Compounds comprising a 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane unit

Abstract

The invention relates to a compound of general formula (I), wherein A is selected from the group consisting of (II) and a six-membered aromatic ring, which optionally contains a heteroatom selected from the group consisting of N, S, or O; n is 0, 1, 2, or 3; m is 1 or 2; Y is an ethyl or propyl group.

Description

Description Compounds containing a 4,4,5,5-tetraalkyl-l,3,2-dioxaborolane unit

[0001] The invention relates to compounds containing a 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane unit, in particular compounds containing a 4,4,5,5-tetraethyl-1,3,2-dioxaborolane unit and compounds containing a 4,4,5,5-tetrapropyl-1,3,2-dioxaborolane unit. The invention further relates to a process for synthesizing these compounds. It further relates to the use of these compounds for producing radiolabeled compounds.

[0002] A 4,4,5,5-tetraalkyl-l,3,2-dioxaborolane unit is a heterocyclic group with five ring atoms: one boron atom, two oxygen atoms, and two carbon atoms. The two carbon atoms are each substituted by two alkyl groups. The best-known representative of a 4,4,5,5-tetraalkyl-l,3,2-dioxaborolane unit is a 4,4,5,5-tetramethyl-l,3,2-dioxaborolane group. It is also called a pinacolborane group or -Bpin group. Further examples of a 4,4,5,5-tetraalkyl-l,3,2-dioxaborolane unit are a 4,4,5,5-tetraethyl-l,3,2-dioxaborolane unit, also referred to as -B(Epin), and a 4,4,5,5-tetrapropyl-l,3,2-dioxaborolane unit, also referred to as B(Ppin).

[0003] Oka et al. disclose compounds containing a -B(epin) group. The group is bonded to an aryl or heteroaryl group. 34

[0004] Radiolabeled compounds are used primarily in the medical field. For this purpose, they are referred to as radiopharmaceutical compounds or radiopharmaceuticals. Of particular medical relevance are radiopharmaceuticals used in positron emission tomography (PET). These radiopharmaceuticals are also referred to as radiotracers.

[0005] Positron emission tomography is a diagnostic non-invasive imaging device combined with MRI or CT imaging devices in in nuclear medicine, which is intended to enable high-precision hybrid real-time visualization of metabolic processes. 1 ' 6 The predominant radionuclide for PET imaging experiments is fluorine-18, which has advantageous physical characteristics including an optimal half-life (109.7 min), a favorable decay mode (97% ß +decay) and a low positron energy (0.635 MeV). Fluorine-18 is therefore an ideal radionuclide for in vivo imaging experiments, multistep radiosynthesis, and radiotracer delivery.

[0006] 2-[ 18 F]Fluoro-2-deoxy-D-glucose ([ 18 [F]FDG) is the predominant 18F-labeled radiotracer in nuclear medicine. It is used to visualize various cancers using PET. 7 Apart from [ 18 F]FDG was only a relatively small number of 18 F-labeled radiopharmaceuticals approved for routine patient use in clinics. 8 ' 9

[0007] Radiopharmaceuticals are produced by radiolabeling a precursor compound. However, radiolabeling reactions have practical limitations that require special attention. In particular, when working with radionuclides, radiochemical reactions must proceed rapidly to minimize product losses due to radioactive decay. Furthermore, the commitment to ensuring safe production methods requires that radiochemical reactions take place behind protective lead shielding to avoid radiation exposure to personnel. Therefore, the majority of clinical PET radiotracers are performed in automated radiosynthesis machines.

[0008] A further obstacle is that standard halogenation chemistry methods from organic synthesis are hardly transferable to radiohalogen reactions. This is due in particular to the different reactivity of radiohalogens (e.g., fluorine-18) at lower concentrations. Efficient radiohalogenation techniques for the production of radiotracers are therefore of great importance to the radiopharmaceutical industry and are urgently sought after.

[0009] To date, numerous radiohalogenation techniques have been described in the literature, such as the “late-stage radiofluorination” reaction protocols. 10-22In late-stage radiofluorination processes, the fluorine-18 radionuclide is used in the final steps of a radiopharmaceutical synthesis to reduce losses of radiolabeled compounds due to radioactive decay. Most late-stage radiofluorination processes require high reaction temperatures, the presence of metal-containing compounds, and organic solvents to achieve rapid radiofluorination rates.

[0010] Copper-mediated radiohalogenation (CMRH) reactions are promising radiolabeling methods for the production of radiopharmaceuticals. These reactions are also referred to as CMRH reactions. Scheme P1 illustrates some relevant applications of CMRH reactions using arylboronic acid or arylboronic acid pinacol esters as radiolabeling precursors. Cu(OTf)2, [ 1S F]KF, pyridine Makaravage et al. DMA, 140 °C, 30 min 2016 Cu2O / 1,10-phenanthroline, [ 131 l]Nal Wilson et al. MeCN, 25 °C, 1 h 2016 [Cu(OTf)2(py)4], [ 125 l]Nal / [ 211 At]NaAt Reilly et al. MeOH / MeCN, 25 °C, 10 min 2018 Mixdorf et al. 2023 phenanthroline, MeOH / H2O, RT, 30 min x = C or N ) Scheme P-1 Scheme P-1 illustrates the time sequence of important copper-mediated halogenation and radiohalogenation reactions. "Me" denotes a methyl group, and "RT" denotes room temperature.

[0011] An important example of a CMRH reaction is the production of 6-[ 18 F]Fluoro-L-DOPA ([ 18 F]FDOPA). ([ 18F]FDOPA) is a radiopharmaceutical routinely used in hospitals and clinics for imaging related to Parkinson's disease, brain tumors, and focal hyperinsulinism in infancy using PET (Scheme P-2). Scheme P-2 Scheme P-2 shows the preparation of [ 18 F]FDOPA via CMRH according to cGMP guidelines. 23 The term “Boc” denotes a tert-butyloxycarbonyl group, the term “MOMO” denotes a methoxymethyl ether group and the term “'Bu” denotes a tert-butyl group.

[0012] Recently, Scott et al. disclosed the automated production of [ 18 F]FDOPA, which is suitable for human applications according to cGMP guidelines (cGMP = Good Manufacturing Practice). 23 This CMRH protocol can also be used to produce 18 F-labeled amino acids and flumazenil can be used. 24 ' 25

[0013] Despite the advantages of CMRH reactions, such as high efficiency and high stability of the radiolabel, arylboronic acid groups and arylboronic acid ester groups, as the main reactive structural elements of the precursors, are often sensitive to typical synthesis and purification conditions, making the preparation of such precursors difficult. Oka et al. illustrate the instability of aryl-Bpin-substituted compounds compared to aryl-B(epin)-substituted compounds in the figure accompanying the abstract. 34

[0014] These practical challenges often prevent the preparation of precursors and thus the application of CMRH reactions. For this reason, several methods have been proposed to improve synthesis strategies toward radiolabeled precursor preparations. 26However, the substantial synthetic effort required to produce a large number of ultimately redundant precursors remains. Therefore, the introduction of more stable and thus more easily accessible precursors for CMRH reactions would significantly facilitate the development of PET radiotracers from a practical and clinical perspective.

[0015] In addition to radiofluorination with fluorine-18, the radioactive labelling of compounds via radioiodination with 123 I, 124 I, 125 I, and 133 I is of great importance. Radioiodinated compounds are currently used in clinical practice for PET and SPECT imaging and therapeutic applications, 27 ' 28 SPEC stands for single-photon emission computed tomography. Due to the diverse applications of radioiodinated compounds and their well-defined chemical properties, these compounds are of great importance in nuclear medicine. 29 '31 Furthermore, the application of radioiodinated compounds is likely to have a significant impact on drug development. Recently, late-stage CMRH reactions of arylboronic acids and arylboronic acid esters have been used to deliver a range of compounds radiolabeled with iodine-131 and iodine-125, respectively (Scheme P1). 32-33

[0016] Another radiohalogen of particular interest in the field of nuclear medicine is astatine-211 ([ 211 At]), which is a -emitting radionuclide suitable for targeted alpha therapy (TAT) applications. 33 Due to the higher linear energy transfer and shorter path of α-particles compared to β-emitting radiopharmaceuticals currently used in endoradiotherapy (e.g. [ 177Lu]Lu-PSMA-617), TAT can be used as an alternative or in addition to existing therapeutic and / or diagnostic applications.

