DE102019110904B4 - N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives and their use - Google Patents

Abstract

Compound of general formula I-Pworin is a phenyl group or a pyridyl group; R 1 is hydrogen or a nitro group; andAG is a leaving group, wherein the leaving group is selected from the group consisting of a nitro group, a diazonium ion or salt, a trialkylammonium ion or salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic ester, alkyltin, aryltin, an iodonium ion or salt, an iodonium ylide and a sulfonic acid ester.

Description

The invention relates to N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives and their use as medicaments. The invention particularly relates to ¹⁸ F-fluorinated N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives and their use as radiopharmaceuticals for nuclear medicine imaging of adenosine A _2A receptors by means of positron emission -Tomography (PET).

Out WO 01/97786 A2 Benzo[d]thiazole derivatives are known, which are described as ligands for adenosine receptors. The benzo[d]thiazole derivatives described are intended to be used as therapeutic agents for treating diseases that are related to A _2A receptors. Adenosine A _2A receptors belong to the group of G protein-coupled receptors (GPCRs), which mediate the effects of adenosine on different organ systems. A _2A receptors couple in particular to stimulatory G _s proteins. The coupled G _s proteins in turn activate adenylyl cyclases and thus stimulate the production of cAMP. A pharmacological blockade or stimulation of the adenosine A _2A receptors can therefore influence human diseases. However, the pharmacological influence exerted by the administration of compounds which _{inhibit or stimulate A 2A} receptors requires, on the one hand, knowledge of their effects which is as precise as possible. On the other hand, it is desirable to develop compounds that have the highest possible effectiveness when diseases associated with changes in adenosine A _2A receptors are to be diagnosed and treated. The effectiveness is largely determined by the binding strength (affinity) to the adenosine A _2A receptor and the selectivity over other protein molecules.

Out WO 2003/043634 other benzo[d]thiazole derivatives are known which are said to have good affinity for the A _2A receptor, high selectivity for the A ₁ and A ₃ receptors and good solubility in water. WO 04/43636 A1 , WO 03/053946 A1 , U.S. 2004/0235842 A1 , US 2004/0242576 A1 and WO 2006/008041 disclose benzo[d]thiazole derivatives, which are also said to have good affinity for the A _2A receptor and high selectivity for the A ₁ and A ₃ receptors. The end U.S. 2005/0261289 A1 well-known 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide is a high affinity _{A 2A receptor antagonist} and high selectivity with potent and long-acting antagonism against behavior _{induced by adenosine A 2A} receptor agonists.

Other modified benzo[d]thiazole derivatives have been described by Basu et al., J. Med. Chem. 2017, 60, 681-694 and by MAR Skraban (Reports by the Research Center Jülich 4405; ISSN 0944-2952, Institute for Neuroscience and Medicine , Nuclear Chemistry INM-5).

The preparation of ¹⁸ F-labeled N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives by suitable precursors and their use as radiotracers are not known from the prior art. An important challenge is the labeling of arenes that are not amenable to ^{aromatic nucleophilic substitution with [ 18 F]fluoride.}

Out WO 2013/167653 A1 the radiofluorination of a folic acid derivative is known.

The object of the invention is to eliminate the disadvantages of the prior art. In particular, N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives are to be specified which have a high affinity and selectivity for adenosine A _2A receptors. In particular, compounds are to be specified which can be used as radiopharmaceuticals for nuclear medicine imaging of adenosine A _2A receptors by means of PET.

This object is solved by the features of claims 1, 8, 12, 14 and 15. Expedient refinements of the invention result from the features of the dependent claims.

vorgesehen, worin

eine Phenylgruppe oder eine Pyridylgruppe ist;
R¹ Wasserstoff oder eine Nitrogruppe ist; und
AG eine Abgangsgruppe ist, wobei die Abgangsgruppe aus der Gruppe ausgewählt ist, die aus einer Nitrogruppe, einem Diazoniumion oder -salz, einem Trialkylammoniumion oder -salz, einem Dialkoxyaren, einem Sulfoxid, einer Boronsäure, einem Boronsäureester, Alkylzinn, Arylzinn, einem Iodoniumion oder -salz, einem Iodonium-Ylid und einem Sulfonsäureester besteht.According to the invention, a compound of the general formula IP

provided in which

is a phenyl group or a pyridyl group;
R ^{1 is} hydrogen or a nitro group; and
AG is a leaving group, wherein the leaving group is selected from the group consisting of a nitro group, a diazonium ion or salt, a trialkylammonium ion or salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic ester, alkyltin, aryltin, an iodonium ion or salt, an iodonium ylide and a sulfonic acid ester.

vorgesehen, worin

eine Phenylgruppe oder eine Pyridylgruppe ist;
R¹ Wasserstoff oder eine Nitrogruppe ist; und
R² [¹⁸F]Fluor ist.It is a compound of general formula I

provided in which

is a phenyl group or a pyridyl group;
R ^{1 is} hydrogen or a nitro group; and
R ^{2 is} [ ¹⁸ F]fluoro.

wird im Folgenden auch als Ar-Gruppe bezeichnet. Die Ar-Gruppe ist ein aromatischer Sechsring. Dieser Ring wird im Folgenden zur Vereinfachung auch als „Sechsring“ bezeichnet. Handelt es sich bei der Ar-Gruppe um eine Phenylgruppe, so sind alle Ringatome Kohlenstoffatome. Handelt es sich bei der Ar-Gruppe um eine Pyridylgruppe, sind fünf der Ringatome Kohlenstoffatome und das sechste Ringatom ein Stickstoffatom. Die Bindung zwischen der Pyridylgruppe und der N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamid-Gruppe kann dabei über ein Kohlenstoffatom des Sechsringes realisiert sein.The rest

is also referred to below as the Ar group. The Ar group is an aromatic six-membered ring. For the sake of simplicity, this ring is also referred to below as a “six-ring”. When the Ar group is phenyl, all ring atoms are carbon atoms. When the Ar group is pyridyl, five of the ring atoms are carbon and the sixth ring atom is nitrogen. The bond between the pyridyl group and the N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide group can be realized via a carbon atom of the six-membered ring.

