JP2002501921A - 8-Azabicyclo [3.2.1] oct-2-ene derivatives in labeled form and 8-azabicyclo [3.2.1] oct-2-ene derivatives in labeled and unlabeled form How to use - Google Patents

Abstract

  (57) [Summary]   The present invention relates to 8-azabicyclo [3.2.1] oct-2-ene derivatives in their labeled form. The invention furthermore relates to the use of the derivatives in labeled and unlabeled form in diagnostic methods, in particular in in vivo receptor imaging (neuro-imaging).

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD This invention relates to 8-azabicyclo [3] in its labeled and unlabeled form.
2.1] Octo-2-ene derivatives. The invention furthermore relates to the use of said derivatives in labeled and unlabelled form in diagnostic methods, in particular in in vivo receptor imaging (neuroimaging). Background International Patent Application Publication No. WO 9713770 discloses reuptake inhibitors for the monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), and therefore at least one of which increases endogenous serotonin levels or 8-Azabicyclo [Effective for the treatment of disorders or diseases caused by reduction
3.2.1] Oct-2-ene derivatives are disclosed. Such disorders or illnesses include, for example, depression and related illnesses, impulse compulsive disorder, panic disorder, memory deficits,
Attention-deficits, hyperactivity disorders, obesity, anxiety and eating disorders.

[0002] Monoamine neurotransmitters (ie, serotonin, dopamine and noradrenaline) are produced in neurons and released into the synaptic cleft by stimulation of presynaptic neurons. Neurotransmitter molecules are diffused through the interstices and specific receptor molecules (transporters) located on the postsynaptic cell membrane
Can be combined. Binding to these receptors results in polarization of the cell, ie transduction of the stimulus. Removal (or inactivation) of monoamine neurotransmitters from the synaptic cleft occurs primarily by reuptake mechanisms into presynaptic nerve endings. Inhibiting reuptake results in increased physiological activity of the monoamine neurotransmitter.

[0003] Major depression is a common disorder that affects about one in six people at some point in their life. The pathophysiology of depression has been incompletely understood to date, and several neurotransmitters have been implicated in the pathophysiology of major depression. Inhibitors that block noradrenaline and serotonin reuptake are currently used as drugs in antidepressant treatment. From several therapeutic lines evidenced by preclinical and clinical practice, increased serotonin-mediated neurotransmission is the most recent and currently used drug in antidepressant treatment, such as fluoxetine, citalopram and It turns out that it may be based on the therapeutic effect of paroxetine [P
. Blier & C deMontigny, TiPS (Review) 199
415220-225].

[0004] Paradoxically, serotonin reuptake inhibitors block the serotonin transporter within minutes after administration, but their full antidepressant effect is only seen after 3-4 weeks of treatment, Rather than indicating that uptake inhibition does not itself elicit an antidepressant response, it indicates that other adaptive changes underlie and / or contribute to its therapeutic effect [P. Willner, Int. Review of Psy
chiatry19902141-156].

[0005] The serotonin-like nervous system of the brain has been shown to affect a variety of physiological functions, and disruption of this system causes various diseases and disorders such as eating disorders, depression, impulse compulsive disorder, panic disorder. , Alcoholism, pain, memory deficits and anxiety. These disorders include depression and related illnesses, such as pseudo dementia or Gander syndrome, migraine, pain, bulimia, obesity, premenstrual (tonic) syndrome or late luteal psychiatric symptoms, alcoholism, tobacco abuse, panic Disability, anxiety, post-traumatic syndrome,
Memory loss, senile dementia, social phobia, attention-deficit hyperactivity disorder (ADHD),
Chronic fatigue syndrome, premature ejaculation, erectile dysfunction, anorexia nervosa, sleep disorder, autism, anthrax
(mutism) and hair removal habits.

[0006] Currently, the standard method for diagnosing depression is a consultation performed between a physician, eg, a psychiatrist, and the patient to evaluate the emotional life of the patient. Depressed patients are characterized by, for example, loss of determination and interest, widespread sorrow, guilt and worthlessness, loss of appetite and libido, and suffering from insomnia.

[0007] These symptoms develop temporarily and with varying severity, which makes the determination of proper diagnosis and treatment extremely difficult. The psychiatrist therefore has an objective laboratory which can justify the diagnosis and predict the response to the procedure as much as possible.
Or clinical-trial studies.

[0008] Recent research has focused on the biochemical context of depression syndrome. Specific area of cerebral blood flow
It has been found that measurement of (rCBF) can be used to diagnose depression. In the brains of depressed patients, three regions showed significantly reduced rCBF (left posterior extrafrontal cortex, left anterior one cortex and left gyrus). When depression was accompanied by cognitive impairment, reduced rCBF in the left medial frontal cortex and increased rCBF in the right cerebral vermis were detected [Ben
chCJ, Friston KJ, BrownRG, ScottLC, Frac
owiakRS &DolanRJ; Theanatomy ofmel-anchoria-focalabnormalitiesofc
erebral bloodfollowinmajordepression-ion; Psychol-Med. 199222 (3) 607-15; and Do
lanRJ, BenchCJ, BrownRG, ScottLC, FristonKJ &Frackwiak-RS; Regional cerebral blood flownormalitiesind
J. Pressed patents with cognitive impairment; Neurol. Neurosurg. Psy-c
hiatry. 1992 55 (9) 768-73]. This method allows parameters that are at least often correlated with pathological depression to be assayed as reliable for the physician. However, treatment with antidepressants is not reflected in changes in rCBF. This means that the treatment effect cannot be monitored by this method.

[0009] The study of serotonin reuptake sites by emission tomography requires the use of radioligands with desirable properties for in vivo receptor imaging. These diagnostic criteria include easy labeling with positron-emitting radionuclides, low rates of peripheral metabolism, high selectivity for brain regions that maintain the neuroreceptor, and relatively high specific / non-specific binding. including. Despite the development of many radioligands for the serotonin transporter, none of this compound fully satisfies all of the criteria desired for an ideal ligand. SUMMARY OF THE INVENTION The compounds of the present invention and their derivatives are the first substances known to bind specifically to serotonin transporters. This substance makes it possible, for the first time, to reliably determine the number of serotonin binding sites and the associated Kd values, and the assay of changes in serotonin release and serotonin metabolism in response to therapeutic agents.