[0017] In the production of radiotracers for PET applications, radiohalogenation is usually performed as the final synthetic step by radiohalogenating a precursor. Due to the instability of the boronic acid or Bpin group, the introduction of the boronic acid or Bpin group is only performed in the last synthetic step of the precursor preparation. However, the introduction of the boronic acid or Bpin group is required for CMRH. However, the introduction of the boron substituents in the last step of the precursor synthesis is very demanding and restrictive (see Oka et al., figure in the abstract). 35

[0018] Oka et al. have pointed out the improved stability of aryl-B(epin) compounds compared to aryl-B(pin) compounds. 34However, the use of aryl-B(E-pin) for radiopharmaceutical applications is unknown.

[0019] Stable compounds suitable for copper-mediated radiohalogenation reactions are therefore still desirable.

[0020] The object of the invention is to eliminate the disadvantages of the prior art. In particular, compounds are to be provided that are suitable as precursors for the production of radiolabeled compounds by copper-mediated radiohalogenation reactions.

[0021] This object is achieved by the features of claims 1, 6, 8 and 15. Advantageous embodiments of the inventions emerge from the features of the subclaims.

[0022] According to the invention, a compound of general formula I (Formula 1) provided, in which A is selected from the group consisting of and a six-membered aromatic ring optionally containing a heteroatom selected from the group consisting of N, S, or O; n is 0, 1, 2, or 3; m is 1 or 2; Y is an ethyl or propyl group, wherein when Y is an ethyl group, n is 1, 2 or 3 and R is independently selected at each occurrence from the group consisting of -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, wherein Ri is Cb-G-alkyl, -SO3H, -CN, -NO2, halide, substituted or unsubstituted C2-Ce-alkyl, substituted or unsubstituted C2-Ce-alkoxy and exists, whereby R2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and wherein two R together may form a 5- to 7-membered, substituted or unsubstituted alkyl or heteroalkyl ring; and wherein, when Y is a propyl group, R is independently selected at each occurrence from the group consisting of -H, -OH, -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, where Ri is H or C1-C8 alkyl, -SO3H, -CN, -NO2, halide, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy and the following where R2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and wherein two R together may form a 5- to 7-membered, substituted or unsubstituted alkyl or heteroalkyl ring.

[0023] According to the invention, R.3 is a -CH2-CH2-O- unit. Preferably, a is 0 or 4.

[0024] Preferably, n is 1. Preferably, m is 1. Preferably, both n and m are 1. Preferably, A is a six-membered aromatic ring which contains no or exactly contains a heteroatom selected from the group consisting of N, S, or O. A preferred heteroatom is N. Preferably, A is a benzene ring or a pyridine ring.

[0025] It may be provided that Y is an ethyl group at each occurrence. It may be provided that Y is a propyl group at each occurrence. A compound in which Y is a propyl group at each occurrence is preferred.

[0026] A compound of general formula I in which Y is an ethyl group at each occurrence is a compound having a 4,4,5,5-tetraethyl-1,3,2-dioxaborolane unit. A compound of general formula I in which Y is a propyl group at each occurrence is a compound having a 4,4,5,5-tetrapropyl-1,3,2-dioxaborolane unit.

[0027] In a first embodiment of the invention, the invention is thus directed to a compound of general formula I in which Y is an ethyl group at each occurrence. Such a compound is hereinafter referred to as a B(Epin) compound. In a second embodiment of the invention, the invention is thus directed to a compound of general formula I in which Y is a propyl group at each occurrence. Such a compound is hereinafter referred to as a B(Ppin) compound. First embodiment of the invention: B(Epin) compound

[0028] The first embodiment of the invention is a compound of the general formula IE (Formula IE), where A is selected from the group consisting of and a six-membered aromatic ring optionally containing a heteroatom selected from the group consisting of N, S, or O; n is 1, 2, or 3; ml is 1 or 2; Y is at each occurrence an ethyl group, wherein R is independently selected at each occurrence from the group consisting of -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, wherein Ri is C2-C6 alkyl, -SO3H, -CN, -NO2, halide, substituted or unsubstituted C2-Ce alkyl, substituted or unsubstituted C2-Ce alkoxy and exists, whereby R2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and where two R together may form a 5- to 7-membered alkyl or heteroalkyl ring.

[0029] Preferably, n is 1. Preferably, m is 1. Preferably, both n and m are 1. Preferably, A is a six-membered aromatic ring containing no or exactly one heteroatom selected from the group consisting of N, S, or O. A preferred heteroatom is N. Preferably, A is a benzene ring or a pyridine ring.

[0030] Preferably, R is independently selected at each occurrence from the group consisting of where R2, R3 and a have the meanings given in connection with the general formula I.

[0031] In an alternative to the first embodiment, a compound of general formula IE is provided in which R is independently selected at each occurrence from the group consisting of -H, -OH, -SH, -CO-Ri, -C(O)-O-Ri, -C(O)-Ri, -NH-C(O)-Ri, -NH-Ri, where Ri is H or C1-C6-alkyl, -SO3H, -CN, NO2, halide, substituted or unsubstituted C1-C8-alkyl, substituted or unsubstituted C1-C8-alkoxy, aryl, -O-CH2-aryl. Ri is H or C1-C8-alkyl. All other radicals have the meanings given above in connection with the compound of general formula IE.

[0032] In the alternative, R is preferably selected from the group consisting of -C(O)-H, -NH-C(O)-CH3, phenyl, and -O-CFB-phenyl. Second embodiment of the invention: BIPpin ) compound

[0033] The second embodiment of the invention is a compound of the general formula IP (Formula IP), where A is selected from the group consisting of and a six-membered aromatic ring optionally containing a heteroatom selected from the group consisting of N, S, or O; n is 0, 1, 2, or 3; m is 1 or 2; Y is at each occurrence a propyl group, wherein R is independently selected at each occurrence from the group consisting of -H, -OH, -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, wherein Ri is H or Ci-C6 alkyl, -SO3H, -CN, -NO2, halide, substituted or unsubstituted Ci-Ce alkyl, substituted or unsubstituted Ci-Ce alkoxy and the following where R2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and where two R together may form a 5- to 7-membered alkyl or heteroalkyl ring.

[0034] Preferably, n is 1. Preferably, m is 1. Preferably, both n and m are 1. Preferably, A is a six-membered aromatic ring containing no or exactly one heteroatom selected from the group consisting of N, S, or O. A preferred heteroatom is N. Preferably, A is a benzene ring or a pyridine ring.

[0035] Preferably, R is independently selected at each occurrence from the group consisting of where R2, R3 and a have the meanings given in connection with the general formula I.

[0036] It may be provided that in the compound of general formula IP, R is not H. It may be provided that in the compound of general formula IP, m is not 2.

[0037] In an alternative of the second embodiment, a compound of general formula IP is provided, in which R is independently selected at each occurrence from the group consisting of -C(O)-R1, -NH-C(O)-R1, aryl, and -O-CEE-aryl. R1 is H or C1-C8-alkyl. All other radicals have the meanings given above in connection with the compound of general formula IP.

