Preparation of 18f-labelled compounds from nitroso-substituted arenes

Abstract

The invention relates to a method for preparing an organic compound, which comprises a group of general formula (I), where A is an aryl or heteroaryl group, which optionally has 1 to 3 heteroatoms selected from O, N or S, R1 and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, carboxy C1-C6 alkyl, oxo C1-C6 alkyl, hydroxy C1-C6 alkyl, nitro, cyano or -C(O)-Ra, where Ra is selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; characterised in that an organic compound comprising a group of general formula (II), where A, R1 and R2 have the meanings given above, is subjected to radiofluorination.

Description

Description Production of 18 F-labeled compounds of nitroso-substituted arenes

[0001] The invention relates to a method for producing 18 F-labeled compounds made from nitroso-substituted arenes. It also concerns the use of nitroso-substituted arenes for the production of 18 F-labeled compounds.

[0002] Fluorine-18 is a widely used radionuclide for diagnostic imaging with positron emission tomography. The nuclide's physical properties are ideal. Its half-life of 109.7 minutes and the ability to produce large quantities, e.g., up to the terabecquerel level, using commercially available cyclotron devices, enable the production and delivery of radiopharmaceuticals in batches sufficient for more than 100 patients at a time, and delivery over a relatively large area around the production site. Furthermore, the low energy (0.635 MeV) of the emitted β- +Fluorine particles form the basis for high image resolution compared to other PET nuclides, such as gallium-68 or carbon-11. From a medicinal chemistry perspective, the incorporation of fluorine into a molecule is a widely used strategy for drug development. This is based on the fact that metabolic stabilization of the molecule can be achieved, and the replacement of, for example, hydrogen atoms or hydroxyl groups by fluorine is often tolerated with regard to binding affinity to the target enzyme, transporter, or receptor. Therefore, a large number of fluorinated compounds have been developed and tested for their biological properties. The radioactive labeling of molecules with fluorine-18 remains a challenge, based on the fact that radiofluorination of the molecule must be achieved at a late stage during the synthesis process. Currently, several radiofluorination techniques have been developed for this purpose.[1] used for aliphatic or aromatic organic compounds as well as for chelating agent-containing molecules that were initially developed for radiometallic complexation. M 254547 Registration text.docx

[0003] Within this body of techniques, strategies for radioactive labeling for accessing 18F-labeled aromatic compounds are of major importance due to the widespread occurrence of fluoroarenes in pharmacologically active molecules. Nucleophilic aromatic substitution reactions are one of the most widely used reaction classes, with a wealth of methods described in the literature for their application, each with a specific reaction scope. An overview of leaving groups used in the prior art is shown in Scheme 1 in Fig. 5. Trimethylammonium or nitro groups have been most frequently used as leaving groups for nucleophilic exchange. Recent developments include the radiofluorination of triarylsulfonic acid salts. [2 ' 3] , Diaryliodonium salts [4 ' 5] , spirocycli see hypervalent iodine(III)-yl-dene [6] , N-arylsydnones [1] or oxidized iodarenes [7] as well as ruthenium-mediated deoxyfluorination of phenols [8] .

[0004] Nucleophilic aromatic substitution (SNAr) is a class of reactions widely used in pharmaceutical and chemical studies, providing a versatile framework for the modification of aromatic ring structures. [9] When applied to benzene derivatives, these reactions involve the exchange of a leaving group (LG) by a nucleophile on a ring bearing activating electron-withdrawing groups (Z) at the ortho and / or para positions of the leaving group. The generally accepted mechanism for SNAr reactions involves a two-phase addition-elimination sequence, often via a unique, non-aromatic Meisenheimer complex. Recent advances in mechanistic research have also revealed the involvement of concerted [10,11] and single electron transfer (SET)

[0012] -Mechanisms proposed.

[0005] The diverse reactivity exhibited by nitrosoarenes makes them promising starting materials in organic chemistry. They can be considered effective nucleophiles and electrophiles and have demonstrated widespread application in recent decades for the efficient synthesis of a variety of CN bonds. 113 ' 141 The ability of the nitroso group to assume different conjugation states with an aromatic ring can compensate for the electron deficiency of the ring M 254547 (Registration text.docx). Influencing SNAr reactions, protonated nitrosoarenes can form stable cations due to the delocalization of p-electrons. Consequently, the nucleophilic reaction site undergoes a transition from the nitroso group to the aryl group. Based on this principle, diarylamines were synthesized via reactions between anilines and protonated p-nitrosophenyl ethers. 115 ' 16]In these reactions, the nitroso group acts as the activating group (Z).

[0006] Therefore, in SNAr reactions, the leaving group (LG) plays a central role in influencing the reactivity of the substrate and consequently the overall efficiency of the reaction. Although several nitrogen-containing groups are known to be good leaving groups in SNAr reactions (e.g., diazonium salts, aryldiazonium derivatives, and A-ryltrialkylammonium salts),

[0017] Nevertheless, it is desirable to find alternative leaving groups that exhibit at least equally good properties as the known leaving groups, but are suitable for reactions where the previously known leaving groups have disadvantages. This applies, for example, when reactions are to proceed without a transition metal.

[0007] It is particularly desirable to find a way that 18F-labeled aromatic compounds are more easily and efficiently accessible via precursors with a suitable leaving group.

[0008] The object of the invention is to eliminate the disadvantages of the prior art. In particular, it aims to provide a method for manufacturing 18 F-labeled aromatic compounds are specified, which enables rapid and cost-effective radiofluorination with high radiochemical transformations and yields.

[0009] This problem is solved by the features of claims 1 and 12. Advantageous embodiments of the inventions result from the features of the dependent claims.

[0010] According to the invention, a process for producing an organic compound comprising a group of general formula I M 254547 Registration text.docx 18 F R2 (Formula 1) features, provided for, whereby A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; Ri and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; characterized in that an organic compound comprising a group of general formula II NO R2 (Formula II) The compound, wherein A, Ri and R2 have the meanings given above, is subjected to radiofluorination. The compounds of general formula II are also referred to as nitrosoarenes in the present invention. The terms arenes and aromatic hydrocarbon are used synonymously in the present invention.