[0010] Accordingly, an object of the present invention can be used to diagnose diseases or disorders associated with altered levels of serotonin in vivo and in vitro, and can also be used to monitor the effects of treatment. It is to provide a compound that can be used.

It is a further object of the present invention to provide a method for diagnosing some diseases associated with increased or decreased serotonin in neurotransmitters in vivo and in vitro using specifically detectable compounds. Is to do. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 illustrates only one very specific incorporation and shows that the compounds of the invention (3
4 shows a characteristic PET scan labeling the serotonin nerve endings (having the serotonin reuptake transporter) by -4); coronal (left), cross-sectional (left), porcine brains labeled with compound (3-4) Center) and sagittal section (right). The accumulation of this compound occurs in the medial midbrain (serotonin-like raphe nuclei) and cerebellum (diecephalo
n) (Thalamus and basal ganglia). DETAILED DESCRIPTION OF THE INVENTION The object of the present invention can be used to diagnose diseases or disorders associated with altered levels of serotonin in vivo and in vitro, and can also be used to monitor the effects of treatment. It is to provide a compound that can be used. The purpose of this is that of formula (I)

[0012]

Embedded image By providing a labeled or unlabeled compound derived from

[0013] It is an object of the present invention to provide compounds that can be used to diagnose diseases or disorders associated with altered levels of serotonin in vivo and in vitro and can also be used to monitor the effects of treatment. Is to provide. The purpose of this is that of formula (I)

[0014]

Embedded image Wherein R is hydrogen, alkyl, haloalkyl, thioalkyl, alkenyl, thioalkenyl, haloalkenyl, alkynyl, thioalkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R ⁴ is phenyl} It is substituted one or more times with a substituent selected from the group consisting of halogen, CF ₃ , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. 3,4-methylenedioxyphenyl; benzyl} which is halogen, CF ₃ , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl From the group consisting of Barre was once by a substituent or more substituted may have ───; heteroaryl ──── This halogen, CF _3, CN, alkoxy, sik Roarukokishi, alkyl, cycloalkyl, alkenyl, alkynyl , amino, nitro, heteroaryl and substituents therefore one or more may be substituted ─── selected from the group consisting of aryl; naphthyl ──── This halogen, CF _3, CN, alkoxy , A cycloalkoxy, an alkyl, a cycloalkyl, an alkenyl, an alkynyl, an amino, a nitro, a heteroaryl and an aryl, which may be substituted one or more times by a substituent selected from the group consisting of: is there. The problem is solved by providing a labeled compound derived from the compound represented by the formula, any enantiomer thereof or any mixture thereof, or a pharmaceutically acceptable salt thereof. Definition of substituents Within the scope of the present invention, halogen represents a fluorine-, chlorine-, bromine- or iodine atom.

In the context of the present invention, an alkyl group denotes a monovalent, saturated, straight-chain or branched hydrocarbon chain. The hydrocarbon chain preferably has 1 to 18 carbon atoms (C _1-18 alkyl), more preferably has 1 to 6 carbon atoms (C _1-6 alkyl: lower alkyl).
, Which includes pentyl, isopentyl, neopentyl, t-pentyl, hexyl and isohexyl. In a preferred embodiment, alkyl represents a C _1-4 alkyl group, including butyl, isobutyl, s-butyl and t-butyl.

Within the scope of the present invention, haloalkyl groups are mono- or poly-substituted with the abovementioned halogens.
Shows the above-mentioned alkyl group. This is, for example, CX_Three, CHX_Two, CH_TwoX, C
H_TwoCX_Three, CH_TwoCH_TwoX, XCHCH_TwoX, C_ThreeH₆X, C_ThreeH_FiveX_Two, C _Three H_FourX_Three, C_ThreeH_ThreeX_Four, C_ThreeH_TwoX_Five, C_ThreeX₇Etc. (X represents the above halogen)
). Preferred groups are C with one halogen_1-4Is haloalkyl
. A particularly preferred group is -CH_TwoF, -CH_TwoI, -C_TwoH_FiveF, -C_ThreeH₆I,-
C_ThreeH₆F and -CF_ThreeIt is.

In the context of the present invention, a cycloalkyl group is a cyclic alkyl group, preferably a cycloalkyl group having 3 to 7 carbon atoms (C _3-7 cycloalkyl), which is cyclopropyl, cyclobutyl, cyclopentyl , And cyclohexyl.

Within the scope of the present invention, an alkenyl group refers to a carbon chain having one or more double bonds, including dienes, trienes and polyenes. In a preferred embodiment, the alkenyl groups of the present invention have 2 to 6 carbon atoms and contain at least one double bond (C _2-6 alkenyl). In the most preferred embodiments, the alkenyl groups of the invention are ethenyl, 1- or 2-propenyl or 1-, 2- or 3-butenyl.

Within the scope of the present invention, haloalkenyl refers to the above-mentioned alkenyl groups mono- or poly-substituted with the above-mentioned halogens. In a preferred scope of the present invention, haloalkenyl groups 2-4 hydrocarbon substituted by halogen, for example -CH ₂ CH = CH
_{I, -CH 2 CH = CHF,} -CH = CHF, -CH = CHI, -CF = CH 2, -CH = CF 2, -CH = CHCH 2 I, -CH = CHCH 2 F, -CH = C
H-CH = CHI, -CH = CH-CH = CHF, -CH 2 CH 2 CH = CHI
Shows a -CH ₂ CH ₂ CH = CHF and so on.

In the scope of the present invention, an alkynyl group refers to a carbon chain having one or more triple bonds, including diynes, triynes and polyynes. In a preferred embodiment, the alkynyl groups of the invention have 2 to 6 carbon atoms and contain at least one triple bond ( _C2-6 alkynyl). In a most preferred embodiment, the alkynyl group of the invention is ethynyl, 1,2- or 2,3-propynyl or 1,2-, 2,3-
Or 3,4-butynyl.

Within the scope of the present invention, a haloalkynyl group is substituted with one or more of the above halogens
The substituted alkynyl group described above. An example of this is -C た と え ば C-CH _Two I, -C≡C-CH_TwoF, -C≡C-CH_TwoCl, -CHI-C≡CH, -C
HF-C≡CH, -CHCl-C≡CH, -CH_TwoC≡C-CH_Two1, -CH_Two C≡C-CH_TwoCl, -CH_TwoC≡C-CH_TwoF and so on.

