds of formula II, e.g. hemangioma, liver adenoma, focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), bile duct adenoma; hepatocellular carcinoma, bile duct carcinoma, cystadenocarcinoma, angiosarcoma and hepatoblastoma, metastases of other tumors, such as colorectal carcinoma; carcinoids from the appendix; breast carcinoma, ovarian carcinoma, lung carcinoma, kidney carcinoma, prostate carcinoma, etc.

[0050] In a further aspect, the invention relates to a treatment method or diagnostic method comprising administering a compound of formula II or a (radio)pharmaceutical composition comprising a compound of formula II to a subject in a therapeutically active amount or in an amount sufficient to perform a diagnostic method. The subject is, for example, an animal, preferably a mammal, or particularly preferably a human.

[0051] Preferred according to the invention is the use or administration of a compound of formula II or a (radio)pharmaceutical composition comprising a compound of formula II for PET / CT imaging of the liver.

[0052] In a particularly preferred embodiment of the invention, a method for obtaining an image of the liver of an animal or a human is provided, the method comprising the following steps: (a) administering to an animal or human a pharmaceutical composition comprising a compound of formula II according to any one of claims 2-9 or 11, (b) performing a PET or PET / CT scan of the treated animal or human; (c) detecting a detectable emission signal from the compound of formula II from the animal or human in question; and (d) generating an image of the detectable signal, thereby obtaining an image of the liver of the animal or human. Examples of implementation 1. Synthesis description

[0053] The synthesis of the compounds of formula I is carried out as shown in Scheme 1. Synthesis of the precursors / Synthesis of 1

[0054] In a round-bottomed flask, 1,4-diazepan-6-amine (65 mg, 0.57 mmol) and 4-methoxy-2-hydroxybenzaldehyde (172 mg, 1.13 mmol) were combined 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 in vacuo dried (205 mg, 0.54 mmol, 94%).

[0055] 1< H-NMR (400.1 MHz, CDCl 3 ): δ = 13.17 (s, wide, 1H), 11.85 (s, wide, 1H), 8.28 (s, 2H), 7.26-7.23 (m, 1H), 7.12 (d, 3 < JH,H = 8.4 Hz, 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).

[0056] 13< C NMR (100.6 MHz, CDCl 3 ): 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.

[0057] MS (ESI pos., CH 3 OH): m / z = 383 ([M] +<, 100%).

[0058] EA [%] (C21 H25 N3 O4 ): C 65.46 (65.78), H 6.72 (6.57), N 11.07 (10.96). Synthesis of the precursors / Synthesis of 2

[0059] In a round-bottomed flask, 1,4-diazepan-6-amine (30 mg, 0.26 mmol) and 4-ethoxy-2-hydroxybenzaldehyde (86 mg, 0.52 mmol) were combined 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 in vacuo dried (100 mg, 0.24 mmol, 94%).

[0060] 1< H-NMR (400.1 MHz, CDCl 3 ): 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).

[0061] 13< C NMR (62.9 MHz, CDCl 3 ): δ = 165.0, 163.4, 163.0, 160.5, 158.5, 132.7, 128.0, 112.3, 107.4, 106.1, 102.3, 101.6, 87.4, 63.8, 63.5, 60.6, 59.1, 50.6, 15.0, 14.8.

[0062] MS (ESI pos., CH 3 OH): m / z = 434 ([M+Na] +< , 100%), 412 ([M+H] +< , 45%).

[0063] EA[%] (C23 H29 N3 O4 ): C 66.90 (67.13), H 7.13 (7.10), N 10.26 (10.21). Synthesis of the ligand TMeOHB-DAZA

[0064] To a solution of 1 (200 mg, 0.52 mmol) in 10 mL of a mixture of methanol and chloroform (1:1) was added portionwise 71 mg (1.89 mmol) of NaBH 4, whereupon the solution decolorized. The reaction solution was stirred for one hour. The solvent was then removed under reduced pressure, and the residue was resuspended in methanol. The solid was filtered, washed with methanol, and then in vacuo dried (163 mg, 0.31 mmol, 60%).