[0011] This invention describes a method for manufacturing 18 F-labeled arenes starting from nitrosoarenes under transition metal-free conditions, enabling faster and more cost-effective radiofluorination with high radiochemical transformations and yields.

[0012] The group of general formula I and the group of general formula II have a unit i — “. This unit denotes a hydrocarbon M 254547 application text.docx residue that is bonded to the aryl or heteroaryl group A or hydrogen that is bonded to the aryl or heteroaryl group A.

[0013] The group of general formula I is preferably a group of general formula IA. 18 F R , R2 Formula IA.

[0014] The group of general formula IA is an independent organic compound that has a group of general formula I in which the unit “ “Hydrogen bonded to the aryl or heteroaryl group A. The group of general formula IA is therefore referred to below as the compound of general formula IA.”

[0015] The group of general formula II is preferably a group of general formula II A NO R2 Formula II A.

[0016] The group of general formula IIA is an independent organic compound that includes a group of general formula II in which the unit “ — “Hydrogen bonded to the aryl or heteroaryl group A. The group of general formula IIA is therefore referred to below as the compound of general formula IIA. M 254547 Registration text.docx

[0017] The aryl or heteroaryl group A is preferably a pyridinyl, indolyl, or biphenylyl group, or a 5- or 6-membered aromatic ring, optionally comprising a heteroatom selected from O, N, or S. More preferably, the aryl or heteroaryl group A is an indolyl group or a 5- or 6-membered aromatic ring, optionally comprising a nitrogen atom. Particularly preferably, the aryl or heteroaryl group A is a pyridinyl or phenyl group.

[0018] In one embodiment of the process according to the invention, Ri and R2 are independently selected from the group consisting of H, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, carboxymethyl, carboxyethyl, oxomethyl, nitro, or cyano. Preferably, Ri is in the ortho position with respect to the functional group, and R2 is in the meta or para position with respect to Ri.

[0019] In a preferred embodiment of the process according to the invention, Ri is H or cyano and R2 is selected from the group consisting of H, chlorine, methyl, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, methyl ketone, nitro or cyano.

[0020] In a further preferred embodiment of the process according to the invention, Ri H and R2 are selected from the group consisting of chlorine, trifluoromethyl, carboxyethyl, oxomethyl, nitro or cyano.

[0021] In a particularly preferred embodiment of the process according to the invention, Ri is cyano and R2 is selected from the group consisting of H, bromine, chlorine, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, nitro, or cyano. R2 is particularly preferred to be H, bromine, chlorine, or methoxy. Furthermore, Ri is preferably in the ortho position with respect to the functional group, and R2 is preferably in the para position with respect to Ri. Preferred examples of a compound of the general formula IA are: M 254547 Registration text.docx No. Formula Name 1 18 F l-(Fluor- 18 F)-4-(trifluoromethyl)benzene CF3 2 18 F 4-(Fluor- 18 F)benzaldehyd 3 18 F l-(Fluor- 18 F)-4-nitrobenzene NO2 4 18 F 4-(Fluor- 18 F)benzonitril CN 5,a F Ethyl-4-(fluoro- 18 F )b enzoate 0^ 0 6 18F l-Chlor-4-(fluor- 18 F)benzol Cl 7 18 F 2-(Fluor- 18 F)benzonitril M 254547 Anmeldetext.docx Nr. Formel Name 8 18 F 3-Chlor-2-(fluor- 18 F)benzonitril CI^X ^CN 9 18 F 4-Chlor-2-(fluor- 18 F)benzonitril X. CN JT T 10 18 F 5-Chlor-2-(fluor- 18 F)benzonitril Jx XN or Cl 11 18 F 2-(Fluor- 18 F)-5-methoxybenzonitril X^CN or 12 18 F 2-(Fluor- 18 F)-4-(trifluormethyl)benzonitril A^CN F3C^ ? ^ 13 18 F 2-(Fluor- 18 F)-4-methoxybenzonitril ± ^CN 14 18 F 2-(Fluor- 18 F)-6-methylbenzonitril ex 15 18 F 4-(Fluor- 18 F)-3-chlorbenzonitril CN M 254547 Registration text.docx No. Formula Name 16 18 F 5-Bromo-2-(fluorine- 18 F)benzonitrile or Br 17 18 F l-(4-(Fluor- 18 F)phenyl)(phenyl)methan-l-one 0 u 0 18 2-(Fluor- 18 F)pyridine

[0022] Compound 1 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is trifluoromethyl in the para position to 18 F is.

[0023] Compound 2 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is oxomethyl in the para position to 18 F is.

[0024] Compound 3 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is nitro in the para position to 18 F is.

[0025] Compound 4 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is cyano in the para position to 18 F is.

[0026] Compound 5 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is carboxyethyl in the para position to . 18 F is.

[0027] Compound 6 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is chloride in the para position to . 18 F is. M 254547 Registration text.docx

[0028] Compound 7 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 is H.

[0029] Compound 8 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 chlorine in ortho position to 18 F is.

[0030] Compound 9 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 Chlorine in meta-position to 18 F is.

[0031] Compound 10 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 chlorine in para position to 18 F is.

[0032] Compound 11 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 Methoxy is in the para position to 18 F is.

[0033] Compound 12 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 trifluoromethyl in the meta position to 18 F is.

[0034] Compound 13 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 Methoxy in meta-position to 18 F is.

[0035] Compound 14 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18F is and R2 Methyl in meta position to 18 F and ortho position to cyano is.

[0036] Compound 15 is a compound of the general formula IA, where A is phenyl, Ri is chloride, and R2 is cyano in the para position to 18 F is.

[0037] Compound 16 is a compound of the general formula IA, where A is phenyl, Ri is cyano in the ortho position to 18 F is and R2 bromine in para position to 18 F is. M 254547 Registration text.docx

[0038] Compound 17 is a compound of the general formula IA, where A is phenyl, Ri is H, and R2 is a phenyl ketone in the para position to . 18 F is.