In the scope of the present invention, a cycloalkyl-alkyl group refers to the above cycloalkyl group, which is substituted by the above alkyl group. Examples of preferred cycloalkyl-alkyl groups of the present invention include cyclopropylmethyl and cyclopropylethyl.

In the context of the present invention, an alkoxy group is an “alkyl-O—” group, wherein alkyl is as defined above.

Within the scope of the present invention, an alkoxy-alkyl group is an “alkyl-O-alkyl
-"Group, wherein alkyl is as defined above.

Within the scope of the present invention, the amino group may be a primary (—NH ₂ ) amino group, a secondary (—NH-alkyl) amino group, or a tertiary (—N (alkyl) ₂ ) amino group. That is, this group may be substituted once or twice with the above alkyl.

In the context of the present invention, a thioalkyl group is -alkyl-SH, wherein alkyl is as defined above.

Within the scope of the present invention, a thioalkenyl group is -alkenyl-SH, wherein alkenyl is as defined above.

Within the scope of the present invention, the thioalkynyl group is —alkynyl-SH, wherein alkynyl is as defined above. As the preferred aromatic heterocyclic monocyclic group of the present invention, 1,3,2,4- or 1,
3,4,5-dioxadiazolyl, dioxatriazinyl, dioxazinyl, 1
, 2,3-, 1,2,4-, 1,3,2- or 1,3,4, dioxazolyl,
1,3,2,4- or 1,3,4,5-dithiadiazolyl, dithiatriazinyl, dithiazinyl, 1,2,3-dithiazolyl, furanyl, furazanyl, imidazolyl, isoimidazolyl, 2-isoimidazolyl, isoindazolyl , Isothiazolyl, isoxazolyl, 1,2,3-, 1,2,4-, 1,2,5- or 1,3,4-oxadiazolyl, oxatetrazinyl, oxatriazinyl, 1
, 2,3,4- or 1,2,3,5-oxatriazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl (azolyl), 1,2,3,4- or 2,1 , 3,4-tetrazolyl, thiadiazolyl, thiazolyl, thienyl, 1,2,3-, 1,2,4- or 1,3,5-triazinyl, and 1,2,3-, 1,2,4-, 2,1,3- or 4,1,2-triazolyl, furan-2-yl, furan-3-yl, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-isoxazolyl, 1-, 2- or 3-pyridinyl, and 1- or 2-thienyl. Within the scope of the present invention, "label" means binding a marker to the compound, which label facilitates the quantitative detection of the compound.

The labeled compounds of the present invention preferably contain at least one radionuclide as a label. All positron emitting radionuclides can be used. Within the scope of the present invention, the radionuclide is preferably ¹¹ C, ¹⁸ F, ¹⁵ O, ¹³ N, ^It is selected from the group consisting of ¹²³ I, ¹²⁵ I, ¹³¹ I, ³ H and ^99m Tc.

The fluorescent group of the compound of formula (I) may be a naturally occurring fluorophore or a chemically synthesized fluorescent group such as rhodamine, green fluorescent protein
escent protein) or fluorescein and its derivatives.

In the compounds of the formula (I), R is preferably hydrogen, an alkyl group having 1 to 6 carbon atoms, haloalkyl, haloalkenyl and R ⁴ is substituted one or more times. Preferably it is a good phenyl. This substituent is I, F,
Cl, CF _3, CH preferably selected from _3, and the group consisting of OCH _3.

A preferred compound of the present invention is labeled with at least one radionuclide selected from the group consisting of [ ¹¹ C], [ ¹⁸ F] and [ ¹³ N], (±) -3- (3,4) -Dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct
2-ene; (±) -3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-chlorophenyl) -8-methyl-8 -Azabicyclo [3.2.1] octo-2-
Ene; (±) -3- (4-chlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3-phenyl-8-methyl-8-azabicyclo [3.2.1] oct- 2-ene; (±) -3-phenyl-8-azabicyclo [3.2.1] octo-2-ene; (±) -3- (4-methylphenyl) -8-methyl-8-azabicyclo [3.2.1 ] Oct-2
Ene; (±) -3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [ 3.2.1] Oct-2
-Ene; (±) -3- (4-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-methyl-8 -Azabicyclo [3.2.1
] Oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-fluorophenyl) -8 -Methyl-8-azabicyclo [3.2.1] oct-2
Or (±) -3- (4-fluorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; or a pharmaceutically acceptable salt of the labeled compound.

Other preferred compounds of formula (I) are those wherein R is haloalkenyl, for example 1-iodo-prop-1-en-3-yl, wherein iodine is a radioisotope of iodine. And R ⁴ represents phenyl substituted with F, CH ₃ , CF ₃ , Cl or H, or R ⁴ represents 3,4-dichlorophenyl.

Other preferred compounds are those wherein R is haloalkenyl, such as methyl iodide, ethyl iodide, propyl iodide, methyl fluoride, ethyl fluoride, propyl fluoride,
(Wherein halogen is optionally a radioisotope of iodine or fluorine), and R ⁴ represents phenyl substituted with F, CH ₃ , CF ₃ , Cl or H;
Or a compound represented by the formula (I), wherein R ⁴ represents 3,4-dichlorophenyl.

Other preferred compounds are those wherein R is an alkylthio derivative such as thiomethyl,
Represents ethylthio, propylthio, or butylthio, and R ⁴ is F, CH ₃ , CF ₃ , C
A compound represented by the formula (I), which represents phenyl substituted with l or H, or R ⁴ represents 3,4-dichlorophenyl. These compounds are suitable for coordinating to a ^99m Tc complex [MeegallS, et al .; Bioconjugate Chem. 199697421-429].

It will be apparent to those skilled in the art that some of the compounds of formula (I) contain a chiral center and that such compounds exist in isomeric (ie, enantiomeric) forms. The present invention includes all such isomers and all mixtures thereof, including racemic mixtures.