The Ar group, whether phenyl or pyridyl, has one or two substituents other than hydrogen. The bond between the pyridyl group and the radicals R ¹ and R ² can in each case be realized via a carbon atom of the six-membered ring. If the radical R ^{1 is} not hydrogen, it is a nitro group which can be attached to a carbon atom of the six-membered ring.

According to the invention it is provided that R ^{2 is} [ ¹⁸ F]fluorine.

The term "halo" refers to fluoro, chloro, bromo or iodo unless otherwise specified. The term fluorine can designate the non-radioactive isotope ¹⁹ F or the radioactive isotope ¹⁸ F. The term iodine can denote the non-radioactive isotope ¹²⁷ I or the radioactive isotope ^{125 I.}

The term "alkyl", unless otherwise specified, refers in particular to a monovalent, saturated aliphatic hydrocarbon group having a branched or unbranched carbon chain having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms and more preferably from 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 be optionally substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.

The term "heteroalkyl" particularly refers to an alkyl radical, as defined herein, wherein one, two or three hydrogen atoms are substituted by a substituent independently selected from the group consisting of -OR ^a , -NR ^b R ^c and -S(O) _n R ^d (where n is an integer from 0 to 2), with the proviso that the point of attachment of the heteroalkyl radical is a carbon atom, where R ^{a is} hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; R ^b and R ^{c are} independently hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and when n is 0, R ^{d is} hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R ^{d is} alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1 -methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

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

The term "alkoxy", unless otherwise indicated, particularly refers 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 be optionally substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.

The term "aryl", unless otherwise specified, refers to a cyclic aromatic hydrocarbon group consisting of a mono-, bi- or tricyclic aromatic ring system having 5 to 10 ring atoms, preferably 5 or 6 ring atoms. The aryl group may be an optionally substituted aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, adamantyl, naphthalenyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof. The term "substituted aryl group" particularly refers to an aryl group optionally substituted independently 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 -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) is substituted. Unless otherwise stated, the aryl group can be monovalent or polyvalent, for example monovalent or divalent.

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

eine Phenylgruppe oder eine Pyridylgruppe ist;
R¹ Wasserstoff ist; und
R² [¹⁸F]Fluor ist.According to the invention, a compound of general formula I is provided, wherein

is a phenyl group or a pyridyl group;
R ^{1 is} hydrogen; and
R ^{2 is} [ ¹⁸ F]fluoro.

eine Phenylgruppe oder eine Pyridylgruppe ist;
R¹ eine Nitrogruppe ist; und
R² [¹⁸F]Fluor ist.According to the invention, a compound of general formula I is provided, wherein

is a phenyl group or a pyridyl group;
R ^{1 is} a nitro group; and
R ^{2 is} [ ¹⁸ F]fluoro.

hergestellt werden, worin

eine Phenylgruppe oder eine Pyridylgruppe ist;
R¹ Wasserstoff oder eine Nitrogruppe ist; und
AG eine Abgangsgruppe ist, die aus der Gruppe ausgewählt ist, die aus einer Nitrogruppe, einem Diazoniumion oder -salz, einem Trialkylammoniumion oder -salz, einem Dialkoxyaren, einem Sulfoxid, einer Boronsäure, einem Boronsäureester, Alkylzinn, Arylzinn, einem Iodoniumion oder -salz, einem Iodonium-Ylid und einem Sulfonsäureester besteht.Compounds of general formula I in which R ^{2 is} [ ¹⁸ F]fluorine can be prepared using a compound of general formula IP

are made in which

is a phenyl group or a pyridyl group;
R ^{1 is} hydrogen or a nitro group; and
AG is a leaving group selected from the group consisting of a nitro group, a diazonium ion or salt, a trialkylammonium ion or salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic ester, alkyltin, aryltin, an iodonium ion or salt , an iodonium ylide and a sulfonic acid ester.

The leaving group allows the labeling of arenes and heteroarenes that are ^{not amenable to aromatic nucleophilic substitution with [ 18} F]fluoride.

The compound of general formula IP is a compound of general formula I, where R ^{2 is} a leaving group. It can be provided that R ¹ and R ² are each a nitro group. A precursor of general formula IP, in which both R ¹ and R ^{2 are} each a nitro group, is 4-nitro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide. 4-Nitro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide can be used as a precursor for the preparation of 4-[ ¹⁸ F]fluoro-N-(4-methoxy-7 -morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide (Compound A3) can be used. However, it can alternatively be provided that R ¹ and R ^{2 are} not each a nitro group. It can be provided that the precursor contains no fluorine atom.