[0065] 1< H-NMR (400.1 MHz, CDCl 3 ): δ = 10.45 (s, wide, 1H), 6.88 (d, 3< JH,H = 8.1 Hz, 2H), 6.52 (d, 3< JH,H = 8.4 Hz, 1H), 6.41-6.35 (m, 5H), 6.27 (dd, 3< JH,H = 8.3 Hz, 2< JH,H = 2.5 Hz, 1H), 3.82 (d, 2< JH,H = 13.4 Hz, 2H), 3.75 (s, 6H), 3.74 (s, 3H), 3.67 (d, 2< JH,H = 13.4 Hz, 2H), 3.37 (s, 2H), 2.98-2.72 (m, 9H).

[0066] 13< C NMR(100.6 MHz, CDCl 3 ): 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.

[0067] MS (ESI pos., CH 3 OH): m / z = 546 ([M+Na] +<, 45%), 524 ([M+H] +<, 100%).

[0068] EA [%] (C 32 H 45 N 3 O 7 · 0.5 MeOH): C 65.58 (65.66), H 7.07 (7.28), N 7.89 (7.79). Synthesis of the ligand TEOHB-DAZA

[0069] To a suspension of 2 (120 mg, 0.29 mmol) in 10 mL of methanol, 22 mg (0.58 mmol) of NaBH 4 were added in portions, whereupon the yellow suspension decolorized within 10 minutes. The resulting solution was stirred for one hour, and the solvent was then concentrated to 5 mL. A white solid precipitated from the methanolic solution overnight, which was filtered, washed with methanol, and then in vacuo was dried (85 mg, 0.15 mmol, 52%).

[0070] 1< H-NMR(400.1 MHz, CDCl 3 ): δ = 6.86 (d, 3< J H,H = 8.1 Hz, 2H), 6.51 (d, 3< J H,H = 8.3 Hz, 1H), 6.40-6.33 (m, 5H), 6.25 (dd, 3< J H,H = 8.3 Hz, 2< J H,H = 2.5 Hz, 1H), 3.96 (q, 3< J H,H = 7.0 Hz, 6H), 3.82 (d, 2< J H,H = 13.4 Hz, 2H), 3.66 (d, 2< J H,H = 13.4 Hz, 2H), 3.35 (s, 2H), 2.98-2.71 (m, 9H), 1.41-1.36 (m, 6H).

[0071] 13< C NMR (100.6 MHz, CDCl 3 ): δ = 160.4, 159.9, 159.2, 158.6, 129.7, 129.2, 114.3, 113.9, 106.4, 105.6, 102.6, 102.6, 63.5, 63.4, 62.5, 58.3, 57.9, 54.6, 49.4, 15.0.

[0072] MS (ESI pos., CH 3 OH): m / z = 588 ([M+Na] +< , 100%), 566 ([M+H] +< , 62%), 438 ([M-(CH 2 -C 6 H 4 O-OC 2 H 5 )+Na] +< , 25%), 416 ([M-(CH 2 -C 6 H 4 O-OC 2 H 5 )+H] +< , 46%).

[0073] EA [%] (C 32 H 45 N 3 O 7 · H 2 O): C 65.49 (65.84), H 7.43 (7.77), N 7.27 (7.20). Radiolabeling of 68< Ga

[0074] The cationically purified 68< Ga eluate (approx. 1600 MBq) from a 68< Ge / 68< Ga generator (TiO 2 , eluted with 0.6M hydrochloric acid) was mixed with 70µL of a solution of TMeOHB-DAZA or TEOHB-DAZA (1 mg / ml in water ultrapur ®< ) / HCl (1 M) / ethanol, 3:1:1) and 2 ml acetate buffer were added. The solution, with a pH value of 3.8-4.0, was heated for 5 min at 100°C. The solution was then loaded onto a preconditioned C8 reversed-phase cartridge (SepPak ®< , C8 Plus), washed with 2 ml water (ad. in.), and the 68< Ga tracer was eluted with 1 ml ethanol (50%). The radiochemical yield was 65-80% (decay corrected). The sample was diluted with PBS (10 ml). The radiochemical purity was determined by radio-TLC and radio-HPLC and was ≥ 99.6%. The activities were determined in a calibrated activity meter. Radiolabeling of X (64<Cu, 67<Ga, 111<In, 99m<Tc)

