DEUTERED AND TRITIATED N-(4,5-DIMETHYLTHIAZOLE-2(3H)-YLIDENE)-2,2,3,3-TETRAMETHYLCYCLOPROPANE-1-CARBOXAMIDE DERIVATIVES AND THEIR USE

Description

[0001] The invention relates to deuterated and / or tritiated N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives and their use for the preparation of radiofluorinated compounds. It particularly relates to precursors for the preparation of radiofluorinated deuterated and tritiated N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives, the use of the precursors for this purpose and radiofluorinated deuterated and tritiated N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives. References to methods of treating the human or animal body in the following paragraphs are interpreted as references to compounds for use in methods of treating the human or animal body by therapy or diagnosis.

[0002] From WO 2009 / 067613 A1 compounds of the general formula S-1 are known, which are described as ligands for the cannabinoid receptor 2 (CNR 2 or CB 2 ). The compounds of the general formula S-1 are intended to be suitable as therapeutic agents for the treatment of diseases related to CBR 2. The cannabinoid receptor 2 is a component of the endocannabinoid system and is predominantly present in the immune system. The receptor is involved in the regulation of processes in the body, particularly metabolism and immune functions. It mediates pain perception and influences neuronal activity. Influencing the cannabinoid receptor 2 can lead to pain relief, especially chronic pain. In addition, the receptor mediates the effects of cannabinoids, such as (-)-Δ 9< - trans -Tetrahydrocannabinol, in the immune system.

[0003] The compounds known from WO 2009 / 067613 A1 are also said to be suitable for the treatment of inflammatory diseases, immune diseases, neurological disorders, cancers of the immune system, respiratory diseases and cardiovascular diseases.

[0004] Furthermore, the radiolabelled N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives are known. The compound [ 11< C]A836339 was published by Horti et al. (Bioorg. Med. Chem. 2010, 14, 5202-5207). Based on the (4,5-dimethylthiazol-2(3 H Selective, fluorinated CBR 2 ligands were synthesized by Moldovan et al. (J. Med. Chem. 2016, 59, 7840-7855 and J. Nuc. Med. 2015, 56, 53, 1048) using the 2,2,3,3-tetra-methylcyclopropane-1-carboxamide scaffold and studied in a mouse model of neuroinflammation (LPS). These compounds included [ 18< F]JHU94620.Based on Moldovan et al. (J. Med. Chem. 2016, 59, 7840-7855) [ 18< F]2f developed by Caille et al. (Mol. Pharmaceutics 2017, 11, 4064-4078).

[0005] The 18< F-labeled compound [ 18< F]JHU94620 is produced according to the state of the art (Moldovan et al. J. Med. Chem. 2016, 59, 7840-7855) via radiosynthesis starting from a bromine precursor. The bromine precursor corresponds to [ 18< F]JHU94620, except that in place of the [ 18< F] atom there is a bromine atom as a leaving group. [ 18< F]JHU94620 However, it has low metabolic stability.

[0006] For a medical application of compound [ 18< F]JHU94620 and others N -(4,5-Dimethylthiazole-2(3 H -ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives, the compounds should exhibit higher metabolic stability.

[0007] The object of the invention is to eliminate the disadvantages of the prior art. In particular, N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetra-methylcyclopropane-1-carboxamide derivatives are to be specified, which not only have a high affinity and selectivity towards CBR 2 , but also a high metabolic stability and can be used, for example, as radiopharmaceuticals or precursors for the production of radiotracers. In addition, a process for the production of N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide derivatives, which enables their preparation with high radiochemical yields.

[0008] This object is achieved by the features of claims 1, 8, 9, 11, 12, and 13. Advantageous embodiments of the inventions emerge from the features of the subclaims.

[0009] According to the invention, a compound of general formula I is provided: wherein X 1< is a CD 2 group or a CT 2 group; X 2< is oxygen or a group (CZ 1< Z 2< ) n , where Z 1< and Z 2< are each independently hydrogen, deuterium or tritium at each occurrence and n is an integer from 1 to 12; X 3< is a CD 2 group or a CT 2 group; and R is selected from the group consisting of hydroxy, -NO 2 , halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate.

[0010] A compound of general formula I can be its ( E ) isomer, whose ( Z ) isomer or a mixture of the ( E )- and ( Z) isomer.

[0011] A compound of general formula I may be provided, wherein X 1< is a CD 2 group or a CT 2 group; X 2< is selected from the group consisting of (CH 2 ) n , (CD 2 ) n , (CT 2 ) n and O, where n is an integer from 1 to 12; X 3< is a CD 2 group or a CT 2 group; and R is selected from the group consisting of hydroxy, -NO 2 , halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate.

[0012] If at least one of the radicals X 1< , X 2< and X 3< contains a deuterium atom, it can be provided that the radicals X 1< , X 2< and X 3< do not contain a tritium atom. In this case, the compound of the general formula I is either a deuterated compound or a tritiated compound, but not a compound which - apart from its natural occurrence - contains deuterium and tritium. The compounds of the general formula I according to the invention are preferably deuterated compounds. The deuterated compounds are preferably not tritiated compounds. In the following, the term "deuterated compound" refers to a compound which contains deuterium atoms but - apart from its natural occurrence - no tritium atoms. The term "tritiated compound", on the other hand, refers to a compound which contains tritium atoms but - apart from its natural occurrence - no deuterium atoms.

[0013] A compound of general formula I may be provided, wherein X 1< is a CD 2 group; X 2< is oxygen or a group (CZ 1< Z 2< ) n , where Z 1< and Z 2< are each independently hydrogen or deuterium at each occurrence and n is an integer from 1 to 12; X 3< is a CD 2 group; and R is selected from the group consisting of hydroxy, -NO 2 , halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulfonate. Such a compound is a deuterated compound.