Preferable examples of a sulfonic acid ester are toluenesulfonic acid ester, methylsulfonic acid ester and trifluoromethylsulfonic acid ester. The iodonium ylide may be spirocyclic iodonium ylide.

Preferably, AG is selected from the group consisting of a boronic acid, a boronic ester, a spirocyclic iodonium ylide, and a nitro group. A particularly preferred leaving group is a boronic acid, boronic ester or spirocyclic iodonium ylide. Another preferred leaving group is a nitro group.

A compound of the general formula IP can be used as a precursor for the preparation of compounds of the general formula I. A precursor which has a boronic acid, a boronic acid ester or a spirocyclic iodonium ylide as the leaving group makes it possible to label little or non-activated positions in aromatics, particularly in phenyl derivatives, but also in pyridine derivatives, with [ ¹⁸ F]fluoride . It should be noted that phenyl derivatives are even less activated than pyridine derivatives. Precursors with one of these leaving groups are therefore particularly suitable for the preparation of a compound of general formula I. Details on radiofluorination with boranoic acid or boronic acid ester as the leaving group can be found U.S. 2017/0137341 A1 , details on radiofluorination with hypervalent iodine(III) compounds based on spirocyclic iodonium ylides can be found U.S. 2017/0121300 A1 be removed.

A preferred precursor of general formula I-P is N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-6-nitronicotinamide.

• 4-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamid;
• 2-[¹⁸F]Fluor-N(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamid;
• 4-[¹⁸F]Fluor-A^L(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamid;
• 2-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotin-amid;
• 6-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotin-amid;
• 2-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)isonicotin-amid; und
• 6-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)picolin-amid.

Preferred ¹⁸ F-fluorinated compounds of general formula I are:

• 4-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide;
• 2-[ ¹⁸ F]fluoro-N(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide;
• 4-[ ¹⁸ F]fluoro-A ^L (4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide;
• 2-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide;
• 6-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide;
• 2-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)isonicotinamide; and
• 6-[ ¹⁸ F]Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)picolinamide.

It has been found that the ¹⁸ F-fluorinated compounds of the general formula I according to _{the invention are ligands for adenosine A 2A} receptors. They can therefore be used for the diagnosis and therapy of neurodegenerative diseases and/or oncological diseases. The oncological diseases can be neuro-oncological diseases. The ¹⁸ F-fluorinated compounds of the general formula I according to the invention can therefore be used for the diagnosis and therapy of cancer diseases and other hyper- and/or dysproliferative diseases. Cancers include, in particular, benign and malignant tumors (neoplasms), in particular tumors of the lungs, brain, spinal cord, prostate, bladder, kidneys, esophagus, stomach, pancreas, ovary, and skeletal system. An example of a lung tumor is non-small-cell lung carcinoma. The fluorinated or ¹⁸ F-fluorinated compounds according to the invention can thus be used as a medicament, in particular as a medicament for neurodegenerative diseases and/or oncological diseases. A pharmaceutically acceptable salt of a ¹⁸ F-fluorinated compound of the general formula I can also be used as a medicament, in particular as a medicament for neurodegenerative diseases and/or oncological diseases. In one embodiment, the fluorinated or ¹⁸ F-fluorinated compounds of the invention can be used as a medicament for the diagnosis and therapy of non-small cell lung carcinoma. A pharmaceutically acceptable salt of a ¹⁸ F-fluorinated compound of the general formula I can also be used as a medicament, in particular as a medicament for the diagnosis and therapy of a non-small cell lung carcinoma.

According to the invention, the use of a compound of the general formula I as a medicament is thus provided. Furthermore, the use of a compound of the general formula I as a medicament for the diagnosis and therapy of diseases in which an adenosine A _2A receptor is involved is provided. The drug can be a radiopharmaceutical. The medicament is preferably a radiopharmaceutical for nuclear medicine imaging of adenosine A _2A receptors by means of positron emission tomography (PET). Instead of a medicament containing a compound according to the invention, a pharmaceutically acceptable salt of this compound can be used.

According to the invention, a process for the preparation of a compound of general formula I is also provided. In this case, a precursor of the general formula IP is converted into a compound of the general formula I. The process according to the invention is shown in Scheme 1.

The general formula IF corresponds to formula I. The process according to the invention enables the preparation of compounds of the general formula IF from the precursor, with its leaving group AG being replaced by [ ¹⁸ F]fluorine.

The introduction of [ ¹⁸ F]fluoride can take place, for example, in the presence of a phase transfer catalyst or cryptand. For example, the reaction can be carried out in the presence of a complex of [ ¹⁸ F]F ^- /K ₂₂₂ /K ⁺ or in the presence of a [ ¹⁸ F]tetrabutylammonium fluoride complex ([ ¹⁸ F]TBAF). The reaction can take place in polar aprotic or polar protic solvents such as acetonitrile (MeCN), dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).

mit einer Verbindung der allgemeinen Formel II,

umgesetzt. Die Reste R¹ und R² haben in der Verbindung der allgemeinen Formel II die im Zusammenhang mit der allgemeinen Formel I oder der allgemeinen Formel I-P angegebenen Bedeutungen. Eine Verbindung der allgemeinen Formel II ist ein Benzoesäurederivat, wenn Ar eine Phenylgruppe ist. Eine Verbindung der allgemeinen Formel II ist ein Pyridincarbonsäure-Derivat, wenn Ar eine Pyridingruppe ist.To prepare a compound of general formula I or general formula IP, a compound of formula 1

with a compound of general formula II,

implemented. In the compound of the general formula II, the radicals R ¹ and R ² have the meanings given in connection with the general formula I or the general formula IP. A compound of general formula II is a benzoic acid derivative when Ar is a phenyl group. A compound of general formula II is a pyridinecarboxylic acid derivative when Ar is a pyridine group.