[0039] Compound 18 is a compound of the general formula IA, where A is pyridine, Ri and R2 are H.

[0040] The process for the preparation of an organic compound having a group of general formula I is carried out according to Scheme 2. NO [18 F]KF, K2CO3, K 222 R2 Scheme 2 The radiofluorination reaction shown in Scheme 2 is carried out in the exemplary embodiments by elution with a K2CO3-loaded quaternary methylammonium cartridge (QMA) using the phase transfer catalyst K222 and reaction on a microliter scale in HPLC vials at a reaction temperature between 90°C and 130°C and solvents, MeCN, DMF, DMSO with [ 18 F]KF was carried out. The radiochemical reaction (RCC) was determined by radio-thinning chromatography and high-performance liquid chromatography. The radiochemical yield was determined by high-performance liquid chromatography after reaction and subsequent purification. The reaction conditions are described in more detail in the examples. Alternatively, other sources for [ 18 F]fluoride such as tetraethylammonium [ 18F]fluoride can be used, and the reaction can be carried out in other vessels and scales, such as in larger glass vessels or reaction vessels of synthesis machines.

[0041] Unless otherwise specified, the term "aryl" refers to a cyclic aromatic hydrocarbon group consisting of a mono-, bi-, or tricyclic aromatic ring system with 5 to 18 ring atoms, preferably 5 or 6 ring atoms. The aryl group may optionally be a substituted aryl group. M 254547 Application text.docx Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, naphthalenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzozodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. A preferred example is phenyl.The term “substituted aryl group” refers in particular to an aryl group optionally independently modified with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, -COOR (where R is hydrogen or alkyl), -CN, -N3, -NO, -NO2, -SR (where R is hydrogen or alkyl), hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, monoarylamino, alkylaryl-amino, diarylamino, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R”). n -COOR (where n is an integer from 0 to 5, R' and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl) or -(CR'R”) n -CONR a R b (where n is an integer from 0 to 5, R' and R” are independently hydrogen or alkyl, and R a and R bis substituted independently of each other (hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

[0042] Unless otherwise specified, the term "heteroaryl" refers in particular to a monocyclic, bicyclic, or tricyclic group with 5 to 18 ring atoms, wherein at least one aromatic ring contains one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The heteroaryl group may optionally be a substituted heteroaryl group. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, py-rimidyl, quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, Benzothiophenyl, Ben-zothiopyranyl, Benzimidazolyl, Benzoxazolyl, Benzooxadiazolyl, Benzothiazolyl, M 254547 Registration text.docx Benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, and the like. A preferred example is pyridinyl. The term "substituted heteroaryl group" refers in particular to a heteroaryl group optionally independently modified with one to four substituents, preferably one or two substituents, selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl, or phenylalkyl), -(CR'R") n -COOR (where n is an integer from 0 to 5, R' and R” are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl, or phenylalkyl) or -(CR'R”) n -CONRa R b (where n is an integer from 0 to 5, R' and R” are independently hydrogen or alkyl, and R a and R b is substituted independently of each other (hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

[0043] Unless otherwise specified, the term "alkyl" refers in particular to a saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-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 being independently alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0044] Unless otherwise specified, the term "alkoxy" refers in particular to a group of the formula -OR, where R is an alkyl group, as defined herein. Examples of alkoxy components 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 being M 254547 Application text.docx independent of alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.

[0045] The term "acyl" refers to a group of the formula -C(=O)R, where R is alkyl as defined herein.

[0046] Unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine, iodine or astatine.

[0047] According to the invention, the use of an organic compound belonging to a group of general formula II is also possible. NO -h^A^- R i R2 (Formula II), features, provided for, whereby A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; Ri and R2 are independently selected from the group consisting of H, halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-halogenalkyl, carboxy-Ci-Ce-alkyl, oxo-Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; to produce an organic compound comprising a group of the general formula I 18 F -h^A^- R i R2 (Formula 1) exhibits, where A, Ri and R2 have the meanings given above. M 254547 Registration text.docx

[0048] Details of the uses according to the invention can be found in the description of the method according to the invention.

[0049] The invention is explained in more detail below with reference to the drawing and exemplary embodiments which are not intended to limit the invention. Fig. 1 shows detailed results of a radiofluorination of compound 2 as an example of the analytical methods used in the optimization to determine the radiochemical conversion (RCC) to the 18 F-labeled product according to Radio-DC (Fig. 1A) and Radio-HPLC (Fig. 1B). The RCC to 18 F-labeled by-products (NP), if any, are indicated in the corresponding row. Fig. 2 shows radio-DC chromatograms of optimization reactions with compound 2 as a precursor. Fig. 3 shows a radio-HPLC chromatogram of the crude reaction mixture from the radioactive labeling with [ 18 F]Fluoride using the base Normal for elution, DMF as the reaction solvent, and a temperature of 130°C for 15 min. The signals of the y-detector are shown above and the signals of the UV detector at 254 nm are shown below. Fig. 4 shows on the left a radio-HPLC chromatogram of compound 2 and on the right a radio-HPLC chromatogram of compound 2 which was added to 4-fluorobenzaldehyde for product identification, obtained by radiolabeling with [ 18 [F]Fluoride as described above in Fig. 3, followed by semi-preparative HPLC. The signals from the γ-detector are shown above, and the signals from the UV detector, monitored at 254 nm, are shown below. The retention time difference between the UV and γ-detectors was 0.17 min under the applied analytical conditions. M 254547 Registration text.docx Fig. 5 shows in Scheme 1 an overview of outlet groups used in the prior art. Examples

[0050] The examples describe the production and characterization of nitrosoars according to the invention. General procedure for the synthesis of nitrosoarenes

[0051] A solution of oxone (2.51 g, 4.0 mmol) in water (20 mL) was slowly added to a stirred solution of the corresponding aniline (2.0 mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at room temperature until TLC analysis indicated complete consumption of the starting material. The aqueous layer was extracted with CH₂Cl₂ (3 x 10 mL). The combined organic layers were washed successively with HCl IM (20 mL), water (20 mL), 10% NaHCO₃ (20 mL), and saline solution (20 mL). The combined organic compounds were dried over anhydrous MgSO₄, filtered, and concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel, affording nitrosoarenes in 56–89% yield. Example 1 1-Nitroso-4-(trifluoromethyl)benzene (1)

[0052] Following the general procedure, starting from 4-(trifluoromethyl)aniline (322.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 1 was obtained as an orange solid by column chromatography using a mixture of hexane: CH2C12 LI as eluent (245.2 mg, 70%).