[0014] A compound of general formula I may be provided, wherein X 1< is a CD 2 group; X 2< is selected from the group consisting of (CH 2 ) n , (CD 2 ) n and O, where n is an integer from 1 to 12; X 3< is a CD 2 group; and R is selected from the group consisting of hydroxy, -NO 2 , halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate. Such a compound is a deuterated compound.

[0015] A compound of general formula I may be provided, wherein X 1< is a CD 2 group; X 2< is (CH 2 ) n or (CD 2 ) n, where n is an integer from 1 to 12; X 3< is a CD 2 group; and R is selected from the group consisting of hydroxy, -NO 2 , halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulfonate. Such a compound is a deuterated compound.

[0016] According to the invention, n is an integer from 1 to 12. It can be provided that n is 1, 2, 3, 4, 5 or 6. In one example, n = 2. In this case, the N atom of the dimethylthiazole group carries a n -Butyl group.

[0017] It may be provided that the compound of general formula I is a compound of general formula IF or a compound of general formula IP: wherein X 1< , X 2< and X 3< have the meanings given in connection with formula I. AG denotes a leaving group selected from the group consisting of hydroxy, -NO 2 , chlorine, bromine, iodine, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate. A compound of the general formula IF can be its ( E ) isomer, whose ( Z ) isomer or a mixture of the ( E )- and ( Z )-isomer. A compound of the general formula IP can be its ( E ) isomer, whose ( Z) isomer or a mixture of the ( E )- and ( Z ) isomer.

[0018] The compound of formula IF is a compound of general formula I in which R is fluorine. The compounds of formula IF are deuterated and / or tritiated fluorinated compounds. It may be provided that the compound of general formula I is a compound of general formula [ 18< F]IF: where X 1< , X 2< and X 3< have the meanings given in connection with formula I. The compound of the formula [ 18< F]IF is a compound of the general formula I in which R is [ 18< F]fluorine. The compounds of the formula [ 18< F]IF are deuterated and / or tritiated radiofluorinated compounds. A compound of the general formula [ 18< F]IF can be its ( E ) isomer, whose ( Z ) isomer or a mixture of the ( E )- and ( Z ) isomer.

[0019] The compounds of the invention exhibit high metabolic stability. This is particularly advantageous for compounds of the general formula IF and [ 18< F]IF, because they are intended for use in positron emission tomography (PET). The high metabolic stability reduces the amount of metabolites in the brain ( in vivo) strong. The use of compounds in PET imaging requires that only small amounts of metabolites reach the brain. The compounds of the general formula I according to the invention, in particular of the general formula IF, for example the compounds of the general formula [ 18< F]IF, have a high binding affinity and selectivity towards CBR 2. Their binding affinity and selectivity correspond to those of the compounds that do not exhibit deuteration or tritiation. They can therefore be used as high-affinity and selective CBR 2 radiopharmaceuticals. The 18< F-labelled radiotracers of the general formula [ 18< F]IF according to the invention can be used to In vitro and In - vivo-Investigations of the expression and availability of CBR 2 in organisms using suitable detection methods such as positron emission tomography (PET) can be used. These studies make it possible to gain more precise knowledge about the effects of reference compounds and thus to develop other drugs in addition to the radiopharmaceutical and evaluate their potential efficacy.

[0020] The compound of general formula IP is a compound of general formula I, where R is a leaving group AG. The compounds of general formula IP can be used in particular as precursors for the preparation of compounds of general formula [ 18< F]IF.

[0021] It can be provided that AG is a sulfonate. The term "sulfonate" is understood to mean an RS< -SO 2 -O- group. RS< can be, for example, a branched or unbranched substituted or unsubstituted C 1 -C 6 alkyl group, an aryl group, or an alkylaryl group. Preferably, RS< is CH 3 -, CF 3 -, or CH 3 -C 6 H 4 -. The sulfonate can be selected, for example, from the group consisting of a toluenesulfonic acid ester group, a methylsulfonic acid ester group, and a trifluoromethylsulfonic acid ester group. A toluenesulfonic acid ester group is understood to mean an -OTs group, where Ts is tosyl. A methylsulfonic acid ester group is understood to mean an -OMs group, where Ms is mesyl. A trifluoromethylsulfonic acid ester group is understood to mean CF 3 -SO 2 -O-. Preferably, AG is -OMs or -OTs. AG -OTs is particularly preferred.

[0022] It can be provided that AG is an organotin compound. This can be an organotin compound. The organotin compound can be, for example, alkyltin, whose alkyl group(s) can be substituted or unsubstituted, where one or more of the alkyl groups optionally contain one or more heteroatoms, or aryltin, whose aryl group(s) can be substituted or unsubstituted, where one or more of the aryl groups optionally contain one or more heteroatoms. The heteroatoms can be, for example, O, N, S, or P.

[0023] It may be provided that AG is a halogen selected from the group consisting of chlorine, bromine and iodine.

[0024] Preferred examples of compounds of general formula I are given in Table 1 below. The compounds given in Table 1 can each be their ( E) isomer, whose ( Z ) isomer or a mixture of the ( E )- and ( Z ) isomer. Table 1 Connection structure name [ 18< F]JHU94620-D4 N -(3-(4-([ 18< F]Fluor)butyl-1,1,4,4- d 4 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid JHU94620-D4 N -(3-(4-Fluorbutyl-1,1,4,4- d 4 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetra-methylcyclopropan-1-carboxamid 3 4-(4,5-Dimethyl-2-((2,2,3,3-tetramethylcyclopropan-1-carbonyl)-imino)thiazol-3(2 H )-yl)butyl-1,1,4,4- d 4 -4-methylbenzensulfonat [ 18< F]JHU94620-D8 N -(3-(4-([ 18< F]Fluor)butyl-1,1,2,2,3,3,4,4- d 8 )-4,5-dimethylthiazol-2(3 H )-yli-den)-2,2,3,3-tetramethylcy-clopropan-1-carboxamid JHU94620-D8 N -(3-(4-Fluorbutyl-1,1,2,2,3,3,4,4- d 8 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcy-clopropan-1-carboxamid 4 4-(4, 5-Dimethyl-2-((2,2,3,3-tetramethylcyclo-propan-1-carbonyl)imino)-thiazol-3(2 H )-yl)butyl-1,1,2,2,3,3,4,4- d 8 -4-methylbenzensulfonat