Some of the compounds of formula (I) exist in (+) or (−) form as well as in racemic form. Resolving the racemic form into optical enantiomers by known methods, for example by separating the diastereomeric salt with an optically active acid and treating with a base to liberate the optically active amine compound Can be. Another method for resolving racemates into the optical antipodes is based on chromatography on an optically active matrix. The racemates of the present invention can be resolved into their optical antipodes, for example, by fractional crystallization of d- or l-salts (tartrate, mandelate, or camphor sulfonate). The compound of the formula (I) may also be a compound of the formula (I) and an optically activated carboxylic acid such as (+) or (−) phenylalanine, (+) or (−). ) By reacting a carboxylic acid derived from phenylglycine, (+) or (-) camphoric acid to form a diastereomeric amide or to give an optically active chloroformate with a compound of formula (I) The reaction can be resolved by formation of diastereomeric carbamates.

[0038] Other optical isomer resolution methods known to those skilled in the art may be used and will be apparent to those skilled in the art. Such methods include those discussed by Jaques J. et al. [Jaques J. Collet A, and Wilen S, "Enantiomers, Racemate
s and Resolutions ", John Wiley and Sons, New York (1981). Methods of Preparation The labeled compounds of the present invention can be prepared in a variety of ways. Thus, the labeled compounds of the present invention and their pharmaceutically acceptable properties. The derivative can be produced by any method known in the art for producing a compound having a similar structure,
In this case, the label, preferably a radionuclide, is introduced by any suitable means.

The labeled compound according to the present invention is characterized in that at least one of the substances used for the preparation of the compounds of the formula (I) is a label, preferably a radionuclide. Can be prepared in the same manner as the unlabeled compound of formula (I) except that Alternatively, the group of the unlabeled compound of formula (I) can be exchanged for a labeling group, thereby forming a labeled compound of formula (I).

The unlabeled compounds of the formula (I) are described, for example, in International Patent Application Publication No. WO 97 /
According to the method described in the specification of JP 13770, for example, it can be produced as shown in the following scheme. Diagram (1):

[0041]

Embedded image In the formula (1), the substituents R and R ⁴ are as defined above,
Is a Li, MgBr or other type of functional group suitable for generating a carbanion as a counterpart.

The processing of the above reaction scheme is performed by a conventional method. Dehydration of the alcohol is carried out with an acid such as hydrochloric acid or sulfuric acid or other conventional dehydrating agents such as P ₂ O ₅ or SOCl ₂ . An unlabeled compound of formula (I) can be converted to another unlabeled compound of formula (I) in a conventional manner.

The substances used for the preparation of the unlabelled compounds of the formula (I) are known or can be prepared by known methods from commercially available substances.

The products of the above reaction can be obtained by conventional means, for example by extraction, crystallization, distillation and / or
It can be isolated by chromatography.

The labeled compounds of formula (I) can generally be prepared in the same manner as described above for unlabeled compounds. In this case, all of the substances used in the preparation of the unlabeled compound of formula (I) are preferably radioactive so that the label is inserted into the finally prepared labeled compound of formula (I). It can be labeled by nuclide. The labeled compound is commercially available or can be prepared using a commercially available labeling agent.

Examples of commercially available labeling agents that can be used in the preparation of the labeled compounds of the present invention include [ ¹¹ C] O ₂ , ¹⁸ F and Nal with various isotopes of iodine. is there.

In particular, [ ¹¹ C] O ₂ can be converted to a [ ¹¹ C] -methylating agent such as [ ¹¹ C] H ₃ I or [ ¹¹ C] -methyl triflate.

For example, [ ¹²⁵ I] -labeled 1-iodopropane 1 as a substituent on N-8
Labeled compounds containing -en-3-yl can be prepared as described in the prior art [Elmaleh et al; Nucl. Med. 1996
37 1197-1202].

For example, labeled compounds containing [ ¹⁸ F] -alkyl-substituted N-8 can be prepared according to the prior art, for example as described in WO 96/39198. it can.

[0050] Further, R ⁴ and X are other than the compound R ⁴ X in which (in the formula labeled with a reaction shown in labeled compound above scheme (1), R ⁴ contains a label of the present invention is the As defined in the above.). These compounds can be produced by a known method. Illustrative of labeled compound R ⁴ X is, R ⁴ is ^[11 C] H ₃ - substituted phenyl -, benzyl -, heteroaryl - and naphthyl group, ^[11 C] F ₃ - substituted phenyl -, Benzyl-, heteroaryl- and naphthyl groups, [ ¹¹ C] N-substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups, H ₃ [ ¹¹ C] O-substituted phenyl-, benzyl-, hetero Aryl- and naphthyl groups, [ ¹⁸ F] -substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups, [ ¹⁸ F] ₃ C-substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups, H ₃ C ^[15 O] - substituted phenyl -
, Benzyl-, heteroaryl- and naphthyl groups, at least one [ ¹⁵ O],
3,4-methylenedioxyphenyl groups having N [ ¹⁵ O] ₂ -substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups, C [ ¹³ N] -substituted phenyl-, benzyl-, hetero Aryl- and naphthyl groups, [ ¹³ N] amino-substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups, [ ¹²³ I
], [ ¹²⁵ I] or [ ¹³¹ I] -substituted phenyl-, benzyl-, heteroaryl- and naphthyl groups and at least one of the groups attached to or contained in the ring.
Substituted or unsubstituted phenyl-, benzyl- having ^three [3H]
, A heteroaryl- and a naphthyl group.

[0051] As described above, unlabeled compounds of formula (I) can be converted to labeled compounds of formula (I) by using a labeling agent.

The labeled compound of the present invention having a [ ¹¹ C] H ₃ — group is, for example, a free amine compound represented by the formula (I) (ie, wherein R is H and R ⁴ is And [ ¹¹ C] -methylating agent, preferably [ ¹¹ C] H ₃ I or [ ¹¹ C]-.
It can be prepared by reacting with methyl triflate or other suitable leaving groups as exemplified below.

[0053] Similarly, other ^[11 C] labeled radicals R are, for example, formula (I) ^[11 was derivatized with the free amine compound and optionally a suitable leaving group (LG), represented by C
] Can be introduced by reacting with a labeled alkylating agent, such as [ ¹¹ C] -cyclohexyl triflate or other cyclohexyl alkylating agents. Other labeling form of the compound of formula (I) are, for example, R is an alkyl substituted with ^[125 I]; as described in the ^[125 I] In substituted alkenyl, for example, the prior art 1 over ^[125 I] Puropu 1 En 3 Iru, 1 over ^[125 I] Buto 1 En 3 Iru; ^[125 I] in substituted alkynyl or ^[18 F] alkyl substituted with substituted with ^[18 F] Alkenyl,
It also includes the case of representing alkynyl substituted with [ ¹⁸ F]. The standard leaving groups used in these reaction formats are known in the art and a few examples are shown below. The reaction can optionally proceed via an intermediate compound, such as a trialkyltin derivative, which is replaced by the addition of Na [ ¹²⁵ I] or [ ¹⁸ F].