[0038] In the alternative, R is preferably selected from the group consisting of -C(O)-H, -NH-C(O)-CH3, phenyl, and -O-CEE-phenyl. The compounds of general formula I

[0039] The inventors have found that the compounds of general formula I according to the invention are stable compounds. They are suitable as precursors for the preparation of radioactively labeled compounds, especially radiohalogenated compounds. The compounds of general formula I are particularly suitable for the preparation of radiopharmaceuticals. The compounds of general formula I according to the invention are suitable as precursors or precursor compounds for the preparation of radioactively labeled compounds by copper-mediated radiohalogenation reactions.

[0040] It is not necessary to introduce the 4,4,5,5-tetraethyl-l,3,2-dioxaborolane unit or the 4,4,5,5-tetrapropyl-l,3,2-dioxaborolane unit only in the last process step of the synthesis route for preparing a precursor. Due to their stability, they can be introduced in a previous process step (see Scheme 4). The compounds of general formula I according to the invention can therefore be used as protected intermediates in the synthesis route for the preparation of radioactively labelled compounds. The compounds of general formula I according to the invention can therefore be CMRH reactions can be used to convert radioactively labeled compounds. Known CMRH synthesis methods can be used. A Starting material Intermediate Precursor for radiolabeling B1 OH D B(Epin) steps ( B 'OH B(Epin) R TT J Epin Solvent, RT R r N Starting material protected intermediate precursor for radiolabeling B2 OH B(Ppin) steps B(Ppin) Starting material protected intermediate precursor for radiolabeling Scheme 4 Scheme 4 illustrates the preparation of a precursor for radiolabeling according to the prior art (synthesis route A) and using the compounds of general formula I according to the invention (synthesis route B1 or synthesis route B2). It can be seen that (synthesis route A) provides for borylation in the last process step. The intermediates on the way to the preparation of the precursor are not protected. In contrast, the synthesis routes B1 and B2 allow an earlier introduction of -B(Epin) or -B(Ppin), which, due to the stability of this group, results in stable and thus protected intermediates. Therefore, one or more further process steps can follow after the protected intermediate has been obtained. Scheme 4 shows that the leaving group, i.e.the -B(Epin) or -B(Ppin) group located on the aromatic ring can be introduced earlier in a synthetic route due to the stability of the aryl-B(Epin / Ppin) groups compared to those used in the state of the art. Arylboronic acids or aryl-B(pin) groups. Arylboronic acids or aryl-B(pin) groups are (i) unable to tolerate further reaction steps in the synthetic pathway or (ii) degraded on silicon dioxide, as recognized by Oka et al. To mitigate these stability issues, it is usually necessary to introduce arylboronic acid groups or aryl-B(pin) groups at a later stage in the synthetic pathway. Scheme 4 indicates that the protected intermediate containing an aryl-B(epin) or an aryl-B(pin) group can be implemented earlier rather than later in the synthesis.

[0041] The preparation of a radiohalogenated compound via a CMRH reaction using a compound of general formula I as a precursor offers numerous advantages over known methods for radiolabeling: (i) The compounds of general formula I can be easily prepared from arylboronic acids, (ii) The compounds of general formula I can be used as a precursor to prepare radiohalogenated compounds using the commercially available compound ([Cu(OTf)2(py)4]), (iii) The better stability of the -B(Epin) and -B(Ppin) groups enables a faster development of radiolabeled compounds thanks to the flexibility of the synthesis of the compounds of general formula I. (iv) Different radiohalogen methods can be used to obtain numerous radiolabeled compounds. This is due to the stability of the compounds of general formula I.

[0042] The invention is particularly directed to the compounds listed in Table 1: 22 The compounds listed in Table 1 are compounds of general formula I.

[0043] According to the invention, a process for preparing a compound of general formula I (Formula 1), provided, in which A, Y, R, m and n have the meanings given in claim 1, characterized by reacting compounds of the general formula II (Formula II) worm A, R, m, and n have the meanings given in connection with general formula I, with 3,4-diethylhexane-3,4-diol (Epin) and / or 3,4-dipropylhexane-3,4-diol (Ppin). This process is also referred to below as the first process according to the invention.

[0044] To prepare the compound of general formula IE, the compound of general formula II is reacted with 3,4-diethylhexane-3,4-diol (Epin). To prepare the compound of general formula IE, the compound of general formula II is reacted with 3,4-dipropylhexane-3,4-diol (Ppin).

[0045] The first process according to the invention can be carried out at a temperature in a range between 20 and 120°C, preferably at room temperature. The first process according to the invention can be carried out at ambient pressure. The first process according to the invention can be carried out in a conventional solvent. Preferably, the compound of general formula II is reacted with the 3,4-dialkylhexane-3,4-diol in a molar ratio of 1 to 4 or higher. The term "higher" means that the 3,4-dialkylhexane-3,4-diol can be used in stoichiometric excess.

[0046] According to the invention, a process for preparing a compound of the general formula IX (Formula IX), in which X is a radioactive halide; and A, R, m and n have the meanings given above in connection with the general formula I; characterized by reacting a compound of the general formula I (Formula I), wherein Y, A, R, m and n have the meanings given above in connection with the general formula I; with NaX in a polar solvent in the presence of a Cu-based catalyst, where X is selected from the group consisting of fluorine-18, iodine-123, iodine-124, iodine-125, iodine-131, bromine-76, bromine-77, and astatine-211. This process is also referred to below as the second process according to the invention.

[0047] The second process according to the invention enables the preparation of radiohalogenated compounds. The second process according to the invention provides for the replacement of the 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane unit with the radioactive halide. The 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane unit serves as the leaving group. The groups -B(Epin) and -B(Ppin) have proven to be good leaving groups.

[0048] The second process of the invention can be carried out according to the process conditions known to be used in CMRH reactions.

[0049] The inventors conducted experiments in which compounds of general formula I were radiolabeled with fluorine-18 and iodine-123 using a CMRH reaction (Schemes 5 and 6, reaction A). Radiolabeling can be carried out similarly with astatine-211, bromine-76, and bromine-77 (Scheme 6, reactions B and C). The experiments demonstrate that the problem of precursor instability can be circumvented by using aryl-B(epin) compounds and aryl-B(pin) compounds as intermediates, which facilitates the preparation of precursors (see also Scheme 4). The intermediates are protected intermediates and can be subjected to further reaction steps before radiohalogenation. Scheme 5

[0050] Scheme 5 illustrates radiofluorination of aryl-B(epin) precursors. The radiofluorination reactions are shown in the box. The radiofluorination reactions were carried out under the following reaction conditions: After purification of [ 1 S F] F" using a QMA cartridge, dried [ 18 F]Fluoride (50-1000 MBq) was reacted with the aryl-B(epin) precursor and [Cu(OTf)2(py)4] (1.0 molar eq.) in 800 μl DMA / n-BuOH (4:7) at 110 °C for 5 to 25 min. Radio-HPLC was used to determine the radiofluorination efficiency (RCCHPLC), which was determined by Dividing the integrated product peak area by the integrated 18 F-labeled peaks were calculated in total. Below the box, Scheme 5 shows the determined radiofluorination efficiency values ​​for the radiofluorinated compounds shown there. n denotes the number of experiments performed. Scheme 6

[0051] Reaction A shown in Scheme 6 illustrates the copper-mediated radioiodination of a bromoaryl-B(epin) precursor, reaction B the copper-mediated radioiodination of an aryl-B(epin) precursor, and reaction C the copper-mediated radiobromination of an aryl-B(epin) precursor. In Scheme 6, the notation “Et” denotes an ethyl group, the notation “Me” denotes a methyl group, the notation “RT” denotes the reaction temperature, the notation “ 76 / 77 Br" means either 76 Br or 77 Br.

[0052] Preferably, the Cu-based catalyst is selected from the group consisting of - Tetrakis(pyridine)copper(II)-bis(trifluoromethanesulfonate) ([Cu(OTf)2(Py)4]), - Tetrakis(4-phenylpyridine)copper(II) diperchlorate (Cu(4-PhPy)4(C104)2), - Tetrakis(3,4-dimethylpyridine)copper(II) bis(trifluoromethanesulfonate) (Cu(3,4-Me2Py)4(OTf)2) and - Tetrakis(3,4-dimethylpyridine)copper(II) diperchlorate (Cu(3,4-Me2Py)4(C104)2). A preferred catalyst is [Cu(OTf)2(Py)4].