[0025] The connections [ 18< F]JHU94620-D4 and [ 18< F]JHU94620-D8 are compounds of the general formula [ 18< F]IF. The compounds JHU94620-D4 and JHU94620-D8 are compounds of the general formula IF. The compounds 3 and 4 are compounds of the general formula IP. Compound 3 can be used in particular as a precursor for the production of [ 18< F]JHU94620-D4 be used. Connection 4 can be used in particular as a precursor for the production of [ 18< F]JHU94620-D8 be used.

[0026] It has been found that the compounds of general formula I according to the invention, in particular of general formula IF, are ligands for the cannabinoid receptor 2. They can therefore be used for the diagnosis and treatment of inflammatory diseases, immune diseases, neurological disorders, cancers of the immune system, respiratory diseases, and cardiovascular diseases. They can also be used to relieve pain. The compounds of general formula I according to the invention can thus be used as medicaments, in particular as medicaments for inflammatory diseases, immune diseases, neurological disorders, cancers of the immune system, respiratory diseases, and cardiovascular diseases. They can also be used as medicaments for the relief of pain.Likewise, a pharmaceutically acceptable salt of a compound of general formula I can be used as a medicament, particularly as a medicament for inflammatory diseases, immune diseases, neurological disorders, cancers of the immune system, respiratory diseases, and cardiovascular diseases, or as a medicament for the relief of pain. Inflammatory diseases include, for example, inflammation of nerve tissue (also known as neuroinflammation).

[0027] According to the invention, the use of a compound of the general formula IP for the preparation of a compound of the general formula [ 18< F]IF The compound of general formula IP corresponds to the compound of general formula [ 18< F]IF, except that the leaving group AG is replaced by [ 18< F]fluorine. All other substituents, i.e. X 1< , X 2< and X 3< including Z 1< and Z 2< , are unchanged and are in the same position. The substituents X 1< , X 2< , X 3< and AG in formulas IP and [ 18< F]IF have the meanings given above.

[0028] The compounds of general formula IP are particularly suitable precursors for the preparation of compounds of general formula [ 18< F]IF. For example, compound 3 as a precursor for the production of [ 18< F]JHU94620-D4 be used.

[0029] According to the invention, a process for preparing a compound of general formula IF, e.g., a compound of general formula [ 18< F]IF, is also provided. The process comprises the steps: (a) Reacting a compound of formula 11 with a compound of the general formula II wherein X 1< , X 2< , X 3< and AG have the meaning given in connection with the general formula IP and Y is a sulfonate, to a compound of the general formula IP; and (b) reacting the compound of the general formula IP with a fluorinating agent to give the compound of the general formula IF.

[0030] The compound of formula 11 can be its ( E ) isomer, whose ( Z ) isomer or a mixture of the ( E )- and ( Z ) isomer.

[0031] In the compound of general formula II, Y is preferably Y -O-Ts or O-Ms, particularly preferably O-Ts, where Ts denotes a tosyl group and Ms a mesyl group. It can further be provided that AG is also a sulfonate. In this case, for example, Y and AG can each have the same meaning. Thus, in a preferred embodiment, both Y and AG can each be -O-Ts. An example of a compound of general formula II is butane-1,4-diyl-1,1,4,4- d 4 -bis(4-methylbenzenesulfonate) ( 12 ). Another example of a compound of general formula II is butane-1,4-diyl-1,1,2,2,3,3,4,4- d 8 -bis(4-methylbenzenesulfonate) ( 13 ).

[0032] The reaction of compound II with a compound of general formula II provided for in step (a) of the process according to the invention can be carried out in an organic solvent. The organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF), N , N-Dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or mixtures thereof. Dimethylformamide is preferably used as the solvent. The temperature is preferably between 0 and 100°C, more preferably between 20 and 100°C, even more preferably between 40 and 80°C, particularly preferably 60°C. The reaction is preferably carried out at room temperature or an elevated temperature. The reaction is preferably carried out for a period of 10 minutes to 2 hours, more preferably from 30 minutes to 1.5 hours, and particularly preferably 60 minutes. The reaction is preferably carried out at ambient pressure. The reaction is preferably carried out with agitation of the reaction mixture, for example with stirring. Compound II and the compound of general formula II are preferably present in a molar ratio of 1:2 to 2:1, preferably 1:1.The reaction can be carried out in the presence of a hydride, preferably an alkali or alkaline earth metal hydride. A preferred hydride is sodium hydride (NaH). The reaction can be carried out under a protective gas atmosphere, for example, under a nitrogen or argon atmosphere. The concentration of compound II, the compound of general formula II, and, if present, the hydride in the solvent should each be at least 10 wt.%, based on the solution.