[0053] 'H-NMR (300 MHz, CDCh): 5 8.00 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCh): 5,164.2, 136.3, 135.4, 127.2, 127.1, 127.1, 127.0, 125.2, 121.6, 121.0 ppm. 19 F-NMR (282 MHz, CDCh): 5–63.1 ppm. Anal., calculated for C7H4F3NO: C, 48.01; H, 2.30. Found: C, 48.09; H, 2.27. M 254547 Registration text.docx Example 2 Synthesis of 4-nitrosobenzaldehyde (2)

[0054] Following the general procedure, starting from 4-aminobenzaldehyde (242.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 2 was obtained as a light yellow solid by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (183.8 mg, 68%).

[0055] 'HNMR (300 MHz, CDCb): 5 10.2 (s, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDC13): 5 191.4, 163.9, 139.6, 131.2, 121.2 ppm. Anal., calculated, for C7H5NO2: C, 62.22; H, 3.73. Found: C, 62.14; H, 3.76. Example 3 Synthesis of l-nitro-4-nitrosobenzene (3)

[0056] Following the general procedure, starting from 4-nitroaniline (276.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 3 was obtained as yellow platelets by column chromatography using a mixture of hexane: CH2C12 1:1 as eluent (182.5 mg, 60%).

[0057] 'H-NMR (300 MHz, CDCh): 5 8.51 (d, J = 8.6 Hz, 2H), 8.06 (d, J = 8.6 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCh): 5 162.6, 150.5, 125.6, 121.4 ppm. Anal., calculated for C6H4N2O3: C, 47.38; H, 2.65. Found: C, 47.45; H, 2.63. Example 4 Synthesis of 4-Nitrosobenzonitrile (4)

[0058] Following the general procedure, starting from 4-aminobenozonitrile (236.3 mg) and stirring the reaction mixture for 1.5 h, nitrosobenzene 4 was obtained as a greenish-yellow solid by column chromatography using a mixture of hexane: CH2C12 1:1 as eluent (235.2 mg, 89%). M 254547 Registration text.docx

[0059] 1 H NMR (300 MHz, CDCl3): δ 7.97 (s, 4H) ppm. 13 C-NMR (75 MHz, CDCh): 5 162.3, 134.1, 120.9, 118.5, 117.6 ppm. Anal., calculated, for C7H4N2O: C, 63.64; H, 3.05. Found: C, 63.60; H, 3.07. Example 5 Synthesis of ethyl 4-nitrosobenzoate (5)

[0060] Following the general procedure, starting from ethyl 4-ami-nobenzoate (330.4 mg) and stirring the reaction mixture for 4 h, nitrosobenzene 5 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (211.4 mg, 59%).

[0061] 'H-NMR (300 MHz, CDC13): 5 8.30 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H) ppm. “C-NMR (75 MHz, CDCh): 5 165.2, 164.5, 135.6, 131.0, 120.4, 61.8, 14.2 ppm. Anal, calculated, for C9H9NO3: C, 60.33; H, 5.06. Found: C, 60.40; H, 5.03. Example 6 Synthesis of l-chloro-4-nitrosobenzene (6)

[0062] Following the general procedure, starting from 4-chloroaniline (255.1 mg) and stirring the reaction mixture overnight, nitrosobenzene 6 was obtained as a dark yellow solid by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (252.0 mg, 89 %).

[0063] 'H-NMR (300 MHz, CDCh): 5 7.86 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCh): 5 163.9, 142.6, 129.8, 122.3 ppm. Anal., calculated for C6H4C1NO: C, 50.91; H, 2.85. Found: C, 51.01; H, 2.83. Example 7 Synthesis of 2-nitrosobenzonitrile (7)

[0064] Following the general procedure, starting with 2-aminobenozonitrile (236.3 mg) and stirring the reaction mixture for 3 h, nitrosobenzene 7 M 254547 application text.docx obtained as a light yellow solid after column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (171.8 mg, 65%).

[0065] 1 H-NMR (300 MHz, CDCl3): δ 8.06 (dd, J = 7.6, 1.2 Hz, 1H), 7.86 (td, J = 7.6, 1.2 Hz, 1H), 7.76 (td, J = 7.8, 1.3 Hz, 1H), 6.98 (dd, J = 7.8, 1.2Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCh): 5 161.9, 135.4, 134.5, 133.6, 116.7, 114.1, 112.3 ppm. Anal., calculated for C7H4N2O: C, 63.64; H, 3.05. Found: C, 63.59; H, 3.02. Example 8 Synthesis of 3-chloro-2-nitrosobenzonitrile (8)

[0066] Following the general procedure, starting from 2-amino-3-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, nitrosobenzene 8 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (193.2 mg, 58%).

[0067] 'H-NMR (300 MHz, CDCh): 58.05 (dd, J = 8.1, 1.2 Hz, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.64 (dd, J = 7.6, 1.2 Hz, 1H) ppm. “C-NMR (75 MHz, CDCh): 5 158.4, 141.1, 137.1, 135.6, 133.0, 116.1, 96.0 ppm. Anal, calculated, for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.52; H, 1.78. Example 9 Synthesis of 4-chloro-2-nitrosobenzonitrile (9)

[0068] Following the general procedure, starting from 2-amino-4-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, nitrosobenzene 9 was obtained as a yellow solid by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (219.5 mg, 66%).