[0075] An aqueous solution of a compound I is mixed with an aqueous solution of the radiometal X (64<Cu, 67<Ga, 111<In, 99m<Tc) containing an activity of 1 MBq-100 GBq in a pH range of 2-12, together with suitable additives or auxiliaries such as buffers, reducing agents (e.g. SnCl 2 ), stabilizers, emulsifiers, etc. The labeling is carried out, if necessary, by heating to a temperature of up to 100°C for 1 minute up to 12 hours. The solution is then purified, concentrated, buffered, or diluted to obtain a iv have a composition suitable for application. 2. Ostrich egg application and PET / CT examination

[0076] To perform an intravascular injection in an embryonated egg, the first step is to locate an egg membrane vessel. This is done using a high-intensity Schier lamp (Tempo No. 119, Brecker Ltd. & Co. KG, Ruethen, Germany, or Powerlux Eggtester 4.5 VDC, Lyon Technologies Inc., Chula Vista, CA, USA), which illuminates the egg through the eggshell, similar to a diaphanoscopy. After locating a large-caliber vessel, a rectangular piece approximately 2.5 x 5 cm in size is milled from the approximately 2 mm thick eggshell (Dremel ®< 3000, DREMEL Europe - Bosch Powertools BV, Breda, Netherlands). Particular care is taken to ensure the integrity of the inner eggshell membrane, which corresponds to the chorion-allantoic membrane (CAM).

[0077] After removing the eggshell cap, the yolk vessel is punctured with a thin 27G cannula – again using the cannula light – and secured to the eggshell with adhesive tape. Through the access thus created, both CT contrast agent and radiopharmaceuticals can be injected via a small plastic tube (Smiths Medical™< 800 / 100 / 100 Smiths, Smiths Medical International Ltd, Ashford, Great Britain). To prevent obstruction by refluxing and coagulating blood, the tube is flushed with heparin.

[0078] The tracers 68< Ga[ produced according to the described procedure TMeOHB-DAZA ] and 68< Ga[ TEOHB-DAZA ] in PBS solution were injected through the access (approximately 10 MBq each, in 0.3-0.8 ml), and the access was immediately flushed with 1 ml of isotonic saline (0.9%). The application took place at the start of the PET scan in list mode. Summary of the results of the implementation examples

[0079] The compounds of formula I, TEOHB-DAZA and TMeOHB-DAZA, are ligands suitable for labeling with 68< Ga and 64< Cu. In contrast to the known ligands EOB-DTPA and EHIDA, the 68< Ga complexes do not exhibit demetallation or decomposition. in vivo. The ligands are stable and can be stored as precursors for labeling with 68< Ga or 64< Cu. Due to the small amounts of substance administered, no toxicological side effects are to be expected. The labeling of 68< Ga or 64< Cu for the synthesis of the complex is carried out according to standard radiopharmaceutical methods. The application of 68< Ga-[TEOHB-DAZA] in the embryonated ostrich egg ( in vivo in the incubated egg) shows an almost exclusive accumulation in the liver. The easy accessibility of the ligands TEOHB-DAZA and TMeOHB-DAZA starting from DAZA via an efficient one-pot synthesis, using only NaBH4 as a reducing agent, is a further advantage. References

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Claims

1. A compound according to general formula I or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate thereof, including a radiolabeled complex thereof, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are selected independently of one another from hydrogen and alkoxy, characterized in that one of substituents R1, R2, R3 and R4 is alkoxy and the other three substituents are hydrogen; and one of substituents R5, R6, R7 and R8 is alkoxy and the other three substituents are hydrogen; and one of substituents R9, R10, R11 and R12 is alkoxy and the other three substituents are hydrogen.

2. Compound according to claim 1, wherein the radiolabeled complex consists of a compound of formula I and a radioisotope selected from the group comprising 68Ga, 64Cu, 67Ga, 111In and 99mTc, or is a complex according to general formula II: or a pharmaceutically acceptable salt of an inorganic or organic acid, a hydrate, a stereoisomer or a solvate thereof, where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined in claim 1, and where X is selected from 68Ga, 67Ga and 111In.