[0033] Step (b) involves reacting the compound of general formula IP with a fluorinating agent to form the compound of general formula IF. The choice of fluorinating agent and reaction conditions may depend on whether the compound of general formula IF is a compound of general formula [ 18< F]IF or is not radiofluorinated. Step (b): Conversion to a compound of the general formula [ 18 < F]IF

[0034] If the compound of general formula IF is a compound of general formula [18<F]IF, the fluorinating agent can be [18<F]fluoride anions. The [18<F]fluoride anions can be present in a solution, which is referred to below as the [18<F]fluoride-containing solution. In step (b), the [18<F]fluoride anion can be prepared using known methods to prepare the [18<F]fluoride-containing solution. For example, the [18<F]fluoride anion is prepared in a cyclotron by irradiating at least 97% enriched H218<O with protons having an energy of 9.6 MeV. The aqueous [ 18< F]fluoride-containing solution obtained in this way can be fixed on an anion exchange cartridge (QMA) and eluted with an aqueous solution of a base such as potassium carbonate, cesium carbonate, sodium hydride or tetraalkylammonium hydrogen carbonate.Preferably, an aqueous solution of potassium carbonate is used as the base. The basic [ 18< F]fluoride-containing solution is eluted into a reaction vessel containing a phase-transfer catalyst (PTC), such as crown ethers, quaternary ammonium salts, or alkali or alkaline earth metal salts. The PTC preferably used is a [2,2,2]-cryptand (Kryptofix®< or K222), tetra-n-butyl ammonium phosphate, hydroxide, oxalate, toluenesulfonate, or optionally other crown ethers such as 18-crown-6. The [ 18< F]fluoride complex obtained in this way can be subjected to azeotropic drying under vacuum. The organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF). N , N-Dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), or mixtures thereof. Acetonitrile is preferably used as the solvent. Azeotropic drying is preferably carried out under thermal conditions in a closed reaction vessel at elevated temperature. The temperature is preferably between 50 and 60 °C. Azeotropic drying can also be carried out with the assistance of microwaves. Microwaves with a power of 50 to 150 W, preferably 65 to 85 W, and particularly preferably 75 W, can be used for this purpose.

[0035] To carry out step (b), the azeotropically dried [ 18< F]fluoride complex is preferably dissolved in an organic solvent. This yields the [ 18< F]fluoride-containing solution. The organic solvent can be a non-protic, polar solvent such as acetonitrile (MeCN), dimethylformamide (DMF), N , N-Dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or mixtures thereof. Preferably, acetonitrile is used as the solvent. The precursor of the general formula P-1 is then added to this solution. The precursor is preferably dissolved beforehand in an organic solvent. This solvent is preferably the same solvent that is present as the solvent in the [ 18< F]fluoride-containing solution, i.e. acetonitrile. The precursor dissolved in the solvent is then added to the [ 18< F]fluoride-containing solution. Step (b) of the process according to the invention is preferably carried out at an elevated temperature. The temperature is preferably between 80 and 110 °C, more preferably 90 °C. Preferably, step (b) is carried out for a period of 5 to 15 minutes and most preferably 10 minutes.Step (b) of the process according to the invention is preferably carried out at ambient pressure. Step (b) is preferably carried out with agitation of the reaction mixture, for example with stirring. Step (b): Conversion to a compound of general formula 1-F, which does not contain [ 18 < F]-Fluorine contains

[0036] If the compound of general formula IF is not a compound of general formula [ 18< F]IF, the fluorinating agent may be a compound that enables nucleophilic fluorination of the compound of general formula IP. For example, the fluorinating agent may be a tetraalkylammonium fluoride. The tetraalkylammonium fluoride may be selected from the group consisting of tetrabutylammonium fluoride (TBAF), tetraethylammonium fluoride (TEAF), and tetramethylammonium fluoride (TMAF).

[0037] Step (b) can be carried out in an organic solvent. The organic solvent can be a non-protic, polar solvent such as tetrahydrofuran (THF), acetonitrile (MeCN), dimethylformamide (DMF), N , N-Dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or mixtures thereof. Tetrahydrofuran is preferably used as the solvent. The temperature is preferably between 0 and 100 °C, more preferably between 20 and 80 °C, even more preferably between 40 and 60 °C, particularly preferably at 60 °C. The reaction is preferably carried out at room temperature or an elevated temperature. The reaction is preferably carried out for a period of 10 minutes to 2 hours, more preferably from 30 minutes to 1.5 hours and particularly preferably 60 minutes. The reaction is preferably carried out at ambient pressure. The reaction is preferably carried out with agitation of the reaction mixture, for example with stirring. The compound of the general formula IP and the fluorinating agent are preferably present in a molar ratio of 1:3 to 2:1, preferably 2:1.The reaction can be carried out under a protective gas atmosphere, for example, under nitrogen or argon. The concentration of the compound of general formula IP and the fluorinating agent should each be at least 10 wt.%, based on the solution.

[0038] Scheme 1 illustrates the preparation of a compound of the general formula [ 18< F]IF according to the process of the invention:

[0039] Scheme 2 illustrates the preparation of a compound of general formula IF which does not contain [ 18< F]fluorine according to the process of the invention:

[0040] Step (a) enables the preparation of compounds of general formula IP. Step (a) is thus a process for preparing a compound of general formula IP. Scheme 3 illustrates the preparation of a compound of general formula IP:

[0041] The procedure described in connection with step (a) can also be used to prepare a compound of general formula IF, with the difference that instead of a compound of general formula II, a compound of general formula III is used. In the compound of general formula III, X 1< , X 2< and X 3< have the meanings given in connection with general formula IF. Scheme 4 illustrates the preparation of a compound of general formula IF. It can be provided that compound III does not contain [ 18< F]fluorine.

[0042] The invention enables, in particular, the radiosynthesis of deuterated compounds of the general formula [ 18< F]IF. In particular, the deuterated compounds of the general formula [ 18< F]IF can be used as radiotracers for nuclear medicine imaging of CBR 2 using positron emission tomography (PET). The deuterated compounds of the general formula [ 18< F]IF exhibit high affinity and selectivity towards CBR 2.