[0069] 'H-NMR (300 MHz, CDCh): 58.03 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 8.2, 2.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H) ppm. “C-NMR (75 MHz, CDCh): 5 161.0, 141.0, 135.5, M 254547 Registration text.docx 134.9, 115.9, 113.3, 111.9 ppm. Anal, calculated, for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.55; H, 1.79. Example 10 Synthesis of 5-chloro-2-nitrosobenzonitrile (10)

[0070] Following the general procedure, starting from 2-Amino-5-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene 10 was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl21:1 as eluent (229.8 mg, 69%).

[0071] 'H-NMR (300 MHz, CDCh): 5 8.02 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.6, 2.1 Hz, 1H), 6.91 (d, J = 8.6 Hz, lH) ppm. 13 C-NMR (75 MHz, CDCh): 5 160.0, 142.6, 134.1, 133.9, 115.8, 115.4, 113.3 ppm. Anal., calculated, for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.40; H, 1.77. Example 11 Synthesis of 5-methoxy-2-nitrosobenzonitrile (11)

[0072] Following the general procedure, starting from 2-amino-5-methoxybenzonitrile (296.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 11 was obtained as a green solid by column chromatography using a mixture of hexane: CH2Ch 1:1 as eluent (217.3 mg, 67%).

[0073] 'H-NMR (300 MHz, CDCh): 5 7.42 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 9.1, 2.6 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 4.00 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCh): 5 164.9, 160.2, 118.5, 118.4, 117.4, 116.6, 115.3, 56.8 ppm. Anal., calculated, for C8H6N2O2: C, 59.26; H, 3.73. Found: C, 59.18; H, 3.78. M 254547 Registration text.docx Example 12 Synthesis of 2-Nitroso-4-(trifluoromethyl)benzonitrile (12)

[0074] Following the general procedure, starting from 2-Amino-4-(trifluoromethyl)benzonitrile (372.3 mg) and stirring the reaction mixture overnight, Nitrosobenzene 12 was obtained as a yellow solid by column chromatography using a mixture of Hexane:CH2Cl21:1 as eluent (244.1 mg, 61%).

[0075] 'H-NMR (300 MHz, CDCh): 5 8.29 (d, J = 7.9 Hz, 1H), 8.12 (dd, J = 7.9, 0.7 Hz, 1H), 7.16 (d, J = 0.7 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCh): 5 160.3, 135.5, 131.5, 131.4, 117.4, 115.4, 109.3, 109.2 ppm. Anal., calculated, for C8H3F3N2O: C, 48.02; H, 1.51. Found: C, 47.95; H, 1.54. Example 13 Synthesis of 4-methoxy-2-nitrosobenzonitrile (13)

[0076] Following the general procedure, starting from 2-amino-4-methoxybenzonitrile (296.3 mg) and stirring the reaction mixture overnight, nitrosobenzene 13 was obtained as a green solid by column chromatography using a mixture of hexane: CH2C12 1:1 as eluent (201.1 mg, 62%).

[0077] 'H-NMR (300 MHz, CDCh): 5 7.97 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5, 2.7 Hz, 1H), 6.27 (d, J = 2.7 Hz, 1H), 3.89 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCh): 5 163.4, 135.6, 121.9, 117.0, 107.6, 95.2, 56.4 ppm. Anal., calculated, for C8H6N2O2: C, 59.26; H, 3.73. Found: C, 59.19; H, 3.70. Example 14 Synthesis of 2-methyl-6-nitrosobenzonitrile (14)

[0078] Following the general procedure, nitrosobenzene 14 was obtained as a green solid by column chromatography from 2-amino-6-methylbenzonitrile (264.3 mg) by stirring the reaction mixture overnight. (M 254547 Application text.docx) A mixture of hexane: CH2Cl21:1 as eluent (207.5 mg, 71%) was obtained.

[0079] 'H-NMR (300 MHz, CDCh): 5 7.71 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8, 1H), 6.73 (d, J = 7.8 Hz, 1H), 2.81(s, 3H) ppm. 13 C-NMR (75 MHz, CDCh): 5 162.8, 144.8, 136.6, 132.7, 115.8, 115.1, 109.0, 20.4 ppm. Anal., calculated, for C8H6N2O: C, 65.75; H, 4.14. Found: C, 65.70; H, 4.16. Example 15 Synthesis of 3-chloro-4-nitrosobenzonitrile (15)

[0080] Following the general procedure, starting from 4-Amino-3-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, Nitrosobenzene 15 was obtained as a yellow solid by column chromatography using a mixture of hexane: CH2Cl21:1 as eluent (196.5 mg, 59%).

[0081] 'H-NMR (300 MHz, CDCh): 5 8.14 (d, J = 1.5 Hz, 1H), 7.56 (dd, J = 8.3, 1.5 Hz, 1H), 6.23 (d, J = 8.3 Hz, 1H) ppm. “C-NMR (75 MHz, CDCh): 5 157.8, 142.4, 136.6, 131.0, 120.0, 116.4, 109.4 ppm. Anal, calculated, for C7H3C1N2O: C, 50.48; H, 1.82. Found: C, 50.53; H, 1.8. Example 16 Synthesis of 5-bromo-2-nitrosobenzonitrile (16)

[0082] Following the general procedure, starting from 2-amino-5-bromobenzonitrile (394.1 mg) and stirring the reaction mixture overnight, nitrosobenzene 16 was obtained as a yellow solid by column chromatography using a mixture of hexane:ethyl acetate 9:1 as eluent (240.6 mg, 57%).

[0083] 'H NMR (300 MHz, CDCh): 5 8.20 (d, J = 1.9 Hz, 1H), 7.89 (dd, J = 8.6, 1.9 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H) ppm. “C-NMR (75 MHz, CDCh): 5 191.4, 163.9, M 254547 Registration text.docx 139.6, 131.2, 121.2 ppm. Anal. calculated for C7H3BrN2O: C, 39.84; H, 1.43. Found: C, 39.99; H, 1.39. Example 17 Synthesis of (4-Nitrosophenyl)phenylmethanone (17)

[0084] Following the general procedure, starting from (4-Aminophenyl)(phenyl)methanone (394.5 mg) and stirring the reaction mixture overnight, Nitrosobenzene 17 was obtained as a yellowish crystalline solid by column chromatography using a mixture of hexane: CH2C121:1 as eluent (280.1 mg, 71%).