An embodiment of the process for preparing a compound of general formula I is shown in Scheme 2.

For the reaction of compound 1 shown in Scheme 2 with a compound of the general formula II, activation of compound 1 can be provided in a first process step. The activation preferably takes place in the presence of a coupling agent in the presence of a base. The coupling agent can be, for example, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3 -oxide-hexafluorophosphate (HATU). The base can be, for example, triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA). Preferably BOP is used together with TEA or HATU together with DIPEA.

After the activation, which can be carried out for a period of 5 min to 1 h, preferably 10 min to 30 min and particularly preferably for 15 min, the compound of the general formula II is added to the activated compound 1 in a second step. Step 2 can be carried out until the activated compound 1 has reacted completely.

The two process steps can be carried out in an organic solvent, preferably an aprotic organic solvent. They can be carried out at room temperature. They can be carried out at ambient pressure. An example of a suitable solvent is dichloromethane (DCM).

In particular, the invention enables the preparation of ¹⁸ F-labelled N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives using suitable precursors. It thus enables the ¹⁸ F-labeled N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)actamide derivatives to be used as radiotracers. The compounds according to the invention can therefore be used as high-affinity and selective adenosine A _{2A radiopharmaceuticals.} ^{The 18} F-labeled radiotracers accessible by means of the invention can be used for in vitro and in vivo investigations of the expression of A _2A receptors in organisms using positron emission tomography (PET). These investigations make it possible to gain more precise knowledge about the effect of a reference compound and, in addition to the radiopharmaceutical, to gain access to or evaluate other drugs or to make an important contribution to their evaluation. The compounds of the general formula IF are suitable as radiopharmaceuticals for imaging in nuclear medicine. For this purpose, they are evaluated preclinically and clinically. The compounds of the general formula IF according to the invention are particularly suitable for determining the optimal dosages of medicaments which are used for the treatment of diseases which are influenced by A _2A receptors. _{For this purpose, the A 2A} receptor densities can be determined using the compounds of the general formula IF according to the invention.

The preparation of compounds of the general formula IF is based on the established knowledge that little or no activated positions in aromatics and heteroaromatics through the use of precursors which have a boranoic acid, a boronic acid ester or a sterically hindered spirocyclic iodonium ylide as the leaving group, can be ^{labeled with [ 18} F]fluoride.

The solution according to the invention differs from the prior art in particular in that the nucleophilic aromatic substitution with [ ¹⁸ F]fluoride on the phenyl and pyridyl group of N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)acetamide derivatives and the subsequent use as a radiotracer for nuclear medicine imaging of adenosine A _2A receptors using positron emission tomography (PET) has not been shown to date.

• 1 Chromatogramme zum Nachweis von Verbindung [¹⁸F]A5.

The invention is explained in more detail below using exemplary embodiments, which are not intended to restrict the invention, with reference to the drawings. while showing

• 1 Chromatograms for detecting compound [ ¹⁸ F]A5.

4-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamid (nicht erfindungsgemäß) A2

2-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamid (nicht erfindungsgemäß) A3

4-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamid (nicht erfindungsgemäß) A4

2-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamid (nicht erfindungsgemäß) A5

6-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamid (nicht erfindungsgemäß) A6

2-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)isonicotinamid (nicht erfindungsgemäß) A7

6-Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)picolinamid (nicht erfindungsgemäß) A8

N-(4-Methoxy-7-morpholinobenzo [d] thiazol-2-yl)-6-nitronicotinamid [ ¹⁸ F]A5

6-[¹⁸F]Fluor-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2- yl)nicotinamid Examples of compounds according to the invention and not according to the invention are given in Table 1. The structures of Examples 1 to 8 given in Table 1 were confirmed by ¹ H-NMR, ¹³ C-NMR, ¹⁹ F-NMR and ESI-mass spectroscopy. Table 1: connection structure Surname A1

4-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) benzamide (not of the invention) A2

2-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) benzamide (not of the invention) A3

4-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) -3-nitrobenzamide (not of the invention) A4

2-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) nicotinamide (not of the invention) A5

6-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) nicotinamide (not of the invention) A6

2-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) isonicotinamide (not of the invention) A7

6-fluoro- N - (4-methoxy-7-morpholinobenzo [d] thiazol-2-yl) picolinamide (not of the invention) A8

N -(4-Methoxy-7-morpholinobenzo [ d ]thiazol-2-yl)-6-nitronicotinamide [ ¹⁸ F]A5

6-[ ¹⁸ F]Fluoro- N -(4-methoxy-7-morpholinobenzo[ d ]thiazol-2-yl)nicotinamide

The compound [ ¹⁸ F]A5 is an exemplary compound of general formula I. The compound A8 is an exemplary compound of general formula IP, in which R ^{1 is} hydrogen and R ^{2 is} a nitro group. Compound A8 can be used as a precursor for the preparation of radiofluorinated compounds [ ¹⁸ F]A5.