[0043] It is known that hydrogen is a mixed element. In the preparation of the compound known from the prior art [ 18< F]JHU94620Therefore, small amounts of deuterated and / or tritiated isotopologues can be obtained. However, the proportion of deuterated and / or tritiated isotopologues is small because it is determined by the natural abundance of deuterium and tritium. In the present invention, any atom not expressly named as a specific isotope is a stable isotope. Unless otherwise stated, a residue designated as hydrogen or H is understood to mean a residue that has hydrogen in its natural isotopic ratio. Unless otherwise stated, a residue designated as deuterium or D is understood to mean a residue that has deuterium in an abundance that is at least 3000 times greater than the natural abundance of deuterium. Assuming a natural abundance of deuterium of 0.015%, a 3000 times higher abundance means a deuterium incorporation of 45%.Unless otherwise stated, a residue designated as tritium or T is understood to be one that contains tritium in an abundance at least 4.5*10 16 times greater than the natural abundance of tritium. Assuming a natural abundance of tritium of 10 -15%, a 4.5*10 16 times higher abundance means a tritium incorporation of 45%. The term "isotopologues" refers to molecules that differ only in their isotopic composition. They have the same chemical formula and the same bonding relationships between the atoms, but differ in at least one atom having a different number of neutrons.

[0044] The ratio between the abundance of an isotope in a compound and the natural abundance of the isotope is called the "isotope enrichment factor." As described above, the isotope enrichment factor should be at least 3000 (45% incorporation of deuterium for a deuterium residue) for each atom designated as deuterium. The isotopic enrichment factor may be at least 3500 (52.5% incorporation of deuterium), at least 4000 (60% incorporation of deuterium), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 (99% incorporation of deuterium) or at least 6633.3 (99.5% incorporation of deuterium).As described above, the isotopic enrichment factor for each atom designated as tritium should be at least 4.5*10 16< (45% incorporation of tritium for a residue designated as tritium). The isotopic enrichment factor can be at least 5.25*10 16< (52.5% incorporation of tritium), at least 6 *10 16< (60% incorporation of tritium), at least 6.75*10 16< (67.5% incorporation of tritium), at least 7.5*10 16< (75% incorporation of tritium), at least 8.25*10 16< (82.5% incorporation of tritium), at least 9*10 16< (90% incorporation of tritium), at least 9.5*10 16< ,3 (95% incorporation of tritium), at least 9.7*10 16< (97% incorporation of tritium), at least 9.9*10 16< (99% incorporation of tritium) or at least 9.95*10 16< (99.5% incorporation of tritium).

[0045] A compound which, according to the invention, is to have at least one deuterium atom or one tritium atom can be regarded as a group of isotopologues. The proportion of isotopologues forming a compound can vary. A compound which, according to the invention, is to have at least one deuterium atom or one tritium atom contains minor amounts of isotopologues which have hydrogen atoms instead of one or more of the specified deuterium atoms or tritium atoms. The relative amount of these isotopologues should, based on the compound, be less than 55% of the compound. It can be provided that the relative amount of these isotopologues is less than 50%, less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%.

[0046] The term "alkyl," unless otherwise stated, 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 most 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 independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino, unless specifically stated otherwise.

[0047] 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.

[0048] Unless otherwise specified, the term "aryl" or "arene" refers to a cyclic, aromatic hydrocarbon group consisting of a mono-, bi-, or tricyclic aromatic ring system containing 5 to 15 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, anthracenyl, naphthalenyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenyl sulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, 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 which may optionally be substituted independently by 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 (wherein R is hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R") n -COOR (wherein 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'< (wherein n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl and R a'< and R b'< are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).Examples of an arene include, but are not limited to, benzene, naphthalene, and anthracene.

[0049] The term "acyl", unless otherwise stated, refers in particular to a group of the formula -C(=O)R, where R is hydrogen or alkyl as defined herein.

[0050] The term "halogen" refers, unless otherwise specified, to fluorine, chlorine, bromine or iodine.

[0051] The invention will be explained in more detail below using exemplary embodiments, which are not intended to limit the invention, with reference to the drawings. Fig. 1 a UV-HPLC chromatogram of the reference compound JHU94620-D4; Fig. 2 a radio-HPLC chromatogram of the compound according to the invention [ 18< F]JHU94620-D4; Fig. 3 a radio-HPLC chromatogram of brain homogenate 30 pi from [ 18< F]JHU94620; and Fig. 4 a radio-HPLC chromatogram of brain homogenate 30 pi of [ 18< F]JHU94620-D4 Example 1 Synthesis of N -(3-(4-([ 18 < F]Fluor)butyl-1,1,4,4- d 4 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( [ 18 < F]JHU94620-D4 )

[0052] Scheme 5 shows the preparation of the compound according to the invention [ 18< F]JHU94620-D4 by implementing N -(4,5-Dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ( 11 ) with butane-1,4-diyl-1,1,4,4- d 4 -bis(4-methylbenzenesulfonate) ( 12 ) to the precursor ( 3 ) and the subsequent implementation of connection 3 to [ 18< F]JHU94620-D4

[0053] When connected 12 is a compound of general formula II, in which X 1< CD 2, X 2< (CH 2 ) 2, X 3< CD 2, Y is -OTs and AG is -OTs. K[ 18< F]FK 222 denotes the [ 18< F]F -< / K 222 / K +< complex, the preparation of which is described below. Schritt (a): Synthese von 4-(4,5-Dimethyl-2-((2,2,3,3-tetramethylcyclopropan-1-carbonyl)-imino)thiazol-3(2 H )-yl)butyl-1,1,4,4- d 4 -4-methylbenzensulfonat ( 3 )

[0054] To a solution of connection 11NaH (60%, 2 eq, 1.2 mmol) was added to compound 12 (1.5 eq, 0.9 mmol) in 3 mL of DMF, and the mixture was heated to 60 °C for 1 h under an argon atmosphere. The solvent was then removed using a rotary evaporator. The residue was taken up in ethyl acetate (EA) (10 mL) and washed with an aqueous 5% NaHCO 3 solution (10 mL) and then with saturated NaCl solution (100 mL). Drying over MgSO 4 and removal of the solvent yielded a yellow oil, which was purified by column chromatography (silica gel, EA:petroleum ether (PE) from 1 / 20 to 1 / 4). 3 was obtained as a white solid with a yield of 33%.