[0085] 'HNMR (300 MHz, CDCh): 57.99-8.07 (m, 4H), 7.82-7.88 (m, 2H), 7.68 (tt, J= 7.5, 2.1 Hz, 1H), 7.55 (tm, J= 7.5 Hz, 2H) ppm. 13 C-NMR (75 MHz, CDCh): 160.2, 137.1, 136.9, 131.3, 115.9, 115.3, 113.1 ppm. Anal. calculated for C 13 H9NO2: C, 73.92; H, 4.30. Found: C, 73.60; H, 4.1. Example 18 2-Nitrosopyridine (18) is commercially available and has been used directly for radiolabeling. Comparative example 1 Synthesis of l-chloro-2-nitrosobenzene (A)

[0086] Following the general procedure, starting from 2-chloroaniline (255.1 mg) and stirring the reaction mixture overnight, nitrosobenzene A was obtained as a dark green solid by column chromatography using a mixture of hexane: CH2Cl21:1 as eluent (172.7 mg, 61%).

[0087] 'H-NMR (300 MHz, CDCh): δ 7.79 (dd, J = 8.1, 1.1 Hz, 1H), 7.63 (td, J = 7.6, 1.7 Hz, 1H), 7.24 (td, J = 7.6, 1.1 Hz, 1H), 6.23 (dd, J = 8.1, 1.7Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCh): 5 160.9, 142.8, 136.8, 132.2, 126.7, 108.7 ppm. Anal., calculated, for C6H4CINO: C, 50.91; H, 2.85. Found: C, 50.99; H, 2.86. M 254547 Registration text.docx Comparative example 2 Synthesis of ethyl 3-nitrosobenzoate f B )

[0088] Following the general procedure, starting from ethyl 3-ami-nobenzoate (330.4 mg) and stirring the reaction mixture overnight, nitrosobenzene B was obtained as a brown solid by column chromatography using a mixture of hexane : CH2Cl21:1 as eluent (283.1 mg, 79%).

[0089] 'H-NMR (300 MHz, CDCh): 58.63 (t, J = 1.6 Hz, 1H), 8.38 (dt, J = 7.8, 1.6 Hz, 1H), 7.98 (dt, J = 7.8, 1.6 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H) ppm. 13 C-NMR (75 MHz, CDCh): 5 165.3, 165.0, 135.8, 132.2, 129.6, 123.7, 122.6, 61.9, 14.4 ppm. Anal., calculated, for C9H9NO3: C, 60.33; H, 5.06. Found: C, 60.40; H, 5.03. Comparative example 3 Synthesis of l-Methoxy-3-nitrosobenzene (fC)

[0090] Following the general procedure, starting from 3-methoxyaniline (246.3 mg) and stirring the reaction mixture for 4 h, nitrosobenzene C was obtained as a white powder by column chromatography using a mixture of hexane:CH2Cl21:1 as eluent (219.5 mg, 80 %).

[0091] 'H-NMR (300 MHz, CDCh): δ 7.86 (dq, J = 7.9, 1.0 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.29 (ddd, J = 7.9, 2.6, 1.0 Hz, 1H), 6.90 (dd, J = 2.6, 1.0 Hz, 1H), 3.86 (s, 3H) ppm. 13 C-NMR (75 MHz, CDCh): 5 167.0, 160.5, 130.5, 122.9, 119.8, 99.8, 55.8 ppm. Anal., calculated, for C7H7NO2: C, 61.31; H, 5.15. Found: C, 61.24; H, 5.13. Comparative example 4 Synthesis of 2-chloro-5-nitrosobenzonitrile (D)

[0092] Following the general procedure, starting from 5-amino-2-chlorobenzonitrile (305.2 mg) and stirring the reaction mixture overnight, nitrosobenzene D was obtained as a yellow solid by column chromatography using... M 254547 Registration text.docx obtained by dispensing a mixture of hexane:CH2Cl21:1 as eluent (196.5 mg, 59%).

[0093] 'H-NMR (300 MHz, CDCh): 5 8.28 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.5, 2.2 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H) ppm. 13 C-NMR (75 MHz, CDCl3): δ 161.1, 144.0, 131.6, 127.0, 124.4, 115.1, 114.7 ppm. Anal., calculated, for C7H3CIN2O: C, 50.48; H, 1.82. Found: C, 50.44; H, 1.79. Example 16 Radiofluorination

[0094] The radiofluorination reactions were investigated using a microliter-scale radiofluorination approach in HPLC vials

[0022] , taking into account the parameters K₂CO₃ concentration for QMA elution (29.4 mM (normal) vs. 7.3 mM (% base)), reaction temperature (90°C, 110°C, 130°C), and solvent (MeCN, DMF, DMSO). The radiochemical conversion (RCC) was determined by radio-TLC and radio-HPLC after dilution of the reaction mixture with acetonitrile / water 50 / 50 (v / v). Product identification was achieved by adding standards to the reaction mixture using authentic non-radioactive reference substances. For selected compounds, isolated radiochemical yields were determined by radiolabeling under optimized conditions and subsequent purification by semi-preparative HPLC. 18F-labeled products were then analyzed with or without standard addition of the authentic reference in a second analytical radio-HPLC system for product identification. Table 2