[0053] Preferably, the second process according to the invention is carried out in a solvent selected from DMF, DMA, MeOH, EtOH, i-PrOH, n-BuOH, or mixtures thereof. DMF denotes dimethylformamide, DMA dimethylacetamide, MeOH methanol, EtOH ethanol, i-PrOH isopropanol, and n-BuOH n-butanol. A mixture of DMA and n-BuOH is a preferred solvent.

[0054] The second process according to the invention can be carried out in the presence of an eluent. The eluent is preferably a pyridinium sulfonate salt of the general formula where R eis selected from the group consisting of H, -N(C1-C4-alkyl)2, and -O-C1-C4-alkyl, and D is selected from the group consisting of OTf and OTs, where OTf denotes trifluoromethanesulfonate and OTs denotes toluenesulfonate. The eluent is particularly preferably dimethylaminopyridinium trifluoromethanesulfonate.

[0055] In a preferred embodiment, the second process according to the invention is carried out in a mixture of DMA and n-BuOH in the presence of [Cu(OTf)2(Py)4] and dimethylaminopyridinium trifluoromethanesulfonate.

[0056] The second process according to the invention can be carried out at room temperature. The second process according to the invention can be carried out at ambient pressure. Preferably, the compound of general formula I is reacted with NaX in a molar ratio of 1:1 or higher. The term "higher" means that the NaX can be used in stoichiometric excess. Preferably, the compound of general formula I is used in a molar ratio of 1:4 to the Cu-based catalyst.

[0057] According to the invention, the use of a compound of general formula I for the production of radiopharmaceuticals is also provided. Details of this use have already been explained in connection with the compound of general formula I and the second process according to the invention. Reference is made to this explanation.

[0058] Finally, according to the invention, a process for the preparation of a radiohalogenated compound is provided, wherein a compound containing a group P (Group P), in which A is a six-membered aromatic ring optionally containing a heteroatom selected from the group consisting of N, S, or O; m is 1 or 2; and Y is an ethyl or propyl group, to a compound containing a group Z (Group Z), in which X is a radioactive halide; and m has the meaning given in connection with group P; is reacted. This process is referred to as the third process of the invention.

[0059] In the third process according to the invention, the group P is replaced by the group Z. Preferably, the group P is bonded in the compound via the unit A. In other words, this means that the 4,4,5,5-tetraalkyl-1,3,2-dioxaborolane unit is bonded to the remainder of the compound containing the group P via the unit A.

[0060] X is preferably selected from the group consisting of fluorine-18, iodine-123, iodine-124, iodine-125, iodine-131, bromine-76, bromine-77 and astatine-211.

[0061] In group P, preferably m is 1. Preferably, both n and m are 1. Preferably, A is a six-membered aromatic ring containing no or exactly one heteroatom selected from the group consisting of N, S, or O. A preferred heteroatom is N. Preferably, A is a benzene ring or a pyridine ring. In one example, the compound having a group P is a compound having a group Pl (Group Pl), where Y and m have the meanings given in connection with the group P. The compound having a group Pl is converted into a compound having a group Zl group Zl, wherein X and m have the meanings given in connection with the group Z. The compound having a group Zl is a compound having a group Z.

[0062] To convert the compound having a P group into a compound having a Z group, the compound having the P group can be reacted with NaX in a polar solvent in the presence of a Cu-based catalyst.

[0063] The third process of the invention enables the preparation of radiohalogenated compounds. The third process of the invention can be carried out under the process conditions known to be used in CMRH reactions.

[0064] Preferably, the Cu-based catalyst is selected from the group consisting of [Cu(OTf)2(Py)4], Cu(4-PhPy)4(C104)2, Cu(3,4-Me2Py)4(OTf)2 and Cu(3,4-Me2Py)4(C104)2. A preferred catalyst is [Cu(OTf)2(Py)4].

[0065] Preferably, the third process according to the invention is carried out in a solvent selected from DMF, DMA, MeOH, EtOH, i-PrOH, n-BuOH, or mixtures thereof. DMF denotes dimethylformamide, DMA dimethylacetamide, MeOH methanol, EtOH ethanol, i-PrOH isopropanol, and n-BuOH n-butanol. A mixture of DMA and n-BuOH is a preferred solvent.

[0066] The third process according to the invention can be carried out in the presence of an eluent. The eluent is preferably a pyridinium sulfonate salt of the general formula where R eis selected from the group consisting of H, -N(Ci-C4-alkyl)2, and -O-C1-C4-alkyl, and D is selected from the group consisting of OTf and OTs. Particularly preferred is the eluent dimethylaminopyridinium trifluoromethanesulfonate.

[0067] In a preferred embodiment, the third process according to the invention is carried out in a mixture of DMA and n-BuOH in the presence of [Cu(OTf)2(Py)4] and dimethylaminopyridinium trifluoromethanesulfonate.

[0068] The third process according to the invention can be carried out at room temperature. The third process according to the invention can be carried out at ambient pressure. Preferably, the compound containing the P group is reacted with NaX in a molar ratio of 1:1 or higher. The term "higher" means that the NaX can be used in stoichiometric excess. Preferably, the compound containing the P group is used in a molar ratio of 1:4 to the Cu-based catalyst.

[0069] The invention enables in particular the production of 18 F-marked and 123I-labeled compounds. The production of PET or SPECT radiotracers can be accelerated due to high radiochemical yields and the flexibility of the precursor synthesis. The synthesis of the precursors is particularly flexible because the 4,4,5,5-tetraalkyl-l,3,2-dioxaborolane unit does not need to be introduced in the last step of the precursor synthesis pathway. The high yields and flexibility make it possible to circumvent many of the challenges associated with PET radiotracer development.

[0070] The preparation of radioiodinated prosthetic groups—intermediate building blocks to be radiolabeled—using the CMRH reactions described herein provides useful alternatives to the groups commonly used in industry. For example, the [ 125 I]SIB reagent (N-succinimidyl-3-[ 125 I]iodobenzoate), [125 I]SIB-maleimide derivative and 125 I-Bolton-Hunter reagent (N-succinimidyl-3-(4-hydroxy-3-[ 125 I]iodophenyl)propionate) can be used for consumer pharmacokinetic and biodistribution studies. 36

[0071] The invention enables the production of radiopharmaceuticals suitable for therapeutic applications, as precursors that are clinically relevant biovectors with promising radiohalogens, such as astatine-211 (β-emitting radionuclide), iodine-131 (β-emitting radionuclide), and bromine-77 (electron-emitting Auger radionuclide), paving the way for a "theranostic" approach. This approach is conceptually similar to [ 177 Lu]Lu-PSMA-617 radioligand therapy. 211 At-labeled prosthetic groups can be used for radioactive labeling. 37

[0072] CMRH reactions of aryl-B(epin)- or aryl-B(Ppin)-substituted radiolabeling precursors enable the simple preparation of radiohalogenated molecules for diagnostic and therapeutic applications. Automation of the CMRH reaction will significantly facilitate the production of radiopharmaceuticals for routine clinical use. In particular, the additional stability of the B(epin) and B(Ppin) groups provides flexibility in the synthesis pathway for radiolabeling precursors, which can accelerate the production of radiopharmaceuticals by minimizing the synthetic effort associated with radiopharmaceutical development.

[0073] The invention is particularly suitable for the preparation of PSMA-targeting radiopharmaceuticals radioactively labelled with fluorine-18 [ 18 F], Iodine-123 [ 123 I] or astatine-211 [ 211 At] are marked, and [ 123 [123I]Ioflupane is clinically used for Diagnosis of Parkinson's disease using SPECT imaging. The production of [ 123 [I]Ioflupane via a radiolabeled aryl-B(Ppin) precursor can enable the production of the clinically approved radiopharmaceutical in high yields. The radiohalogenation process can also enable the production of radiofluorinated and radiobrominated ioflupane derivatives.