Similarly, other labeled groups can be used to derivatize the free amine compound of formula (I), for example, to have an appropriate leaving group attached to an alkyl chain of appropriate length. To introduce into the R group. The leaving group can then be replaced by a labeled nucleophile. Leaving groups, such as esters of sulfuric acid and sulfonic acid, generally, for example, mesylate, tosylate, brosylate, nosylate, triflate, nonaflate, tresylate; esters of nitric acid, and inorganic ester leaving groups, such as ROPO (OH) ₂ , ROB (OH) ₂ halogen,
Conjugated acids, ethers, quaternary amines, tertiary sulfides, trialkyltin derivatives and the like of alcohols are all known in the art. The reaction with the labeling agent, which acts as a nucleophile, is carried out in a suitable solvent, an aprotic solvent of the preferred polarity and preferably in the essential anhydrous state. Such nucleophiles, such as [ ¹⁸ F], may require auxiliaries for dissolution in solvents. M ⁺ X ^- type (M ⁺ is 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [as described in the prior art)
8.8.8] hexacosane, alkali metal ions, tetraalkylammonium and the like, and X ⁻ is, for example, a carbonate, bicarbonate, hydroxide, formate or other counter ion. The auxiliary agents of the type) can dissolve radionuclides. Such compounds are known in the art.

As another embodiment of the present invention, the compound represented by the formula (I) may show a substituent capable of coordinating to a metal complex. Such metals can be positron-emitting isotopes of Tc, whereby the complete complex is radiolabeled and suitable for use in diagnostics [MeegallS et al .; Bioconjug.
ateChem. 1996 7 421-429]. Such substituents are, for example, alkylthio, alkenylthio, and alkynylthio.

Further, the preparation of the labeled compound of the present invention is described by the following examples (Preparation Examples 1-4). Pharmaceutical formulations The present invention further provides pharmaceutical formulations comprising a diagnostically effective amount of a labeled compound of formula (I) or a mixture thereof together with at least one pharmaceutically acceptable carrier or diluent. I do. In this case, the labeled compound of formula (I) is defined as above. The carrier or diluent must be acceptable in that it is compatible with the other ingredients of the formulation, must not be harmful to its recipients, and must not be specifically restricted.

The pharmaceutical compositions are suitable for parenteral administration, including intramuscular, subcutaneous and intravenous administration. Intravenous administration is a preferred mode of administration.

[0058] Formulations in liquid form include solutions, suspensions, and emulsions, for example, water or water-
Propylene glycol solution. For example, parenteral injection liquid preparations can be prepared as solutions in aqueous polyethylene glycol solution.

Thus, the labeled compounds of the present invention are prepared for parenteral administration (eg, administration by injection) and are in unit dosage form in ampules, pre-filled syringes, small volume syringes or various dosage containers. Can be present with preservatives added. The formulations take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid, or lyophilized from a solution of suitable excipients, eg, sterile pyrogen-free water, before use. .

Aqueous solutions suitable for oral application are prepared by dissolving the labeled compound of the invention in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired. be able to.

Aqueous suspensions suitable for oral application include the labeled compounds of the invention, which are comminuted with a viscous substance, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other known suspending agents. Can be prepared by dispersing in water.

Also included are solid preparations which are intended to be converted, shortly before use, to liquid preparations for oral administration. Such liquids include solutions, suspensions, and emulsions. In addition to the labeled compounds of the present invention, these formulations may also contain, for example, colorings, flavoring agents,
It may contain stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners and / or solubilizers.

Alternatively, the active ingredient may be in the form of a dry powder, for example a powder mixture containing the labeled compound of the invention in a suitable powder base such as lactose, starch, starch derivatives such as hydroxymethylcellulose and polyvinylpyrrolidone (PVP). Can be supplied at The powder formulation may be presented in unit dosage form, for example, in capsules or cartridges of, or blister packs of, gelatin.

Tablets or capsules for oral administration and liquids for intravenous administration are preferred formulations.

[0065] Suitable dosage ranges are from about 0.1 ng to about 100 g of the labeled compound of the present invention. Administration of the appropriate dosage will, of course, be dependent on the precise route and form of administration, the type of diagnosis, the patient being treated and the weight of the patient being treated, and the preferences and experience of the attending physician or veterinarian. Diagnostic methods and in vivo receptor imaging (neuroimagin)
g) Method The second object of the present invention is achieved in a first embodiment of the present invention by a method for measuring the level of a monoamine neurotransmitter reuptake site in a blood sample. The method comprises the steps of: (a) converting a compound of formula (I) in labeled or unlabeled form, or any enantiomer or any mixture thereof, or a pharmaceutically acceptable salt thereof, into blood (B) measuring the amount of the compound of formula (I) bound to a predetermined portion of the blood sample, and (c) determining the monoamine from the data obtained in step (b). Calculating the level of the neurotransmitter reuptake site.

Hereinafter, this method is referred to as the “in-vitro method” of the present invention.

In particular, the in vitro method allows accurate calculation of the serotonin reuptake site in the cell fraction obtained in step (b). Preferably, the predetermined portion of the blood sample is a blood fraction containing platelets.

In step (b) of the in vitro method of the present invention, the labeled or unlabeled compound (I), any enantiomer thereof or any mixture thereof, or a pharmaceutically acceptable salt thereof is treated with blood. Add to sample. Generally, the compound of formula (I) added in step (a) is bound to a predetermined portion of the blood sample used in step (b) of the in vitro method of the present invention ( It is selected according to the method for measuring the amount of the compound represented by I).

When the compound of formula (I) used in step (a) of the above method is a labeled compound of the present invention, the compound is labeled with at least one radionuclide. Is preferred. Preferred radionuclides are those described above. In formula (I), R and R ⁴ are as defined above, and preferred groups R and R ⁴ are as defined above. Further, R ⁴ is preferably a fluorescent group.