[0055] 1< H-NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H), 2.16 (s, 6H), 1.75 (m, 4H) 1.50 (s, 1H), 1.33 (s, 6H), 1.21 (s, 6H). HRMS (ESI+): m / z(%) = 483.2278, calc. 483.2284 for C 24 H 31 D 4 FN 2 O 4 S 2 +< [M+H] +< . Step (b): Synthesis of N -(3-(4-([ 18 < F]Fluor)butyl-1,1,4,4- d 4 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( [ 18 < F]JHU94620-D4 )

[0056] The aqueous [ 18< F]fluoride (2 to 3 GBq) obtained after irradiation was added to 1 ml of water, fixed on an anion exchange cartridge (QMA), and eluted with an aqueous K 2 CO 3 solution (1.8 mg in 300 ml water) into a solution of 1 ml MeCN and Kryptofix (K 222 , 5.6 mg). Azeotropic drying of the complex was carried out under vacuum with microwave assistance (power cycling, 75 W, 50-60 °C, argon flow). The formed [ 18< F]F -< K 222 / K +< complex was treated with 2 mg of the precursor 3 (in 600 ml MeCN). The reaction mixture was then stirred at 90 °C for 10 min.

[0057] To determine the labeling yield, an aliquot was taken and analyzed by radio-TLC (49 ± 4%, n = 3) and radio-HPLC (48 ± 5%, n = 2). Purification and isolation of the radiotracer was performed using semi-preparative RP-HPLC (column: ReproSil-Pur 120 C18-AQ, 250 x 20 mm, 5 mm; eluent: 65% MeCN / 20 mM NH 4 OAc aq.; flow rate: 4.2 ml / min). The collected product fraction was diluted with water (20 ml), sorbed onto a Sep-Pak®-C18-Plus cartridge, and eluted with ethanol (EtOH) (1.0 ml). The solvent was then removed by heating in an argon stream and formulated in a 0.9% saline solution (≤ 10% ethanol, v / v). The product was obtained within a synthesis time of approximately 102 min. [ 18< F]JHU94620-D4 isolated and analyzed by radio-HPLC and radio-TLC, with the identity of the product being confirmed by co-injection of the reference compound (see Figures 1 and 2). The radiochemical purity was ≥ 99%. The radiochemical yield was approximately 20 to 25%. The molar activity was 200 ± 20 GBq / µmol. Comparison example 1 Synthesis of N -(3-(4-([ 18 < F]Fluor)butyl)-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( [ 18 < F]JHU94620 )

[0058] For comparison purposes, [ 18< F]JHU94620, as described in Moldovan et al. J. Med. Chem. 2016, 59, 7840-7855, using a bromine precursor. [ 18< F]JHU94620 was obtained with a radiochemical yield of 16% and a molar activity of 170 GBq / µmol. Example 2 Synthesis of N -(3-(4-Fluorobutyl-1,1,4,4- d 4 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( JHU94620-D4 )

[0059] Scheme 6 shows the preparation of the compound according to the invention JHU94620-D4 by implementing N -(4,5-Dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ( 11 ) with butane-1,4-diyl-1,1,4,4- d 4 -bis(4-methylbenzenesulfonate) ( 12 ) to the precursor ( 3) and the subsequent implementation of connection 3 to JHU94620-D4. TBAF stands for tetrabutylammonium fluoride. Schritt (a): Synthese von 4-(4,5-Dimethyl-2-((2,2,3,3-tetramethylcyclopropan-1-carbonyl)-imino)thiazol-3(2 H )-yl)butyl-1,1,4,4- d 4 -4-methylbenzensulfonat ( 3 )

[0060] Step (a) of the process shown in Scheme 6 was carried out as described in Example 1, step (a). Step (b): Synthesis of N -(3-(4-Fluorobutyl-1,1,4,4- d 4 )-4,5-dimethylthiazole-2(3 H )-y-lidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ( JHU94620-D4 )

[0061] To a solution of connection 3TBAF (1M in THF, 2 eq, 1 mmol) was added to the reaction mixture (1 eq, 0.5 mmol) in 3 mL of THF, and the mixture was heated to 50 °C for 1 h under an argon atmosphere. The solvent was then removed using a rotary evaporator. The residue was taken up in ethyl acetate (EA) (10 mL) and washed with an aqueous 5% NaHCO 3 solution (10 mL) and then with saturated NaCl solution (100 mL). Drying over MgSO 4 and removal of the solvent yielded a yellow oil, which was purified by column chromatography (silica gel, EA:petroleum ether (PE) from 1 / 20 to 1 / 4). JHU94620-D4 was obtained as a white solid with a yield of 72%.

[0062] 1< H-NMR (300 MHz, CDCl 3 ) δ 2.20 (s, 3H), 2.18 (s, 3H), 1.55 (s, 1H), 1.36 (s, 6H), 1.24 (s, 6H). HRMS (ESI+): m / z (%) = 331.2152, calc. 331.2152 for C 17 H 24 D 4 FN 2 OS +< [M+H] +< . Example 3 Synthesis of N -(3-(4-([ 18 < F]Fluor)butyl-1,1,2,2,3,3,4,4- d 8)-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( [ 18 < F]JHU94620-D8 )

[0063] Scheme 7 shows the preparation of the compound according to the invention [ 18< F]JHU94620-D8 by implementing N -(4,5-Dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ( 11 ) with butane-1,4-diyl-1,1,2,2,3,3,4,4- d 8 -bis(4-methylbenzenesulfonate) ( 13 ) to the precursor ( 4 ) and the subsequent implementation of connection 4 to [ 18< F]JHU94620-D8.