General synthetic procedure for compounds A1 to A8

Compounds A1 to A8 were prepared according to the procedure shown in Scheme 2, above. 1.1 eq. a compound of general formula III were dissolved in dichloromethane (DCM) and by the addition of the coupling agent, which is benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP; 1,3 eq.) or 1-[bis(dimethylamine) -methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU; 1.3 eq.) and a base which was triethylamine (TEA, 3 eq.) or N,N diisopropylethylamine (DIPEA, 3 eq.) with stirring at room temperature for 30 min. After the addition of 4-methoxy-7-morpholinobenzo[d]thiazol-2-amine (1) (1 eq.), the reaction mixture is stirred at room temperature until the reaction is complete. The reaction was diluted with water, the aqueous phase extracted with dichloromethane, the combined organic phases washed with saturated NaCl solution and dried _{with MgSO 4 .} After removing the solvent, purification is carried out using flash chromatography.

Example 1 (comparative example)

4-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide (Compound A1)

Compound A1 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 4-fluorobenzoic acid (29 mg, 1.1 eq.) as the carboxylic acid, Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 108 mg, 1.3 eq.) as the coupling agent and triethylamine (TEA, 78 μl, 3 eq.) as the base were used. After purification by means of flash chromatography (gradient ethyl acetate/petroleum ether 1:2→3:5→4:5→1:1), 33 mg (45%) of compound A1 were obtained.

¹ H NMR (400 MHz, DMSO-d6): δ = 13.04 (s, 1H), 8.24 (ddd, J = 2.8, 5.7, 8.7 Hz, 2H), 7.41 (t, J = 8.8 Hz, 2H), 6.95 (q, J=8.5 Hz, 2H), 3.89 (s, 3H), 3.86-3.74 (m, 4H), 3.04 (dd, J=3.5, 5.7 Hz, 4H); ¹⁹ F NMR (377 MHz, DMSO-d6): δ = -70.17 (d, J = 711.2 Hz); ¹³ C-NMR (101 MHz, DMSO-d6): δ = 166.08, 163.58, 161.51, 148.23, 140.07, 133.13, 131.16 (d, J = 9.5 Hz, 2C), 128.28, 115.76 (d, J = 22.0 Hz, 2C), 113.06, 113.06, 108.12, 66.56 (2C), 55.93, 51.51 (2C); HRMS (ESI+): 388.1119 (calcd 388.1126 for [M+H] ⁺ ).

Example 2 (comparative example)

2-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide (Compound A2)

Compound A2 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 2-fluorobenzoic acid (29 mg, 1.1 eq.) as the carboxylic acid, Benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 108 mg, 1.3 eq.) as the coupling agent and triethylamine (TEA, 78 μl, 3 eq.) as the base were used. After cleanup Using flash chromatography (gradient ethyl acetate/petroleum ether 1:2→3:5→4:5→1:1), 63 mg (86%) of compound A2 were obtained.

¹ H NMR (400 MHz, DMSO-d6): δ = 12.95 (s, 1H), 7.79 (td, J = 1.8, 7.6 Hz, 1H), 7.66 (tdd, J = 1.8, 6.2, 8.4 Hz, 1H ), 7.49-7.29 (m, 2H), 7.03-6.87 (m, 2H), 3.89 (s, 3H), 3.80 (dd, J = 3.3, 5.7 Hz, 4H), 3.09-2.84 (m, 4H); ¹⁹ F NMR (377 MHz, DMSO-d6): δ = -70.16 (d, J = 711.3 Hz); ¹³ C-NMR (101 MHz, DMSO-d6): δ = 163.78, 161.20, 158.70, 156.87, 148.79, 140.56, 134.44 (d, J = 8.1 Hz), 130.82, 127.20, 125.13, 122.42 (d, J = 13.0 Hz), 116.92 {d, J = 21.5 Hz), 113.73, 108.77, 67.04 (2C), 56.46, 51.99 (2C); HRMS (ESI+): 388.1118 (calcd 388.1126 for [M+H] ⁺ ).

Example 3 (Comparative Example) 4-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide (Compound A3)

Compound A3 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 4-fluoro-3-nitro-benzoic acid (42 mg, 1.1 eq.) as carboxylic acid, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 108 mg, 1.3 eq.) as coupling reagent and triethylamine (TEA, 78 μl, 3 eq.) as base. After purification by means of flash chromatography (gradient dichloromethane/methanol 100:1→100:2→100:3), 34 mg (42%) of compound A3 were obtained.

¹ H NMR (400 MHz, DMSO-d6): δ = 13.35 (s, 1H), 8.98 (dd, J = 2.3, 7.2 Hz, 1H), 8.54 (ddd, J = 2.4, 4.2, 8.8 Hz, 1H ), 7.80 (dd, J = 8.7, 11.0 Hz, 1H), 7.12- 6.86 (m, 2H), 3.91 (s, 3H), 3.81 (t, J = 4.6 Hz, 4H), 3.05 (t, J = 4.5Hz, 4H); ¹⁹ F NMR (282MHz, DMSO-d6): δ = -112.77; ¹³ C NMR (101 MHz, DMSO-d6): δ = 158.24, 155.57, 151.68 (d, J = 301.8 Hz), 140.05, 140.05, 136.77 (d, J = 7.9 Hz), 136.20, 136.10 (d, J = 10.3 Hz), 136.05, 126.53, 119.09 (d, J = 13.5 Hz), 113.28 (2C), 108.39, 66.46 (2C), 55.97, 51.44 (2C); HRMS (ESI+): 433.1045 (calculated 433.0982 for [M+H] ⁺ ).