In the step (a) of the in vitro method of the present invention, the compound represented by the formula (I) is labeled
It can also be used in unpredicted form. In this case, R and R^FourIs defined above
And the preferred groups R and R^FourIs as defined above. Further, R ^Four Is preferably a fluorescent group.

The labeled or unlabeled compound of the formula (I) added in step (a) of the in vitro method of the invention may be prepared by a suitable spectroscopy, in particular UV spectroscopy and / or fluorescence spectroscopy Can be detected by

In step (c) of the in vitro method of the present invention, the level of the monoamine neurotransmitter reuptake site can be determined, for example, by using a scattered plot (ScatchardPlod).
t) It can be calculated from the data obtained in step (c) using analysis.

In a second embodiment, a second object of the present invention is solved by a method for non-invasively measuring the distribution of a tracer compound in a complete, intact animal organism or human body by means of a physical detection method. The tracer compound is the compound of formula (I) in labeled or unlabeled form or any enantiomer or any mixture thereof, or a pharmaceutically acceptable salt thereof.

Hereinafter, this method is also referred to as “in-vivo method” of the present invention.

In the in vivo method of the present invention, the physical method for detecting the tracer compound of the formula (I) is preferably PositronEmission Tomography (PET).
), SinglePhotonImagingComputed Tomgr
aphy (SPECT), Magnetic Resonance Spectr
oscopy (MRS), MagneticResonanceImaging
(MRI), and Computed Axial X-ray Tomograph
y (CAT) or a combination thereof.

The tracer compound of formula (I) can be selected according to the detection method chosen. The compounds of the above formula (I) can be used in labeled or unlabeled form.

When the labeled compounds of the formula (I) are used in the in vivo method according to the invention, they are preferably ¹¹ C,¹⁸F,¹⁵O,¹³N,^{one two Three}I,¹²⁵I,¹³¹I and^ThreeConsists of H
Preferably, it is labeled with a radionuclide selected from the group consisting of: The mark of the formula (I) of the present invention
Preferred examples of the identified compound are as described above.

The following table summarizes the preferred detection methods and the use of suitable radionuclides.

Detection Methods Suitable Radionuclides PET ¹¹ C, ¹⁵ O, ¹³ N, ¹⁸ F SPECT ¹²³ I, ¹²⁵ I, ¹³¹ I Unlabeled compounds of formula (I) are used in the in vivo method of the invention. Preferably, the compounds have at least one substituent containing ¹⁹ F. Particularly preferred unlabeled compounds of formula (I) are those wherein R ⁴ is a phenyl group containing at least one substituent selected from F and CF ₃ .

A specific example of an unlabeled compound of formula (I) that can be used in the in vivo method of the present invention is (±) -3- (3,4-dichlorophenyl) -8-methyl-8- Azabicyclo [3.2.1] oct
2-ene; (±) -3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-chlorophenyl) -8-methyl-8 -Azabicyclo [3.2.1] octo-2-
Ene; (±) -3- (4-chlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3-phenyl-8-methyl-8-azabicyclo [3.2.1] oct- 2-ene; (±) -3-phenyl-8-azabicyclo [3.2.1] octo-2-ene; (±) -3- (4-methylphenyl) -8-methyl-8-azabicyclo [3.2.1 ] Oct-2
Ene; (±) -3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [ 3.2.1] Oct-2
-Ene; (±) -3- (4-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-methyl-8 -Azabicyclo [3.2.1
] Oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-fluorophenyl) -8 -Methyl-8-azabicyclo [3.2.1] oct-2
Or (±) -3- (4-fluorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; or a pharmaceutically acceptable salt thereof.

Examples of physical detection methods that can be used to detect unlabeled compounds of formula (I) are HPLC and mass spectrometry.

The compound of formula (I) in labeled or unlabeled form, or any enantiomer or any mixture thereof, may be a disorder or disease of living organisms, including humans, The disease responds to inhibition of monoamine neurotransmitter reuptake in the central nervous system and can be used as a diagnostic agent for ──. It is particularly preferred to use these compounds in the diagnosis of disorders or diseases that respond to inhibition of serotonin neurotransmitter reuptake. In addition, the labeled or unlabeled compounds of formula (I) may be used in depression or related disorders such as pseudo dementia or Ganser syndrome, impulse compulsive disorder, panic disorder, memory deficits, attention-deficit hyperactivity disorder (ADHD syndrome)
Can be used to diagnose disorders or diseases that are obesity, anxiety and eating disorders.

Prior to performing the in vivo methods of the present invention, a diagnostically effective amount of a labeled or unlabeled compound is administered to a living organism, including a human. The labeled or unlabeled compounds of formula (I) can be administered neat, but are preferably administered in the form of a pharmaceutical preparation.

When administering the labeled compound of formula (I) in the form of a pharmaceutical formulation, the pharmaceutical formulations of the present invention as described above may be used.

When the unlabeled compound of formula (I) is administered in the form of a pharmaceutical composition,
Pharmaceutical preparations which differ from the above-mentioned pharmaceutical preparations according to the invention in that they comprise unlabeled compounds of the formula (I) instead of the labeled compounds of I).

The diagnostically effective amount of labeled or unlabeled compound of formula (I) to be administered prior to performing the in vivo method of the present invention is from 0.1 ng to 100 μg / kg body weight.
And preferably in the range of 1 ng to 10 μg per kg of body weight.

By using the in vivo method of the present invention, the labeled or unlabeled compound of the above formula (I) can be measured by physical methods in the body or any desired place thereof. The distribution in a part of the nervous system, particularly preferably in the brain, is measured.

From the data obtained from the in vivo method of the invention, the extent of the disease can be assessed, for example, by a physician, preferably a neurologist.

This evaluation can be performed by comparing data obtained from the in vivo method of the present invention with control data. This control data can be obtained, for example, from a human control group. This group may consist of healthy persons or persons suffering from one of the above disorders or diseases.

Further, the present invention provides a method for diagnosing a disorder or disease of a living body of a human or an animal, wherein the disorder or disease is responsive to inhibition of monoamine neurotransmitter reuptake.
(A) administering to said organism a diagnostically effective amount of a compound of formula (I) in its labeled or unlabeled form; and (b) at least one portion of said organism by a physical method. And (c) comparing the obtained data with control data to provide the above-mentioned diagnostic method.