3. Compound according to either of claims 1 or 2, where R1 is alkoxy and R2, R3 and R4 are hydrogen; and R5 is alkoxy and R6, R7 and R8 are hydrogen; and R9 is alkoxy and R10, R11 and R12 are hydrogen; or R2 is alkoxy and R1, R3 and R4 are hydrogen; and R6 is alkoxy and R5, R7 and R8 are hydrogen; and R10 is alkoxy and R9, R11 and R12 are hydrogen; or R3 is alkoxy and R1, R2 and R4 are hydrogen; and R7 is alkoxy and R5, R6 and R8 are hydrogen; and R11 is alkoxy and R9, R10 and R12 are hydrogen; or R4 is alkoxy and R1, R2 and R3 are hydrogen; and R8 is alkoxy and R5, R6 and R7 are hydrogen; and R12 is alkoxy and R9, R10 and R11 are hydrogen.

4. Compound according to claim 1, wherein the compound is selected from tris-N, N', N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine and tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine.

5. Compound according to claim 2, wherein the compound is selected from 68Ga[tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 68Ga[tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111IN[tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111IN[tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(4-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(4-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 68Ga[tris-N,N',N"(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 68Ga[tris-N,N',N"(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 68Ga[tris-N,N',N"(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 68Ga[tris-N,N',N"(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 66Ga[tris-N,N',N"(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 66Ga[tris-N,N',N"(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 64Cu[tris-N,N',N"(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 67Ga[tris-N,N',N"(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 111In[tris-N,N',N"(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(3-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(5-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(6-ethoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(3-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(5-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine] 99mTc[tris-N,N',N"(6-methoxy-2-hydroxybenzyl)-1,4-diazepan-6-amine]6. Pharmaceutical or radiopharmaceutical composition comprising a compound of formula I or formula II according to any of claims 1 to 5, optionally in combination with one or more pharmaceutically acceptable diluents or carriers.

7. Use of a compound according to claim 1 or claim 4 as a ligand for the production of a 68Ga, 64Cu, 67Ga, 111In or 99mTc complex according to either of claims 2 or 5.

8. Compound according to any of claims 2 to 5 or the pharmaceutical or radiopharmaceutical composition according to claim 6 for use in liver imaging.

9. Kit for preparing a radiopharmaceutical preparation, wherein the kit comprises a sealed ampule which contains a predetermined amount of a compound of formula I or the compound of formula II according to any of claims 1 to 5 and optionally instructions for use of the components of the kit.

10. Process for preparing a compound of general formula I according to any of claims 1 and 2 to 4, comprising the steps of a) synthesizing a compound of formula III where R1, R2, R3, R4, R5, R6, R7 and R8 are as defined in any of claims 1 to 3; by reacting a compound of formula IV, where R9, R10, R11 and R12 are as defined in any of claims 1 to 3, with a compound of formula (V): in the presence of a suitable solvent, such as methanol; and b) reacting the compound of formula III under reductive conditions with a suitable reducing agent, such as NaBH4, in the presence of a suitable solvent.

11. Process for preparing a compound of general formula II according to any of claims 2 to 5, comprising treating a compound of formula I with a 68Ga-containing solution at a pH of 5.0 or less; or a 64Cu-containing solution at a pH of 4.0 or higher.

12. Process according to claim 11, wherein the process is performed at 50°C or higher, preferably 80°C or higher, more preferably at 100°C.

13. Compound according to any of claims 2 to 3 and 5 or the pharmaceutical or radiopharmaceutical composition according to claim 6 for use in a process for obtaining an image of the liver of an animal or a human, wherein the process comprises the following steps: (a) administering, to an animal or a human, a pharmaceutical composition comprising a compound of formula II according to any of claims 2 to 3 or 5, (b) performing a PET or PET / CT scan of the animal or human being treated; (c) detecting a detectable emission signal from the compound of formula II from the relevant animal or human; and (d) generating an image of the detectable signal, as a result of which an image of the liver of the animal or human is obtained.

14. Pharmaceutical composition according to claim 6, wherein the composition has an activity of at least 50 MBq.