[0064] When connected 13 is a compound of general formula II, in which X 1< CD 2, X 2< (CD 2 ) 2, X 3< CD 2, Y is -OTs and AG is -OTs. Schritt (a): Synthese von 4-(4.5-Dimethyl-2-((2,2,3,3-tetramethylcyclopropan-1-carbonyl)-imino)thiazol-3(2 H )-yl)butyl-1,1,2,2,3,3,4,4- d 8 -4-methylbenzensulfonat ( 4 )

[0065] Connection 4 was prepared in the same manner as in Example 1, step (a), except that instead of compound 12 Connection 13 was used.

[0066] 1< H-NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H), 2.16 (s, 6H), 1.50 (s, 1H), 1.33 (s, 6H), 1.21 (s, 6H). HRMS (ESI+): m / z (%) = 487.2537, calc. 487.2535 for C 24 H 27 D 8 N 2 O 4 S 2 +< [M+H] +< . Step (b): Synthesis of N -(3-(4-([ 18 < F]Fluoro)butyl-1,1,2,2,3,3,4,4- d 8 )-4,5-dimethylthiazole-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([ 18< F]JHU94620-D8)

[0067] [ 18 < F]JHU94620-D8 was prepared in the same manner as in Example 1, step (b), except that instead of compound 3 Connection 4 was used. Example 4 Synthesis of N -(3-(4-Fluorobutyl-1,1,2,2,3,3,4,4- d 8 )-4,5-dimethylthiazol-2(3 H )-yli-den)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( JHU94620-D8 )

[0068] Scheme 8 shows the preparation of the compound according to the invention JHU94620-D8 by implementing N -(4,5-Dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ( 11 ) with butane-1,4-diyl-1,1,2,2,3,3,4,4- d 8 -bis(4-methylbenzenesulfonate) ( 13 ) to the precursor ( 4) and the subsequent implementation of connection 4 to JHU94620-D8. Schritt (a): Synthese von 4-(4,5-Dimethyl-2-((2,2,3,3-tetramethylcyclopropan-1-carbonyl)-imino)thiazol-3(2 H )-yl)butyl-1,1,2,2,3,3,4,4- d 8 -4-methylbenzensulfonat ( 4 )

[0069] Step (a) of the process shown in Scheme 8 was carried out as described in Example 1, step (a). Step (b): Synthesis of N -(3-(4-Fluorobuiyl-1,1,2,2,3,3,4,4- d 8 )-4,5-dimethylthiazol-2(3 H )-yliden)-2,2,3,3-tetramethylcyclopropan-1-carboxamid ( JHU94620-D8 )

[0070] JHU94620-D8 was prepared in the same manner as in Example 2, step (b), except that instead of compound 3 Connection 4 was used.

[0071] 1< H-NMR (300 MHz, CDCl 3 ) δ 2.20 (s, 3H), 2.18 (s, 3H), 1.93 - 1.81 (m, 2H), 1.77 - 1.68 (m, 2H), 1.55 (s, 1H), 1.36 (s, 6H), 1.24 (s, 6H). HRMS (ESI+): m / z (%) = 335.2402, calc. 335.2403 for C 17 H 20 D 8 FN 2 OS +< [M+H] +< . Beispiel 5 Investigation of the metabolic stability of [ 18< F]JHU94620-D4

[0072] The metabolic stability of [ 18< F]JHU94620-D4 was determined according to the method described by Moldovan et al., J. Med. Chem. 2016, 59, 7840-7855. Similarly, the metabolic stability of JHU94620 and [ 18< F]JHU94620 determined. The Figuren 3 und 4 The radio-HPLC chromatograms shown were determined using a ReproSil-Pur-C18-AQ column 250 x 4.6 mm, 5 mm; eluent: 10 - 90 - 10% MeCN / 20 mM NH 4 OAc; flow: 1 ml / min). JHU94620 has the following formula:

[0073] JHU94620 is the non-radiofluorinated and non-deuterated analogue of [ 18< F]JHU94620-D4 and [ 18< F]JHU94620-D8.

[0074] It is in Fig. 4 to recognize that in the In - vivo -Metabolite study in female CD-1 mice 30 min after injection the proportion of intact radiotracer [ 18< F]JHU94620-D4 in the brain was ~80% (radio-HPLC, extraction yield >97%) and in plasma ~15% (radio-HPLC, extraction yield >95%). Fig. 3 shows that the proportion of intact radiotracer [ 18< F]JHU94620 was only 38%. [ 18< F]JHU94620-D4 thus has a much higher metabolic stability than [ 18< F]JHU94620 on.

[0075] In the In - vivo -Metabolite study in female CD-1 mice was JΣIU94620 30 min after injection, the proportion of intact radiotracer in the brain was 36% (radio-HPLC, n = 3, extraction yield 93%) and in the plasma 7% (radio-HPLC, n = 3, extraction yield 94%) of the total activity.

[0076] The metabolic stability of [ 18< F]JHU94620-D8 is similar to that of [ 18< F]JHU94620-D4 to a high degree. Beispiel 6 Determination of the CBR 2 equilibrium dissociation constant KD of [ 18< F]JHU94620-D8