[0091] Preferably, the pharmaceutical formulation used in the in vitro method of the invention can be supplied in the form of an assay kit system. The pharmaceutical preparations here contain the labeled or unlabeled compound of the formula (I) in unit dosage form in a suitable container.
The unit dosage is preferably adjusted to be sufficient to analyze a single blood sample according to the in vitro method of the invention. Further, the assay kit of the present invention can contain a stabilizer. The stabilizer can be selected from antioxidants, such as ascorbic acid, or from weak acid-base compositions, such as phosphate buffers, or from various forms of cyclodextrin, such as hydroxypropyl β-cyclodextrin.

The compounds of the present invention and derivatives thereof are the first substances known to bind specifically to serotonin transporters. This substance makes it possible, for the first time, to reliably determine the number of serotonin binding sites and the associated Kd values, and the assay of changes in serotonin release and serotonin metabolism in response to therapeutic agents.

In addition, the labeled compounds of formula (I) can be used in the analysis of patients with lower levels of serotonin reuptake compared to normal levels of serotonin uptake inhibitors and in adjusting their treatment. In this case, the compound of the invention is such that the dosage of the administered serotonin reuptake inhibitor is sufficient to occupy a number of serotonin transporter sites, thereby blocking serotonin reuptake and its activation in the synaptic cleft. It can be used to assess whether presence and action are increased. Similarly, the labeled compounds of the invention may be administered at unnecessarily high dosages thereby blocking too many serotonin transporter sites and / or increasing the risk of unwanted side effects. Can be used to find out. If a compound is administered at a sufficient dosage, thereby achieving maximal blockade of serotonin reuptake, higher dosages only increase the risk of side effects.

FIG. 1 is a characteristic PET scan showing only one very specific uptake and labeling of serotonin nerve endings (with a serotonin reuptake transporter) by compound (3-4).

[0095]

【Example】

The invention will be illustrated by the following examples, which do not limit the scope of the invention as claimed. Example 1 Preparation Example [Preparation of Some Intermediate Compounds] Method A: 3- (3,4-dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] octane-3-
All (Compound 1-1) 1-Bromo-3,4-in anhydrous diethyl ether (1430 ml) under an argon atmosphere
A stirred solution containing dichlorobenzene (178.6 g, 0.8 mol) was added to -7.
Cool to 0 ° C. While keeping the temperature below -65 ° C, a solution of n-butyl-lithium (310 ml, 2.5 M; 0.78 mol) in hexane is slowly added (addition time = 1 hour). The resulting solution was stirred at -70 ° C for a further 30 minutes, then 8-methyl-8-azabicyclo [3.2.1] in anhydrous tetrahydrofuran (360 ml).
A solution with octane-3-one (50 g, 0.36 mol) is added. Keep the temperature below -50 ° C during the addition over about 1 hour. The resulting solution was stirred at −50 ° C. for 2 hours, then water (215 ml) was added over 15 minutes and 4M HCl (25 minutes over 25 minutes).
360 ml) are added. The temperature reaches -20 ° C by the end of the addition. The organic phase is discarded and the aqueous phase is washed once with diethyl ether (500 ml). Concentrated NH ₄ OH (about 200 ml) is added to the aqueous phase until a pH of 10 at which precipitation of the desired compound occurs. The crude product is isolated by filtration, suspended twice in water (2 × 300 ml) and finally dried under a lamp to give the title compound as a white solid (88
g, 86%). 179.3-180.5 ° C. The following compound is similarly prepared: 3- (4-chlorophenyl) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol (compound 2-1) The target compound is 4-bromochlorobenzene (15. 4g, 81
mmol), n-butyl-lithium in hexane (31 ml, 2.5 M; 78 mm
ol) and 8-methyl-8-azabicyclo [3.2.1] octan-3-one (5 g, 36 m
mol). Yield 5.7 g (63%) as a white solid. Melting point 186
. 3-187 ° C. 8-methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] octane-3-ol (compound 3-1) 4-bromobenzotrifluoride, n-butyl in hexane Prepared from lithium (31.2 ml, 2.5 M; 77.9 mmol) and 8-methyl-8-azabicyclo [3.2.1] octan-3-one (5 g, 36 mmol). 6.2 g (60%) yield as a yellow solid. 189.2-190.5 ° C. 3- (4-Fluorophenyl) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol (compound 4-1) The target compound was converted to 4-bromofluorobenzene (26.3 ml, 0.15 mol).
N-butyl-lithium in hexane (60 ml, 2.5 M; 0.15 mol) and 8-methyl-8-azabicyclo [3.2.1] octan-3-one (10 g, 71.7 mm)
ol). Yield 9.9 g (59%). 168.5-170 ° C. 8-methyl-3-phenyl-8-azabicyclo [3.2.1] octan-3-ol (compound 5
-1) The target compound was dissolved in bromobenzene (42.1 ml, 0.4 mol) and hexane.
n-Butyl-lithium (156 ml, 2.5 M; 0.39 mol) and 8-methyl-8
-Prepared from azabicyclo [3.2.1] octan-3-one (25 g, 0.18 mol). Yield 14 g (36%). 157-159 [deg.] C. 8-Methyl-3- (4-methylphenyl) -8-azabicyclo [3.2.1] octan-3-ol (Compound 6-1) The target compound was 4-bromotoluene (13.9 g, 81.4 mm).
ol), n-butyl-lithium in hexane (31.2 ml, 2.5 M; 78 mm)
ol) and 8-methyl-8-azabicyclo in anhydrous tetrahydrofuran (40 ml)
[3.2.1] Prepared from octane-3-one (5 g, 35.9 mmol). 3.5 g (42%) as a white solid. Melting point 247-249 [deg.] C. 3- (4-Methoxyphenyl) -8-methyl-8-azabicyclo [3.2.1] octan-3-ol (Compound 7-1) The target compound was 4-bromoanisole (15.1 g, 80.5 mmol), hexane -Methyl-8-azabicyclo [3.2.1] in n-butyl-lithium (31.2 ml, 2.5 M; 77.9 mmol) in anhydrous tetrahydrofuran (40 ml)
Prepared from octane-3-one (5 g, 36 mmol). Yield 2.1 g (24%
). 161.8-162.3 ° C. Example 2 Preparation Example [Preparation of unlabeled compound of formula (I)] Method A: (±) -3- (3,4-dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct
2-ene (Compound 1-2) 3- (3,4-dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] octane-3-ol (Compound 1-1) in glacial acetic acid (160 ml) (50 g, 0.17 mol
) Is added to the stirred solution at room temperature with concentrated hydrochloric acid (50 ml). The reaction mixture is heated at reflux. The starting compound is consumed after 20 minutes and the reaction mixture is poured onto about 1.5 L of crushed ice. Concentrated NH ₄ OH is added to the resulting aqueous solution until pH 10 is achieved.
(Approximately 325 ml) is added, causing a sticky solid to precipitate. The mixture is decanted and the residue is triturated in water (1.5 L) to give a crystalline crude product. The crude product is finally washed with water (300 ml) and dried in a fume hood to yield the desired compound as an off-white solid. 44-52 ° C.