[0074] Fibroblast activation protein (FAP) has recently emerged as a suitable biological target found in tumor stromal cells. There is currently a global unmet need for a 18F-labeled FAPI derivative for use in cancer diagnosis using PET imaging. A radiolabeling precursor containing an aryl-B(Ppin) substituent may facilitate the preparation of a 18F-labeled FAPI derivative.

[0075] The term "alkyl," unless otherwise stated, refers in particular to a saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain of 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and most preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, ec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. The alkyl group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0076] The term “heteroalkyl”, unless otherwise stated, refers in particular to an alkyl radical as defined herein wherein one, two or three hydrogen atoms are replaced by a substituent independently selected from the group consisting of -OR a , -NR b R c and -S(O) n R d (where n is an integer from 0 to 2), provided that the point of attachment of the heteroalkyl radical is a carbon atom, where R a is hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; R b and R c independently of each other hydrogen, acyl, alkyl, cycloalkyl or Cycloalkylalkyl; and when n is 0, R d hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and when n is 1 or 2, R dAlkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[0077] The term "cycloalkyl," unless otherwise specified, refers in particular to saturated carbocyclic groups consisting of mono- or bicyclic rings. The cycloalkyl group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof, such as cyclohexenyl, cyclopentenyl, and the like.

[0078] The term "heterocycloalkyl," unless otherwise specified, refers to a saturated cyclic ring having 5 to 12 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms selected from one or more of N, O, and S, and the remaining ring atoms are carbon atoms. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, thiomorpholinyl, dihydroquinolinyl, and 1,4-diazepane. The heterocycloalkyl group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.

[0079] The term "alkoxy," unless otherwise specified, refers in particular to a group of the formula -OR, wherein R is an alkyl group as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The alkoxy group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0080] The term “acyl” refers to a group of the formula -C(=O)R, where R is alkyl as defined herein.

[0081] The term “halogen” refers, unless otherwise specified, to fluorine, chlorine, bromine, iodine, or astatine. The term fluorine may include the non-radioactive isotope 19 F or the radioactive isotope 18 F. The term iodine can denote the non-radioactive isotope127 I or the radioactive isotopes 123 I, 124 I, 125 I or 131 I. The term astatine can refer to the non-radioactive isotope 210 At or the radioactive isotope 211 At. The term bromine can refer to the non-radioactive isotope 79 Br or the radioactive isotopes 76 Br or 77 Br denote.

[0082] Unless otherwise stated, the term "aryl" refers to a cyclic, aromatic hydrocarbon group consisting of or having a mono- or bicyclic aromatic ring system with 5 to 10 ring atoms, preferably 5 or 6 ring atoms. The aryl group may optionally be a substituted aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, naphthalenyl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenyl sulfidyl, diphenyl sulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. The term "substituted aryl group" refers in particular to an aryl group, which is optionally independently substituted by one to four substituents, preferably one or two substituents, selected from hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.

[0083] The term "alkylene" refers in particular to a divalent saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like. The alkylene group may optionally be substituted with one or more substituents, each substituent independently being alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino.

[0084] The term “substituted” may, unless otherwise indicated, refer to, for example, a substituent which is alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino.

[0085] The invention is explained in more detail below using examples which are not intended to limit the invention. The figures, which serve the same purpose, show Fig. 1 four thin layer chromatograms demonstrating the stability of aryl-B(epin) compounds and aryl-B(Ppin) compounds; Fig. 2 is a diagram demonstrating the solvent stability of aryl-B(epin) compounds and aryl-B(Ppin) compounds; Fig. 3 is a UHPLC chromatogram showing the radiochemical conversion of an aryl-B(epin) compound under radiofluorination conditions in the presence of 10 l of water at 120 °C after 30 min; and Fig. 4 Thin layer chromatograms demonstrating the stability of aryl-B(epin) compounds and aryl-B(Ppin) compounds. Example 1 Production of radiotracers 104a, 104b and 104c

[0086] The preparation of radiotracers 104a, 104b, and 104c is shown in Schemes B1 and B-2. Radiotracer 104a corresponds to formula 104, where Z 18 F. The radiotracer 104b corresponds to formula 104, in which Z 123 I. The radiotracer 104c corresponds to formula 104, in which Z 211 At is. Radiotracers 104a, 104b, and 104c are PSMA radiotracers (PSMA = prostate-specific membrane antigen). In Schemes B1 and B2, Bu' denotes a tert-butyl group.

[0087] Compound 101 is commercially available. It is reacted with compound 102 to yield compound 103 (Scheme B1). Compound 102 can be prepared according to the first process of the invention. The reaction is carried out in the presence of K2CO3 in DMF for 4 to 12 hours at 23 to 70°C. Compounds 102 and 103 are compounds of the invention of general formula I. Compound 103 is the precursor for radiolabeling. 101 103 Schema Bl

[0088] For radiolabelling, compound 103 is subjected in a first step (step A) to a copper-mediated radiohalogenation reaction and then in a second step (step B) to an acidic deprotection to give compound cation 104a, 104b, or 104c (Scheme B-2). The copper-mediated radiohalogenation reaction can be carried out according to the reaction conditions specified in connection with the second process of the invention. Deprotection can be carried out under reaction conditions generally known for such a reaction. 103 104 Scheme B-2 a) Synthesis of compound 102

[0089] The synthesis of compound 102 (2-(4-(bromomethyl)phenyl)-4,4,5,5-tetrapropyl-l,3,2-dioxaborolane) is described below.

[0090] 2 mL of CH2Q2 was placed in a 10 mL one-neck flask under an argon atmosphere. 4,5-Dipropyloctane-4,5-diol (Ppin, 276 mg, 1.20 mmol, 1.2 eq.), (4-(bromomethyl)phenyl)boronic acid (215 mg, 1.00 mmol, 1.0 eq.), and Na2SC>4 (284 mg, 2.00 mmol, 2.0 eq.) were added sequentially. The suspension was warmed and refluxed overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel containing ethyl acetate (EtOAc) and washed with water. The phases were separated, and the aqueous phase was washed three times with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and the solvent was removed in vacuo. After adsorption on silica gel, the crude product was purified by column chromatography on Silica was purified using a Biotage Select system (mobile phase: ethyl acetate in cyclohexane 0% to 20%). The product was obtained as a colorless oil. Yield: 288 mg (70%).

[0091] 'H-NMR (400 MHz, CDCh) 5 7.78 (d, J = 7.6 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H), 4.49 (s, 2H), 1.73 - 1.56 (m, 8H), 1.54 - 1.41 (m, 4H), 1.41 - 1.25 (m, 4H), 0.93 (t, J = 7.2 Hz, 12H). 13 C-NMR (101 MHz, CDCh) 5 140.63, 135.43, 128.41, 88.73, 37.20, 33.54, 17.81, 14.96. b) Synthesis of compound 103

[0092] The synthesis of compound 103 (Di- / c / 7-butyl((CS')- l -(lerl-butoxy)-l-oxo-6-((4-(4,4,5,5-tetrapropyl-l,3,2-dioxaborolan-2-yl)benzyl)amino)hexan-2-yl)carbamoyl)-Z-glutamate) is described below.

[0093] Di- / c 7-butyl (((k)-6-amino- 1-( / c77-butoxy)- 1-oxohexan-2-yl)carbamoyl)-Z-glutamate (50.0 mg, 103 mol, 1.0 eq.) was dissolved in 1.0 mL of acetonitrile in a 10 mL one-neck flask under argon. 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetrapropyl-1,3,2-dioxaborolane 102 (46.2 mg, 113 pmol, 1.1 eq.) and K2CO3 (17.0 mg, 123 pmol, 1.2 eq.) were added, and the reaction mixture was stirred at 80 °C for 17 h. The solvent was removed under vacuum, and the crude product was purified by HPLC. The product was obtained as a white solid. The yield was 23.5 mg (28%).