Example 4 (Comparative Example) 2-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide (Compound A4)

Compound A4 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 2-fluoronicotinic acid (30 mg, 1.1 eq.) as the carboxylic acid, Benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 108 mg, 1.3 eq.) as the coupling agent and triethylamine (TEA, 78 μl, 3 eq.) as the base were used. After purification by means of flash chromatography (dichloromethane/methanol gradient 100:1→100:2→100:3), 38 mg (38%) of compound A4 were obtained.

¹ H NMR 300 MHz, DMSO-d6): δ = 13.13 (s, 1H), 8.46 (ddd, J = 1.0, 2.0, 4.9 Hz, 1H), 8.38 (ddd, J = 2.0, 7.5, 9.5 Hz, 1H), 7.55 (ddd, J = 1.8, 4.9, 7.1 Hz, 1H), 6.97 (d, J = 2.1 Hz, 2H), 3.89 (s, 3H), 3.84 - 3.69 (m, 4H), 3.12 - 2.96 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6): δ = -66.97 (d, J = 10.1 Hz; ¹³ C NMR (101 MHz, DMSO- d6): δ = 162.39, 160.57, 158.17, 150.67 (d, J = 15.0 Hz), 148.34, 142.21-141.65 (m), 140.10, 126.74, 122.25 (d, J = 4.3 Hz), 116.68, 113.43, 108.40, 66.56 (2C), 56.05, 51.52 (2C); HRMS (ESI+ ): 389.1072 (calculated 389.1084 for [M+H] ⁺ ).

Example 5 (Comparative Example) 6-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide (Compound A5)

Compound A5 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 6-fluoronicotinic acid (30 mg, 1.1 eq.) as the carboxylic acid, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU; 93 mg; 1.3 eq.) as coupling agent and N ,N-diisopropylethylamine (DIPEA, 99 μl, 3 eq.) were used as base. After purification by means of flash chromatography (gradient dichloromethane/methanol 100:1→100:2→100:3), 59 mg (81%) of compound A5 were obtained.

¹ H NMR (300 MHz, DMSO-d6): δ = 13.26 (s, 1H), 9.07-8.85 (m, 1H), 8.66 (ddd, J = 2.6, 7.7, 8.7 Hz, 1H), 7.41 (dd , J = 2.7, 8.6 Hz, 1H), 7.09-6.82 (m, 2H), 3.90 (s, 3H), 3.85-3.76 (m, 4H), 3.09-3.00 (m, 4H); ¹⁹ F NMR (282 MHz, DMSO-d6): δ = -63.35; ¹³ C NMR (101 MHz, DMSO-d6): δ = 166.07, 163.67, 163.14, 148.74 (d, J = 16.7 Hz), 148.28, 142.39 (d, J = 9.5 Hz), 140.08, 127.38-125.20 (m ), 1 13.25, 109.84 (d, J = 37.8 Hz), 108.22, 66.56 (2C), 55.98, 51.51 (2C); HRMS (ESI+): 389.1086 (calcd 389.1084 for [M+H] ⁺ ).

Example 6 (Comparative Example) 2-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)isonicotinamide (Compound A6)

Compound A6 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 2-fluoro-isonicotinic acid (30 mg, 1.1 eq.) as Carboxylic acid, 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 93 mg; 1.3 eq.) as a coupling agent and N,N-diisopropylethylamine (DIPEA, 99 µl, 3 eq.) was used as base. After purification by means of flash chromatography (gradient dichloromethane/methanol 100:1→100:2→100:3), 24 mg (33%) of compound A6 were obtained.

¹ H NMR (400 MHz, DMSO-d6): δ = 12.40 (s, 1H), 8.28 (q, J = 7.9 Hz, 1H), 8.12 (dd, J = 2.3, 7.4 Hz, 1H), 7.54 ( d, J = 8.3 Hz, 1H), 7.16-6.81 (m, 2H), 3.91 (s, 3H), 3.81 (t, J = 4.6 Hz, 4H), 3.05 (t, J = 4.6 Hz, 4H); ¹⁹ F NMR (377 MHz, DMSO-d6): δ = -67.19; ¹³ C-NMR (101MHz, DMSO-d6): δ = 166.21, 163.46, 162.12 (d, J = 78.1 Hz), 150.88, 148.92, 147.14, 144.50, 140.56, 121.96, 118.92, 114.96, 110.87.96, 110.87.96, 110.87.96 (2C), 56.51, 52.01 (2C); HRMS (ESI+): 389.1071 (calcd 389.1084 for [M+H] ⁺ ).

Example 7 (Comparative Example) 6-Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)picolinamide (Compound A7)

Compound A7 was prepared according to the general synthetic procedures given above using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (50 mg, 1 eq.), 6-fluoro-picolinic acid (30 mg, 1.1 eq.) as Carboxylic acid, benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 108 mg, 1.3 eq.) as coupling reagent and triethylamine (TEA, 78 μl, 3 eq.) as base were used. After purification by means of flash chromatography (gradient dichloromethane/methanol 100:1→100:2→100:3), 21 mg (29%) of compound A4 were obtained.