[0095] The table below lists the maximum radiochemical conversion, radiochemical yield, reaction conditions with respect to solvent used, temperature, and the amount of base used. M 254547 Registration text.docx Table 2 Max. radio-insulated solution temperature, quantity of chemical, dichemical, base conversion, °C, yield (RCC) in % (RCY) in % and information the analytical method (DC / HPLC) to Determination Compound 1 19 (HPLC) 12, 13 DMF 130 Normal Compound 2 41 (HPLC) 22, 19 DMF 130 Normal Compound 3 35 (HPLC) 12, 14 DMSO 90 Normal Compound 4 8 (HPLC) 2, 18 DMSO 130 Normal Compound 5 14 (DC) 4, 10 (at DMF 130 Normal 110°C) Verb. 6 2 (DC) Not beDMF 130 Normal correct Verb. 7 45 (DC) 34, 52 DMF 130 Normal Verb. 8 22 (DC) 23, 27 DMSO 190 Normal Verb. 9 78 (DC) 45, 17 DMSO 110 Normal Verb. 10 45 (DC) 40, 43 DMSO 130 Normal Verb. 11 2 (DC) Not beDMF 130 Normal correct Verb. 12 14 (DC) Not beDMSO 130 ¼ true Verb. 13 70 (DC) 54, 50 DMF 130 Normal Verb. 14 6 (DC) Not DMF 130 Normal correct M 254547 Registration text.docx Verb. 15 8 (DC) Not beDMSO 110 Normal correct Verb. 16 18 (DC) 22, 21 DMSO 130 Normal Verb. 17 29 (DC) 18, 21 DMSO 130 Normal Verb. 18 62 (HPLC) 46, 45 DMSO 130 Normal

[0096] For compounds 1 to 18 listed in Table 2, the formation of a 18 F-marked product by [ 18[F]Fluorine-for-nitroso exchange was observed and verified by standard addition and analysis using radio-HPLC. The RCC as a measure of efficacy ranged from 2% for precursor compound 11 to 78% for precursor compound 9. It is advantageous for the reaction to use the normal K₂CO₃ concentration and to carry out the radioactive labeling at higher temperatures of 110°C or 130°C in DMSO or DMF. Selected 18 F-labeled compounds were isolated after radiolabeling by semi-preparative radio-HPLC to obtain isolated radiochemical yields calculated from the decay-corrected product activity of the collected product-containing HPLC fraction divided by the initial activity.

[0097] For nitroso compounds A to D, a reaction product was found that is solely due to [ 18 Fluorine-for-nitroso exchange does not occur, but the formation of 18F-labeled byproducts were observed in 2–8% RCC. These results suggest that the starting substrates should contain an electron-withdrawing group in the ortho- or para-position to the NO group. This is consistent with an SN1Ar mechanism, where the NO group acts as a leaving group. M 254547 Registration text.docx List of abbreviations used DMF Dimethylformamide DMSO Dimethyl sulfoxide MeCN Acetonitril Oxon potassium peroxymonosulfate RCC radiochemical conversion RCY radiochemical yield HPLC High-performance liquid chromatography DC Thin-layer chromatography PET positron emission tomography QMA quaternary methylammonium LG Departure Group SNAr nucleophilic aromatic substitution M 254547 Registration text.docx literature 1. Narayanam, MK; Ma, G.; Champagne, PA; Houk, KN; Murphy, J.M Synthesis of [(18) FJFluoroarenes by Nucleophilic Radiofluorination of N- Arylsydnones. Angew Chem Int Ed Engl 2017, 56, 13006-13010, doi:10.1002 / anie.201707274. 2. Mu, L.; Fischer, C. R.; Holland, J. P.; Becaud, J.; Schubiger, P. A.; Schibli, R.; Ametamey, S. M.; Graham, K.; Stellfeld, T.; Dinkelborg, L.M.; et al. 18F- Radiolabeling of Aromatic Compounds Using Triarylsulfonium Salts. European J Org Chem 2012, 2012, 889-892, doi:10.1002 / ejoc.201101730. 3. Sander, K., Gendron, T.; Yiannaki, E.; Cybulska, K.; Kalber, T. L.; Lythgoe, M. F.; Arstad, E. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18. Sci Rep 2015, 5, 9941, doi:10.1038 / srep09941. 4. Ross, T.L.; Ermert, J.; Hocke, C.; Coenen, H.H. Nucleophilic 18F- Fluorination of Heteroaromatic Iodonium Salts with No-Carrier-Added [18F]Fluoride. J Am Chem Soc 2007, 129, 8018-8025, doi:10.1021 / ja066850h. 5. Pike, V. W.; Aigbirhio, F. I. Reactions of cyclotron-produced [18F]fluoride with diaryl iodonium salts - a novel single-step route to no-carrier-added