[0077] The equilibrium dissociation constant KD was determined using a homologous competition assay. For this purpose, a constant amount of binding protein (homogenate of CHO cells stably transfected with human CBR 2 receptor; 2 million cells / ml) was mixed with a constant amount of [ 18< F]JHU94620-D8 (0.101 nM in the batch) and an increasing concentration of JHU94620 (0.01 nM - 10 µM in the mixture) for 60 minutes at room temperature in binding buffer (50 mM TRIS-HCl, pH 7.4, with 5 mM MgCl 2 , 1 mM EDTA, 1% BSA). The separation of receptor-bound and free radioligand was carried out by filtration through a GF / B glass fiber filter incubated with 0.3% polyethyleneimine. The quantification of receptor-bound radioligand was carried out by measuring the filter-bound radioactivity in a gamma counter. The determination of the nonspecific binding of [ 18< F]JHU94620-D8 was carried out by co-incubation with CP55940 (10 µM in the mixture), the determination of the adsorption of the radioligand to the glass fiber filter was carried out by incubation without binding protein. From the IC 50 value obtained in this experiment (2.82 nM), the KD value of the compound can be calculated using the Cheng-Prusoff equation (KD = IC 50 (M) - radioligand (M)) simplified according to the experimental approach. [ 18< F]JHU94620-D8 The binding potential of the radioligand to human CBR 2 receptors is calculated to be KD = 2.72 nM. CP55940 is a synthetic cannabinoid. Beispiel 7 Determination of the CBR 2 equilibrium dissociation constant K i of JHU94620

[0078] Using the Cheng-Prusoff equation K i = IC 50 ( 1 + L K D the CBR 2 equilibrium dissociation constant K i was JHU94620 L denotes the concentration of the free ligand. Compound JHU94620 showed a CBR 2 affinity of K i = 0.4 nM (n = 3). Replacing hydrogen atoms with deuterium ions is said to have no effect on the K i value. This also applies to replacing hydrogen atoms with tritium ions.

Claims

1. A compound of general formula I wherein X1 is a CD2 group or a CT2 group; X2 is oxygen or a group (CZ1Z2)n, wherein Z1 and Z2 on each occurrence independently each are hydrogen, deuterium, or tritium and n is an integer from 1 to 12; X3 is a CD2 group or a CT2 group; and R is selected from the group consisting of hydroxy, -NO2, halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulphoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulphonate.

2. The compound according to claim 1, characterized in that X1 is a CD2 group or a CT2 group; X2 is selected from the group consisting of (CH2)n, (CD2)n, (CT2)n, and O, wherein n is an integer from 1 to 12; X3 is a CD2 group or a CT2 group; and R is selected from the group consisting of hydroxy, -NO2, halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulphoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulphonate.

3. The compound according to claim 1 or claim 2, characterized in that X1 is a CD2 group; X2 is selected from the group consisting of (CH2)n, (CD2)n, and O, wherein n is an integer from 1 to 12; X3 is a CD2 group; and R is selected from the group consisting of hydroxy, -NO2, halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulphoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulphonate.

4. The compound according to any of the preceding claims, characterized in that n is 1, 2, 3, 4, 5, or 6.

5. The compound according to any of the preceding claims, characterized in that R is fluorine.

6. The compound according to any of the preceding claims, characterized in that R is [18F]fluorine.

7. The compound according to any of the preceding claims, characterized in that it is N-(3-(4-([18F]fluoro)butyl-1,1,4,4-d4)-4,5-dimethylthiazole-2(3H)-yli-dene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide; N-(3-(4-fluorobutyl-1,1,4,4-d4)-4,5-dimethylthiazole-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide; 4-(4,5-dimethyl-2-((2,2,3,3-tetramethylcyclopropane-1-carbonyl)-imino)thiazole-3(2H)-yl)butyl-1,1,4,4-d4-4-methylbenzene sulphonate; N-(3-(4-([18F]fluoro)butyl-1,1,2,2,3,3,4,4-d8)-4,5-dimethylthiazole-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide; N-(3-(4-fluorobutyl-1,1,2,2,3,3,4,4-d8)-4,5-dimethylthiazole-2(3H)-yli-dene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide; or 4-(4,5-dimethyl-2-((2,2,3,3 -tetramethylcyclopropane-1-carbonyl)-imino)thiazole-3(2H)-yl)butyl-1,1,2,2,3,3,4,4-d8-4-methylbenzene sulphonate.

8. A compound according to any of claims 1 to 7 for use as a medicament.

9. A compound according to any of claims 1 to 7 for use as a medicament for the diagnostics and therapy of diseases in which a cannabinoid receptor 2 is involved.

10. The compound according to claim 8 or claim 9, characterized in that the medicament is a radiopharmaceutical for the nuclear-medical imaging of the cannabinoid receptor 2 by means of positron emission tomography (PET).

11. A medicament containing a compound according to any of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. Use of a compound of general formula I-P wherein X1 is a CD2 group or a CT2 group; X2 is oxygen or a group (CZ1Z2)n, wherein Z1 and Z2 on each occurrence independently each are hydrogen, deuterium, or tritium and n is an integer from 1 to 12; X3 is a CD2 group or a CT2 group; and AG is selected from the group consisting of hydroxy, -NO2, chlorine, bromine, iodine, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulphonate, for the preparation of a compound of general formula [18F]I-F wherein X1, X2, and X3 have the meanings given in connection with general formula I-P.

13. A method for the preparation of a compound of general formula I-F, wherein X1 is a CD2 group or a CT2 group; X2 is oxygen or a group (CZ1Z2)n, wherein Z1 and Z2 on each occurrence independently each are hydrogen, deuterium, or tritium and n is an integer from 1 to 12; and X3 is a CD2 group or a CT2 group; wherein the method comprises the steps of: (a) reacting a compound of formula 11 with a compound of general formula II wherein X1, X2, and X3 have the meanings given in connection with general formula I-P; Y is a sulphonate; and AG is selected from the group consisting of hydroxy, -NO2, chlorine, bromine, iodine, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide, and a sulphonate; to a compound of general formula I-P wherein X1, X2, X3, and AG have the meanings given in connection with general formula II; and (b) reacting the compound of general formula I-P with a fluorinating agent to the compound of general formula I-F.

14. The method according to claim 13, characterized in that Y is -O-Ts or -O-Ms, wherein Ts designates a tosyl group and Ms a mesyl group.

15. The method according to claim 13 or claim 14, characterized in that Y is -O-Ts, wherein Ts designates a tosyl group.