¹ H NMR (300 MHz, DMSO-d6): δ = 13.42 (s, 1H), 8.49 (dt, J = 0.8, 5.2 Hz, 1H), 7.99 (dt, J = 1.7, 5.2 Hz, 1H), 7.84 (d, J = 1.8 Hz, 1H), 7.07- 6.89 (m, 2H), 3.90 (s, 3H), 3.80 (dd, J = 3.6, 5.6 Hz, 4H), 3.09- 2.96 (m, 4H) ; ¹⁹ F NMR (282 MHz, DMSO-d6): δ = -67.18; ¹³ C NMR (101 MHz, DMSO-d6): δ = 164.59, 162.93, 162.25, 148.80 (d, J = 14.4 Hz, 2C), 148.35, 140.07 (2C), 120.51-120.36 (m, 2C), 113.49 , 108.72, 108.32, 66.55 (2C), 55.99, 51.51 (2C); HRMS (ESI+): 389.1071 (calcd 389.1075 for [M+H] ⁺ ).

Example 8 N-(4-Methoxy-7-morpholino-benzo[d]thiazol-2-yl)-6-nitro-nicotinamide (Compound A8)

Compound A8 was prepared according to the general synthetic procedures given above, using 4-methoxy-7-morpholinobenzo[d]thiazole-2-amine (100 mg, 1 eq.), 6-nitronicotic acid (70 mg, 1.1 eq.) as the carboxylic acid, 1-[bis(dimethylamino)methylene]-1H 1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU; 186 mg; 1.3 eq.) as coupling agent and N, N-diisopropylethylamine (DIPEA, 198 μl, 3 eq.) were used as the base. After purification by means of flash chromatography (gradient dichloromethane/methanol 100:1→100:2→100:3), 47 mg (30%) of compound A8 were obtained.

¹ H NMR (400 MHz, DMSO-d6): δ = 9.29 (d, J = 2.2 Hz, 1H), 8.83 (dd, J = 2.3, 8.5 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 7.15 - 6.80 (m, 2H), 3.91 (s, 3H), 3.80 (t, J = 4.5 Hz, 4H), 3.13 - 2.90 (m, 4H); ¹³ C-NMR (101MHz, DMSO-d6): δ = 164.26, 159.24, 158.38, 149.46, 149.14, 148.55, 141.30, 141.03, 140.87, 134.75, 118.32, 1 13.77, 106.67, 9 106.69m (667.67m) (d, J = 22.3 Hz), 52.07.

example 9

Determination of binding affinities

To demonstrate the affinity and selectivity of the compounds A1 to A6 for adenosine A _2A receptors, the binding affinities of the compounds for adenosine A _2A receptors and for adenosine A ₁ receptors were determined. The determination was made with CHO cells that overexpress the relevant adenosine receptors. The radioligand displacement experiments with finely dispersed suspensions of adenosine A _2A CHO cells and adenosine A ₁ CHO cells were carried out by co-incubation of the test substances with [ ³ H]-ZM241385 or [ ³ H]-DPCPX in incubation buffer ( 50mM TRIS-HCl, pH 7.4, 100mM NaCl, 5mM MgCl ₂ , 1mM EDTA; or _{50mM TRIS-HCl, pH 7.4, 1mM MgCl 2} ) for 60 minutes at room temperature. The non-specific binding of the respective radioligand was carried out by co-incubation with 10 µM ZM241385 or 1 µM DPCPX. The high molecular weight complex of binding site and radioligand was separated from the low molecular weight free radioligand by filtration through polyethyleneimine pre-treated GF/B glass fiber filters. Each of Compounds A1 through A6 was evaluated at 7 concentrations with triplicate determination of each data point (n=2 through 4). Table 2 shows the average values of the respective experiments. Table 2: Binding affinities of compounds A1-A6 to the A _2A and A ₁ receptor. connection K _i (hA _2A ) [nM] K _i (hA ₁ ) [nM] A1 1.04 336 A2 4.87 239 A3 3.23 4278 A4 5.02 1398 A5 1.00 618 A6 2.56 729

In Table 2, the K _i denotes the equilibrium inhibition constant for the displacement of [ ³ H]-ZM241385 (A _2A ) or [ ³ H]-DPCPX (A ₁ ) from the human adenosine A _2A receptor (hA _2A ) and the human adenosine A ₁ receptor (hA ₁ ), respectively.

Example 10 6-[ ¹⁸ F]Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide (Compound [ ¹⁸ F]A5)

The preparation of compound [ ¹⁸ F]A5 is shown in Scheme 3.

The aqueous [ ¹⁸ F]fluoride (2-3 GBq) obtained after irradiation was added to 1 ml water, fixed on an anion exchange cartridge (QMA) and washed with an aqueous K ₂ CO ₃ solution (0.9 mg in 300 µl water ) eluted in a solution of 1 ml MeCN and Kryptafix (K ₂₂₂ , 5.6 mg). The azeotropic drying of the complex takes place with the assistance of microwaves (power cycling, 75 W, 50-60 aq. under vacuum and argon flow). The [ ¹⁸ F]F ^- /K ₂₂₂ /K ⁺ complex formed was dissolved in 200 μl of dimethyl sulfoxide (DMSO) and precursor A8 (0.5 mg) dissolved in DMSO (400 μl) was added. The reaction mixture was then stirred at 180° C. for 15 min. To determine the labeling yield, an aliquot was removed and analyzed by radio-TLC (56 ± 6%) and radio-HPLC (57 ± 18%). The radiotracer is cleaned and isolated using semi-preparative RP-HPLC (column: ReproSil-Pur 120 C18-AQ, 250 x 10 mm, 5 µm; eluent: 36% MeCN / H ₂ O + 0.05% trifluoroacetic acid (TFA ); flow: 4 ml/min). The collected product fraction was diluted with water, ^{sorbed onto a Sep-Pak ®} C18 light cartridge and [ ¹⁸ F]A5 eluted with ethanol (1 mL). The solvent was then removed with heating in a stream of argon and formulated in a 0.9% saline solution (≤10% ethanol, v/v). ^{The product [ 18} F]A5 was isolated within a synthesis time of about 110 min.