[0094] Rt: 13.00 min on an RP-HPLC, analytical (Agilent Zorbax 300 C-18.5 pm, 4.6 x 150 mm) with 10-95% acetonitrile (0.1% trifluoroacetic acid) in H2O (0.1% trifluoroacetic acid), 1 min isocratic, then with a linear gradient over 14 min, 1 ml / min. MS (HR-ESI + ): Exact mass calculated for [M + H] + : m / z = 816.5903; measured: m / z = 816.592. Example 2 Production of radiotracer 106

[0095] Scheme B-3 illustrates the preparation of compound 106. Compound 106 is a [ 123 I]Ioflupane. [ 123 [I]Ioflupane is a radiotracer. Starting material for the Preparation of compound 106 is compound 105. Compound 105 is a compound of the invention of general formula I. For radiolabeling, compound 105 is subjected in one step (step A) to a copper-mediated radiohalogenation reaction to obtain compound 106. The copper-mediated radiohalogenation reaction can be carried out according to the reaction conditions specified in connection with the second process of the invention. Scheme B-3 Example 3 Production of radiotracer 108

[0096] Scheme B-4 illustrates the preparation of compound 108. Compound 108 is a radiopharmaceutical used as an inhibitor for the fibroblast activation protein (FAPI). The starting material for the preparation of compound 108 is compound 107. Compound 107 is a compound according to the invention of general formula I. For radiolabeling, compound 107 is subjected to a copper-mediated radiohalogenation reaction in one step (step A) to obtain Compound 108. The copper-mediated radiohalogenation reaction can be carried out according to the reaction conditions specified in connection with the second process of the invention. 108 Scheme B-4 In compounds 107 and 108, R3 has the meanings given in connection with the general formula I and a is 1, 2, 3 or 4. Example 4 General procedure for the production of radiolabeled arenes by copper-mediated radiofluorination (CMRF)

[0097] Copper-mediated radiofluorination (CMRF) is an embodiment of copper-mediated radiohalogenation reactions (CMRH), in which radiohalogenation with [ 18 F]-fluoride to obtain a radiofluorinated compound of general formula I. The precursor to be subjected to radiofluorination is a compound of general formula I.

[0098] The copper-mediated radiofluorination began with the adsorption of [ 18 F]Fluoride (50-10,000 MBq) on an anion exchange resin (QMA light carbonate cartridge, Waters Corp.), followed by washing with dry methanol (MeOH, 0.7 ml) from the male side and elution of 18F with a solution of 3.0 mg (9.6 mmol) of benzyltributylammonium chloride (BnBuaNCl) in 0.7 mL of methanol from the female side. The methanolic solution was removed in vacuo at 70 °C for 5 min. The precursor (10 mmol) in 1.2 mL of l,3-dimethyl-2-imidazolidinone / z-butanol (2:1, vol. 1 vol.) was added to the cooled reaction vessel and allowed to react for 30 min at 120 °C with stirring. The reaction mixture containing the crude radiofluorinated products was quenched with 2 mL of FLO and analyzed using analytical radio-UHPLC for product identification and determination of the radiochemical conversion (RCC). The RCC determination was performed after quenching the reaction mixture, for which an aliquot (5-20 ml) of the crude reaction mixture was taken and the mixture was added to a sample (50-200 ml) of EEO / acrylonitrile (1:1, vol.) and analyzed using radio-UHPLC.The RCC value was determined by integrating the peak area of ​​the radiolabeled product, dividing this value by all integrated peak area values, and multiplying the value by 100. Unless otherwise stated, each experiment was performed in triplicate. "UHPLC" refers to ultra-high performance liquid chromatography. The precursor to be radiofluorinated is a compound of general formula I. Example 5 General procedure for the production of radiolabeled arenes using copper-mediated radioiodination (CMRF)

[0099] Copper-mediated radioiodination (CMRI) is an embodiment of copper-mediated radiohalogenation (CMRH) reactions, in which radiohalogenation with [ 123 I] iodide to obtain a radioiodinated compound of general formula I.

[0100] CMRI was performed according to the method described by Wilson, T., et al.

[0032] . The substrate scope was screened in duplicate for each substrate by adding 0.5-2 MBq [ 123 [I]Iodide in 0.02 M NaOH (1 mL) was added to a solution of the precursor in acetonitrile (20 mL, final concentration 0.8 mM) and [Cu(OTf)2(py)4] in methanol (40 mL, final concentration: 4 mM). The reaction mixture was allowed to react without stirring for 10 min at room temperature. The solution was then diluted with 200 mL of EEO / acetonitrile (1:1, v / v). The reaction mixture was analyzed by radio-HPLC (gradient C 30 min), and identification was performed by coinjection with the authentic non-radioactive reference at a concentration of 100 mg / mL. Example 6

[0101] The connections [ 18 F]55 to [ 18F]72 were prepared according to the general procedure described in Example 4. For this purpose, a compound of general formula P-2 or P-3 is subjected to radiofluorination to obtain a compound of general formula Z-2. The reaction is shown in Schemes B-5 and B-6. P-3 Z-2 Scheme B-6

[0102] Example 6 serves particularly to illustrate the third process according to the invention. Compound P-2 is an example of a compound having a group Pl, where Y is ethyl and m is 1. Compound P-3 is a Example of a compound having a group Pl, where Y is propyl and m is 1. Compound Z-2 is an example of a compound having a group Zl, where X 18F is and m is 1. In compounds P-2, P-3, and Z-2, R has the meaning given in Table 2. Table 2 shows the radiochemical conversion (RCC) values ​​achieved in percent. RCCp-2 refers to the radiochemical conversion obtained when compound P-2 is used as the precursor. RCCp-3 refers to the radiochemical conversion obtained when compound P-3 is used as the precursor. Table 2 Example 7

[0103] The connections [ 18 F]36 to [ 18 F]54 were prepared according to the general procedure described in Example 5. For this purpose, a compound of general formula P-2 or P-3 is subjected to radioiodination to obtain a compound of general formula Z-3. The reaction is shown in Schemes B-7 and B-8. P-3 Z- Scheme B-8

[0104] Example 7 serves particularly to illustrate the third process according to the invention. Compound P-2 is an example of a compound having a group Pl, where Y is ethyl and m is 1. Compound P-3 is an example of a compound having a group Pl, where Y is propyl and m is 1. Compound Z-3 is an example of a compound having a group Zl, where X 123 I is and m is 1. In compounds P-2, P-3, and Z-3, R has the meaning given in Table 3. Table 3 shows the radiochemical conversion (RCC) values ​​achieved in percent. RCCp-2 refers to the radiochemical conversion obtained when compound P-2 is used as the precursor. RCCp-3 refers to the radiochemical conversion obtained when compound P-3 is used as the precursor. Table 3 Example 8 Stability of aryl-B(epin) compounds and aryl-B(ppin) compounds a) Thin layer chromatography

[0105] To demonstrate the stability of aryl-B(epin) compounds and aryl- B(Ppin) compounds, the compounds shown in Fig. 1 were investigated by thin layer chromatography. A mixture of cyclohexane and ethyl acetate in a volume ratio of 4 : 1 was used as the eluent. A mixture of Cyclohexane and ethyl acetate is a solvent commonly used for purifying compounds.