[0018] fluoroarenes. J Chem Soc, Chem Commun 1995, 2215-2216, doi:10.1039 / C39950002215. 6. Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat Commun 2014, 5, 4365, doi:10.1038 / ncomms5365. 7. Kwon, Y.-D.; Son, J.; Chun, J.-H. Catalyst-Free Aromatic Radiofluorination via Oxidized Iodoarene Precursors. Org Lett 2018, doi:10.1021 / acs.orglett.8b03450. 8. Neumann, C.N.; Hooker, J.M.; Ritter, T. Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-). Nature 2016, 534, 369-373, doi:10.1038 / nature17667. 9. Terrier, F. Modern Nucleophilic Aromatic Substitution. 2013. M 254547 Anmeldetext.docx 10. Kwan, E. E.; Zeng, Y.; Besser, H. A.; Jacobsen, E. N. Concerted nucleophilic aromatic substitutions. Nat Chem 2018, 10, 917-923, doi:10.1038 / s41557- 018-0079-7. 11. Rohrbach, S.; Smith, A.J.; Pang, J.H.; Poole, D.L.; Tuttle, T.; Chiba, S.; Murphy, J.A. Concerted Nucleophilic Aromatic Substitution Reactions. Angew Chem Int Ed Engl 2019, 58, 16368-16388, doi:10.1002 / anie.201902216. 12. Makosza, M. Does Nucleophilic Substitution in Nitroarenes Proceed via Single Electron Transfer (SET)? European J Org Chem 2021, 2021, 6175-6179, doi:10.1002 / ejoc.202101017. 13. Gao, Y.; Yang, S.; Xiao, W.; Nie, J.; Hu, X.Q. Radical chemistry of nitrosoarenes: concepts, synthetic applications and directions. Chem Commun (Camb) 2020, 56, 13719-13730, doi:10.1039 / d0cc06023b. 14. Roscales, S.; Csaky, A.G. How to make C-N bonds using boronic acids and their derivatives without transition metals. Chem Soc Rev 2020, 49, 5159-5177, doi:10.1039 / c9cs00735k. 15. Hays, J.T.; Young, H.L.; Espy, H.H. p-Nitrosophenol chemistry. II. Amination of p-nitrosophenol ethers with primary aromatic amines. J Org Chem 1967, 32, 158-162, doi:10.1021 / jo01277a039. 16. Zou, S.; Zhang, V.; Wu, Q.; Zhao, T.; Li, V.; Liu, B.; Ma, X. Metal-Free, Hindered, Regioselective Access to Multifunctional Groups Diarylamines via S(N) Ar Substitution of P-Nitroso Aromatic Methyl Ether by Arylamines. Chemistry 2024, 30, e202303421, doi:10.1002 / chem.202303421. 17. Raviola, C.; Protti, S. Leaving Groups in Metal-Free Arylations: Make Your Choice! European J Org Chem 2020, 2020, 5292-5304, doi:10.1002 / ejoc.202000143. 18. Priewisch, B.; Rück-Braun, K. Efficient Preparation of Nitrosoarenes for the Synthesis of Azobenzenes. J Org Chem 2005, 70, 2350-2352, doi:10.1021 / jo048544x. 19. Garcia-Lacuna, J.; Baumann, M. Continuous Flow Synthesis of Nitrosoarenes via Photochemical Rearrangement of Aryl Imines. J Org Chem 2024, 89, 617–623. M 254547 Reviewtext.docx 20. Gooden , DM ; Chakrapani , H. ; Toone, EJ C-nitroso compounds: synthesis, physicochemical properties and biological activities. Curr Top Med Chem 2005, 5, 687–705. 21. van der Werf, A.; Selander, N. Para-Selective Halogenation of Nitrosoarenes with Copper(II) Halides. Org Lett 2015, 17, 6210–6213. orglett.5b03198. [CrossRef] [PubMed] 22. Laube, M.; Wodtke , R ; Kopka, K.; Kniess , T. ; Pietzsch, J. SP-050 - 18F- Chemistry in HPLC vials - a microliter scale radiofluorination approach. Nucl Med Biol 2021, 96–97, S61, doi:htt ps: / / doi.org / 10.1016 / S0969-8051(21)00367-X. 23. Pathuri, G.; Hedrick, A. F.; Awasthi, V.; Gali, H. Single-step radiosynthesis and in vivo evaluation of a novel fluorine- 18 labeled hippurate for use as a PET renal agent. Nucl Med Biol 2012, 39, 1195-1201, doi: 10.1016 / j.nucmedbio.2012.07.002. 24. Pascali, C.; Luthra, S. K.; Pike, V. W.; Price, G.W.; Ahier, R. G.; Hume, S. P.; Myers, R.; Manjil, L.; Cremer, J. E. The radiosynthesis of [18F]PK 14105 as an alternative radioligand for peripheral type benzodiazepine binding sites. Int J Rad Appl Instrum A 1990, 41, 477-482, doi: 10.1016 / 0883- 2889(90)90008-5. M 254547 Anmeldetext.docx

Claims

Patent claims 1. Method for the preparation of an organic compound comprising a group of general formula I R2 (Formula 1) exhibits, whereby A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; Ri and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; characterized in that an organic compound comprising a group of general formula II R2 (Formula II) exhibits, where A, Ri and R2 have the meanings given above, is subjected to radiofluorination.

2. The method according to claim 1, characterized in that the aryl or heteroaryl group A is a pyridinyl, indolyl, biphenylyl group or a 5- or 6-membered aromatic ring, which optionally comprises a heteroatom selected from O, N or S. M 254547 Registration text.docx 3. Method according to one of the preceding claims, characterized in that the aryl or heteroaryl group A is a 5- or 6-membered aromatic ring, which optionally has an N atom.

4. Method according to one of the preceding claims, characterized in that the aryl or heteroaryl group A is phenyl.

5. Method according to one of the preceding claims, characterized in that Ri and R2 are independently selected from the group consisting of H, Chlorine, Methyl, Ethyl, Methoxy, Ethoxy, Trifluoromethyl, Carboxymethyl, Carboxyethyl, Oxomethyl, Nitro or Cyano.

6. Method according to one of the preceding claims, characterized in that Ri is in ortho position with respect to the functional group and R2 is in meta or para position with respect to Ri.

7. The method of claim 6, characterized in that Ri is H or cyano and R2 is selected from the group consisting of H, chlorine, methyl, methoxy, trifluoromethyl, carboxyethyl, oxomethyl, methyl ketone, nitro or cyano.

8. Method according to one of claims 6 and 7, characterized in that Ri is H and R2 is selected from the group consisting of chlorine, trifluoromethyl, carboxyethyl, oxomethyl, nitro or cyano.

9. Method according to one of claims 6 and 7, characterized in that Ri is cyano and R2 is selected from the group consisting of H, Chlorine, Methoxy, Trifluoromethyl, Carboxyethyl, Oxomethyl, Nitro or Cyano.

10. The method of claim 9, characterized in that Ri is cyano and R2 is selected from the group consisting of H, chlorine and methoxy. M 254547 Registration text.docx 11. Method according to claim 9, characterized in that Ri cyano is in the ortho position with respect to the functional group and R2 chlorine or methoxy is in the para position with respect to Ri.

12. Use of an organic compound belonging to a group of general formula II NO R2 (Formula II) exhibits, whereby A is an aryl or heteroaryl group, optionally comprising 1 to 3 heteroatoms selected from O, N or S; Ri and R2 are independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 halogen alkyl, carboxy-C1-C6 alkyl, oxo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, nitro, cyano or -C(O)-R a , consists of R a selected from the group consisting of halogen, C1-C6 alkyl or an aryl group; to produce an organic compound comprising a group of the general formula I R2 (Formula 1) exhibits, where A, Ri and R2 have the meanings given above. M 254547 Registration text.docx

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