Using radio-HPLC and radio-DC, the identity of the product was confirmed by co-injection of the reference compound A5 ( 1 ). The product [ ¹⁸ F]A5 was obtained in a radiochemical yield of 37 ± 7% (EOB, n = 3), a radiochemical purity ≥ 98% and a molar activity of 92 ± 7 GBq/)µmol (EOS, n = 2) receive. In 1 a radio-HPLC chromatogram of the formulated radiotracer [ ¹⁸ F]A5 and the UV chromatogram of the co-injected reference compound A5 are shown. The two chromatograms were prepared as follows: ReproSil-Pur 120 CN column, 250 x 4.6 mm, 5 µm; eluent: 10-90-10% MeCN / 20mM NH ₄ OAc; Flow: 1ml/min).

Example 11

In vitro and in vivo studies with 6-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide (compound [ ¹⁸ F]A5)

For [ ¹⁸ F]A5, both the first in vitro and in vivo studies were carried out: [ ¹⁸ F]A5 proved to be stable in sodium chloride, PBS, n-octaonol solution and in porcine plasma at 37° C for an hour. Using the conventional "shake-flask" method, a logD _7.4 = 1.72 ± 0.08 (n = 3) was determined. In the in vivo metabolite study in female CD-1 mice, after 30 min pi in the brain 75 ± 1% (radio DC, n = 2, extraction yield 91%), in the plasma 84 ± 6% (radio DC, n = 2, extraction yield 91%) and 87% (BAT, n = 1, radio-DC, extraction yield 99%) of intact radiotracers were detected in brown adipose tissue. The in vitro autoradiography study in mouse brain slices showed a selective accumulation of the radiotracer in the desired target region (striatum) and also a displacement of the radiotracer by means of A _2A -selective ligands. The first PET studies in healthy CD-1 mice show a brain uptake of SUV _max = 0.6 (striatum, 10 min pi, n = 4).

Claims (15)

Compound of general formula IP

wherein

is a phenyl group or a pyridyl group; R ^{1 is} hydrogen or a nitro group; and AG is a leaving group, wherein the leaving group is selected from the group consisting of a nitro group, a diazonium ion or salt, a trialkylammonium ion or salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic ester, alkyltin, aryltin, an iodonium ion or salt, an iodonium ylide and a sulfonic acid ester. connection after claim 1 characterized in that AG is selected from the group consisting of boronic acid, a boronic ester, a spirocyclic iodonium ylide, and a nitro group. connection after claim 1 , characterized in that AG is a nitro group. connection after claim 1 , characterized in that the sulfonic acid ester is selected from the group consisting of toluene sulfonic acid ester, methyl sulfonic acid ester and trifluoromethyl sulfonic acid ester. connection after claim 1 , characterized in that the iodonium ylide is a spirocyclic iodonium ylide. connection after claim 1 or claim 2 , characterized in that R ^{1 is} a nitro group and that AG is a nitro group. connection after claim 1 or claim 2 characterized in that it is N-(4-Methoxy-7-morpholinobenzo[d]thiazol-2-yl)-6-nitronicotinamide. Process for the preparation of a compound of general formula I

by reacting a precursor of the general formula IP

in which

is a phenyl group or a pyridyl group; R ^{1 is} hydrogen or nitro; R ^{2 is} [ ¹⁸ F]fluoro; and AG is a leaving group selected from the group consisting of a nitro group, a diazonium ion or salt, a trialkylammonium ion or salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic ester, alkyltin, aryltin, an iodonium ion, or - salt, an iodonium ylide and a sulfonic acid ester; in the presence of a phase-transfer catalyst or cryptand. procedure after claim 8 , characterized in that the leaving group is nitro. procedure after claim 8 or claim 9 , characterized in that the reaction takes place in the presence of a complex of [ ¹⁸ F]F ^- /K ₂₂₂ /K ⁺ or in the presence of a [ ¹⁸ F]tetrabutylammonium fluoride complex ([ ¹⁸ F]TBAF). Process according to one of the preceding claims, characterized in that the reaction takes place in polar aprotic or polar protic solvents. Compound of general formula I

wherein

is a phenyl group or a pyridyl group; R ^{1 is} hydrogen or nitro; and R ^{2 is} [ ¹⁸ F]fluoro. connection after claim 12 characterized in that it is selected from the group consisting of 4-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide; 2-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)benzamide; 4-[ ¹⁸ F]Fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-3-nitrobenzamide 2-[ ¹⁸ F]Fluoro-N-(4-methoxy-7-morpholinobenzo[ d]thiazol-2-yl)nicotinamide; 6-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)nicotinamide; 2-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)isonicotinamide; and 6-[ ¹⁸ F]fluoro-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)picolinamide. using a connection after claim 12 or Claim 13 as a drug. using a connection after claim 12 or Claim 13 for use as a medicament for the diagnosis and therapy of diseases in which an adenosine A _2A receptor is involved.

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