[0106] In Fig. 1, the designation “Ph” denotes a phenyl group, the designation “B(pin)” denotes a 4,4,5,5-tetramethyl-l,3,2-dioxaborolane unit, the designation “B(Epin)” denotes a 4,4,5,5-tetraethyl-l,3,2-dioxaborolane unit, and the designation “B(Ppin)” denotes a 4,4,5,5-tetrapropyl-l,3,2-dioxaborolane unit. It can be seen in Fig. 1 that aryl-B(Epin) compounds and aryl-B(Ppin) compounds are more stable than compounds that have a B(OH)2 unit or a B(pin) unit instead of the B(Epin) unit or the B(Ppin) unit. The stability of the aryl-B(Ppin) compounds is greater than the stability of the Aryl-B(epin) compounds. b) Temporal stability

[0107] To determine the stability of aryl-B(epin) precursors and aryl-B(Ppin) precursors, the compounds indicated in Fig. 1 were dissolved in a mixture of water and acrylonitrile in a volume ratio of 1:1. Solutions were prepared, each containing exactly one of these compounds. After 20, 40, 60, and 80 minutes, the percentage of intact compound in each solution was determined. A mixture of water and acrylonitrile is a solvent commonly used for compound purification. The determination was performed by UHPLC.

[0108] In Fig. 2, "Ph" denotes a phenyl group, "B(pin)" denotes a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane unit, "B(Epin)" denotes a 4,4,5,5-tetraethyl-1,3,2-dioxaborolane unit, and "B(Ppin)" denotes a 4,4,5,5-tetrapropyl-1,3,2-dioxaborolane unit. It can be seen in Fig. 2 that the aryl-B(Epin) and aryl-B(Ppin) compounds are stable over a period of 80 min, while only 60% of the aryl-B(pin) compound remained intact after 20 min. c) Stability under labeling conditions

[0109] The stability of the aryl-B(Epin) compounds and aryl-B(Ppin) compounds under labeling conditions was investigated. For labeling of the aryl-B(Epin) compounds and aryl-B(Ppin) compounds with [ 18For [F]-fluoride, the precursors used must be stable to water and moisture. One of the most common reasons for radiosynthesis failure is the presence of water or moisture in a reaction mixture, such as that used during routine radiopharmaceutical production.

[0110] [ 18 F]Fluoride must be thoroughly dried to ensure the nucleophilicity necessary for reaction with precursors, often by sequential azeotropic drying steps. If traces of water are present in the reaction mixture, the [ 18 F]Fluoride forms strong hydrogen bonds with water, and the radioactive labeling will not progress.

[0111] When using aryl-B(epin) compounds and aryl-B(Ppin) compounds as precursors, it was found that even in the presence of traces of water (10 μl), radiolabeling occurs to a sufficient extent, offering a clear practical advantage over the current state of the art. Scheme 8 shows the conversion of compound 55 to compound [ 18 F]55. Scheme B-9 The resulting radiochemical conversion was 24% despite the presence of 10 μl of water in the reaction mixture (Fig. 3). This demonstrates that aryl-B(epin) compounds and aryl-B(Ppin) compounds exhibit greater robustness towards water and moisture during radiolabeling than known precursors. Example 9 Preparation of aryl-B(epin) compounds

[0112] To prepare aryl-B(epin) compounds, a compound of general formula B was reacted with 3,4-diethylhexane-3,4-diol (epin) to form a compound of general formula P-2. The reaction is shown in Scheme B-9. Scheme B-9 The reaction was carried out by dehydrating esterification according to the procedure described in

[0038] .

[0113] Example 9 serves in particular to illustrate the first process according to the invention. The compound of general formula B is an example of a compound of general formula II, where m is 1. The compound of general formula P-2 is an example of a compound of general formula I, where Y is ethyl and m is 1. It is also an example of a compound having a group Pl, where Y is ethyl and m is 1. In compounds B and P-2, R has the meaning shown in Table 4. The compounds of general formula B are arylboronic acids. Arylboronic acids are commercially available.

[0114] Compounds 1a to 19a shown in Table 4 were prepared according to

[0038] . Compounds 1a to 19a are examples of aryl-B(epin) compounds. Table 4 lists the yields of the reaction shown in Scheme B-9. In addition, the radiofluorinated and radioiodinated compounds for which compounds 1a to 19a can be used as precursors are listed in the "Use" column of Table 4. Table 4 Example 10

[0115] To prepare aryl-B(Ppin) compounds, a compound of general formula B was reacted with 4,5-dipropyloctane-4,5-diol (Ppin) to form a compound of general formula P-3. The reaction is shown in Scheme B-10. Scheme B-10 The reaction was carried out by dehydrating esterification according to the procedure described in

[0038] .

[0116] Example 10 serves in particular to illustrate the first process according to the invention. The compound of general formula B is an example of a compound of general formula II, where m is 1. The compound of general formula P-3 is an example of a compound of general formula I, where Y is propyl and m is 1. It is also an example of a compound having a group Pl, where Y is propyl and m is 1. In compounds B and P-3, R The meanings of these compounds can be found in Table 4. The compounds of general formula B are arylboronic acids. Arylboronic acids are commercially available.

[0117] Compounds 1b to 19b shown in Table 5 were prepared according to

[0038] . Compounds 1b to 19b are examples of aryl-B(Ppin) compounds. Table 5 lists the yields of the reaction shown in Scheme B-10. In addition, the radiofluorinated and radioiodinated compounds for which compounds 1b to 19b can be used as precursors are listed in the "Use" column of Table 5. Table 5 Example 11 Stability of aryl-B(epin) compounds and aryl-B(ppin) compounds

[0118] To demonstrate stability, the aryl-B(epin) compounds 1a to 19a and aryl-B(Ppin) compounds 1b to 19b were investigated by thin-layer chromatography. A mixture of cyclohexane and ethyl acetate in a volume ratio of 4:1 was used as the eluent. A mixture of cyclohexane and ethyl acetate is a standard solvent used for compound purification. The results are shown in Fig. 4. literature 1. Fowler, J.S.; Wolf AP Acc. Chem. Res. 1997, 30 (4), 181-188. 2. Phelps, ME Proc. Natl. Acad. Be. USA 2000, 97 (16), 9226-9233. 3. Gambhir, SS Nat. Rev. Cancer 2002, 2 (9), 683-693. 4. Tsien, RY Nat. Rev. Mol. Cell Bio. 2003, SS16-SS21. 5. Willmann, JK; van Brüggen, N.; Dinkelborg, LM; Gambhir, SS Nat. Rev. Drug Discovery 2008, 7 (7), 591-607. 6. Ametamey, SM; Honer, M.; Schubiger , PA Chem. Rev. Fr. Rev. 2008, 108(5), 1501–1516. 7. Ido, T.; One, CN; Casella, V.; Fowler , JS ; Wolf AP; Reivich , M. ; Kuhl, DAY Labeled Compd. Radiopharm. 1978, 14(2), 175-1 8. Clarke, BNJ Nucl. Med. Technol. 2018, 46, 12–7 9. FDA-Approved PET Radiopharmaceuticals: http : / / www. radiopharmaceuticals. info / pet-radiopharmaceuticals. html (retrieved 2021-08-12). 10. Lee, E.; Kamlet, AS; Powers , DC ; Neumann , CN ; Boursalian , GB ; Furuya, T.; Choi, DC; Hooker , JM ; Ritter, T. Science 2011, 334(6056), 639–642. 11. Huiban, M.; Treadwell , M. ; Mizuta, S.; Wan, ZH; Zhang , XM ; Collier , TL ; Governor, V.; Passchier , J. Nat. Chem. 2013, 5(11), 941–9 12. Graham, TJA; Lambert , RF ; Ploessl , K. ; Kung, HF; Doyle, AGJ Am. Chem. Soc. Rev. 2014, 136(14), 5291–5294. 13. Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H. Nat. Commun. 2014, 5, 4365. 14. Neumann, C. N.; Hooker, J. M.; Ritter, T. Nature 2016, 534 (7624), 369-373. 15. Levin, M. D.; Chen, T. Q.; Neubig, M. E.; Hong, C. M.; Theulier, C. A.; Kobyli- anskii, I. J.; Janabi, M.; O'Neil, J. P.; Toste, F. D. Science 2017, 356 (6344), 1272- 1275. 16. Chen, W .; Huang, Z.; Tay, N. E. S.; Giglio, B.; Wang, M.; Wang, H.; Wu, Z.; Nicewicz, D. A; Li, Z. Science 2019, 364 (6446), 1170-1174. 17. Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.; Sanford, M. S.; Scott, P. J. H. Org. Lett. 2014, 16, 3224-3227. 18. Tredwell, M.; Preshlock, S. M.; Taylor, N. J.; Gruber, S.; Huiban, M; Passchier, J.; Mercier, J.; Genicot, C.; Gouverneur, V. Angew. Chem. Int. Ed. 2014, 53, 7751-7755. 19. Mossine, AV; Brooks , AF ; Macaravage , KJ ; Miller , JM ; Ichiishi, N.; Sanford, MS; Scott , PJH ; Org. Let. Rev. 2015, 77, 5780–5783. 20. Macaravage, KJ; Brooks , AF ; Mossine, AV; Sanford, MS; Scott , PJH ; Org. Let. Rev. 2016, 18(20), 5440–5 21. Lee , SJ ; Macaravage , KJ ; Brooks , AF ; Scott , PJH ; Sanford, MS; Angew. Chem. Int. Ed. Rev. 2019, 58, 22. Preshlock, S.; Treadwell , M. ; V. Governor, V. Patent Location: US102872208B2 23. Mossine, AV; Tanzey , SS ; Brooks, AF et al. Nat. Protoc. 2020, 15, 1742-1 24. Craig A.; Kolks, N.; Urusova, EA et al. Chem. Commun., 2020, 56, 9505–9508. 25. Gendron, T.; Destro, G.; Strathoff, NJW et al. EJNMMI radiopharm. chem. 2022 , 7 , 26. Taylor, NJ; Emer, E.; Preshlock , S. ; Schedler , M. ; Treadwell , M. ; Verhoog , S. ; Mercier, J.; Genicot , C. ; Governor, V.; JACS 2017, 139(24), 8267–8276. 27. SL Pimlott, A. Sutherland, Chem. Soc. Freeze. 2011, 40, 149-162. 28. MJ Adam, DS Wilbur, Chem. Soc. Freeze. 2005, 34, 153-163. 29. R. Yan, K. Sander, E. Galante, V. Rajkumar, A. Badar, M. Robson, E. El-Emir, MF Lythgoe, RB Pedley, E. Arstad, J. Am. Chem. Soc. 2013, 135, 703-709. 30. M. Eisenhut, W. Mier, in Handbook of Nuclear Chemistry, Springer, 2011, 2121- 2141. 31. Petrov, SA, Yusubov, MS; Beloglazkina, EK; Nenajdenko, VG International Journal of Molecular Sciences 2022, 23 (22), 13789. 32. Wilson, TC; McSweeney, G.; Preshlock, S.; Verhoog, S.; Tredwell, M.; Jail- lyac T.; Veronica Gouverneur, V. Chem. Commun., 2016, 52, 13277-13280. 33. Reilly SW; Makwandi, M.; Xu, K.; Mach, RH; Org. Lett. 2018; 20(7), 1752- 1755. 34. N. Oka et al. Org Lett. 2022, 24 (19), 3510-3514. 35. Craig, A. Doctoral Thesis, University of Cologne, 2020. Chelatec website: https: / / www.chelatec.eom / radiolabeling / #radioligand (accessed on April 4, 2023). Tetrakit website: https: / / tetrakit.com / science / (accessed on April 4, 2023). Rubio-Presa, R.; Suärez-Pantiga, S.; Pedrosa, MR; Sanz, R. Molybdenum-Catalyzed Sustainable Friedländer Synthesis of Quinolines. Adv Synth Catal 2018, 360 (11), 2216-2220. https: / / doi.org / 10.1002 / adsc.201800278.

Claims

Patent claims 1. Compound of general formula I (Formula I) where A is selected from the group consisting of and a six-membered aromatic ring optionally containing a heteroatom selected from the group consisting of N, S, or O; n is 0, 1, 2, or 3; m is 1 or 2; Y is each an ethyl or propyl group, wherein when Y is an ethyl group, n is 1, 2 or 3 and R is independently selected at each occurrence from the group consisting of -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, wherein Ri is C2-Ce-alkyl, -SO3H, -CN, NO2, halide, substituted or unsubstituted C2-Ce-alkyl, substituted or unsubstituted C2-Ce-alkoxy and the following: where R2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and wherein two R together may form a 5- to 7-membered, substituted or unsubstituted alkyl or heteroalkyl ring; and wherein, when Y is a propyl group, R is independently selected at each occurrence from the group consisting of -H, -OH, -SH, -CO-Ri, -C(O)-O-Ri, -NH-Ri, where Ri is H or C1-C6 alkyl, -SO3H, -CN, NO2, halide, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy and the following: where R.2 is a tert-butoxy group, R3 is -CH2-CH2-O- and a is 0, 1, 2, 3 or 4; and wherein two R together may form a 5- to 7-membered, substituted or unsubstituted alkyl or heteroalkyl ring.

2. A compound according to claim 1, characterized in that Y is ethyl at each occurrence.

3. A compound according to claim 1 or claim 2, characterized in that R is selected from the group consisting of where R2, R3 and a have the meanings given in claim 1.

4. A compound according to claim 1, characterized in that Y is propyl at each occurrence.

5. A compound according to claim 1 or claim 4, characterized in that R is selected from the group consisting of: where R2, R3 and a have the meanings given in claim 1.

6. A process for preparing a compound of general formula I (Formula I), where A, Y, R, m and n have the meanings given in claim 1, characterized by reacting compounds of the general formula II where A, R, m and n have the meanings given in claim 1, with 3,4-diethylhexane-3,4-diol (Epin) and / or 3,4-dipropylhexane-3,4-diol (Ppin).

7. Process according to claim 6, characterized in that the reaction takes place at a temperature in a range between 20 and 120 °C.

8. Process for preparing a compound of formula IX (Formula IX) where X is a radioactive halide; A, R, m and n have the meanings given in claim 1; characterized by reacting a compound of formula I (Formula I), where Y, A, R, m and n have the meanings given in claim 1; with NaX in a polar solvent in the presence of a Cu-based catalyst, wherein X is selected from the group consisting of fluorine-18, iodine-123, iodine-124, iodine-125, iodine-131, bromine-76, bromine-77 and astatine-211.

9. The process according to claim 8, characterized in that the Cu-based catalyst is selected from the group consisting of [Cu(OTf)2(Py)4], Cu(4-PhPy CKL), Cu(3,4-Me2Py)4(OTf)2, and Cu(3,4-Me2Py)4(ClO4)2.

10. The process according to claim 8 or 9, characterized in that the solvent is DMF, DMA, MeOH, EtOH, i-PrOH, n-BuOH or mixtures thereof.

11. Process according to claims 8 to 10, characterized in that the Cu-based catalyst is [Cu(OTf)2(Py)4].

12. Process according to one of claims 8 to 11, characterized in that the reaction is carried out in the presence of an eluent, wherein the eluent is a pyridinium sulfonate salt of the general formula where R e is selected from the group consisting of H, -N(Ci-C4-alkyl)2 and -O-Ci-C4-alkyl, and D is selected from the group consisting of OTf and OTs.

13. The process according to claim 12, characterized in that the eluent is dimethylaminopyridinium trifluoromethanesulfonate.

14. The process according to claim 12 or claim 13, characterized in that the reaction is carried out in a mixture of DMA and n-BuOH in the presence of [Cu(OTf)2(Py)4] and dimethylaminopyridinium trifluoromethanesulfonate.

15. The use of compounds according to claims 1-5 in the preparation of radiopharmaceuticals.

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