The following compound is prepared similarly: (±) -3- (4-chlorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-
Emmalonate (Compound 2-2) 3- (4-chlorophenyl) -8-methyl-8-azabicyclo [3.2.1] octane-3-
The target compound is prepared from all (compound 2-1) (4 g, 16 mmol), glacial acetic acid (15 ml) and concentrated hydrochloric acid (15 ml). Yield of free base (3.6 g, 97%
). Dissolve a small amount of the free base (1.44 g, 6 mmol) in ethanol (96%) and add malonic acid (0.62 g, 6 mmol) in ethanol (96%). The resulting solution is concentrated to an oil, which is triturated in diethyl ether. The desired compound precipitates as a powder and is finally isolated by filtration. Yield as white crystals (1.4 g, 71%). Melting point 100.8-102.1 ° C. (±) -8-Methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1
] Oct-2-enmalonate (Compound 2-2) 8-Methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] octan-3-ol (Compound 3-1) (5 g) , 17.5 mmol), glacial acetic acid (16
ml) and concentrated hydrochloric acid (16 ml) to produce the desired compound. The free base of the target compound is dissolved in ethanol (96%), and malonic acid (1.
17 g, 11.2 mmol) are added. The solution is concentrated to dryness and the residue is triturated in diethyl ether. The desired compound precipitates as a powder and is finally isolated by filtration. Yield 3.9 g (60%). Melting point 106.7-107.8C. (±) -3- (4-Fluorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2
-Emmalonic acid salt (compound 4-2) 3- (4-fluorophenyl) -8-methyl-8-azabicyclo [3.2.1] octane-3
-The desired compound is prepared from all (compound 4-1) (4.7 g, 20 mmol), glacial acetic acid (20 ml) and concentrated hydrochloric acid (20 ml). Dissolve the free base of the desired compound in isopropanol and add malonic acid (1.7 g, 16.3 mmol).
After some time, the desired compound precipitates as a powder and is finally isolated by filtration. Yield 4.6 g (72%). 122.2-123 ° C. (±) -8-Methyl-3-phenyl-8-azabicyclo [3.2.1] oct-2-emanalate (compound 5-2) 8-methyl-3-phenyl-8-azabicyclo [3.2.1] octane -3-all (8g
, 37 mmol), glacial acetic acid (25 ml) and concentrated hydrochloric acid (8 ml) to produce the desired compound. The free base of the target compound (7.4 g, 37 mmol) was dissolved in absolute ethanol (20 ml), and malonic acid (3.9 g, 37.5 mmol) was added.
The solution is heated at reflux for a few minutes, while the solution is still hot, small amounts of impurities are removed by filtration, the solution is cooled, kept at 5 ° C. for a while, then seeded with seed crystals to initiate precipitation of the desired compound. After 2 hours at C, the desired compound is isolated by filtration and the crystals are washed with cold absolute ethanol (10 ml). Yield 5.9 g (53%). 131-131.8 ° C. (±) -8-Methyl-3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-
Enfumarate (Compound 6-2) 8-Methyl-3- (4-methylphenyl) -8-azabicyclo [3.2.1] octan-3-ol (3.4 g, 14.7 mmol), glacial acetic acid (11 ml) And concentrated hydrochloric acid (11m
The target compound is prepared from 1). Dissolve the free base of the desired compound in diethyl ether and add fumaric acid in methanol (1.3 g, 11.2 mmol). The resulting solution is concentrated to dryness and the residue is triturated in diethyl ether. The target compound precipitates as a powder and is isolated by filtration. Yield 2.46 g (51%). 156.8-157.4 ° C. (±) -3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2
-Enfumarate (compound 7-2) 3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [3.2.1] octane-3
-All (2 g, 8 mmol), glacial acetic acid (6.4 ml) and concentrated hydrochloric acid (6.4 ml)
)) To produce the desired compound. The free base of the target compound was dissolved in ethanol (96%), fumaric acid (0.8 g, 6.9 mmol) was added, no precipitation occurred, the solution was concentrated to dryness, and the residue was concentrated in anhydrous ethanol. Crystallizes from. 1.1 g (40%) yield as white crystals. 167.3-168.7 ° C. Example 3 Preparation Example [Preparation of unlabeled compound of formula (I)] (±) -3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-emmalonate (Compound 1) -3) (±) -3- (3,4-dichlorophenyl) in anhydrous 1,2-dichloroethane (100 ml)
-8-methyl-8-azabicyclo [3.2.1] oct-2-ene (compound 1-2) (10
g, 37 mol) under a nitrogen atmosphere is added to 1-chloroethylchloroformate (8 ml, 10.6 g, 74 mmol). The reaction mixture was heated at reflux overnight and 1-chloroethyl chloroformate (4 ml, 5.3 g, 37 m
mol) is added and the mixture is heated at reflux for 4 hours. The reaction mixture is concentrated to dryness. The residue is dissolved in methanol, the reaction mixture is heated at reflux for 2 hours and then concentrated to dryness. The residue is chromatographed on silica gel (dichloromethane / methanol (9/1, v / v), then dichloromethane / acetone / methanol (4/1/1, v / v / v) and finally eluted with methanol Do). The product fractions were concentrated to dryness and the residue (1.8 g, the rest being starting compound) was treated with glacial acetic acid (1 g).
0 ml) and water (5 ml) and zinc dust (1 g, 15.2 mmol) are added. The reaction mixture is stirred overnight at room temperature. The reaction mixture was poured into water, concentrated NH ₄ OH was added until pH = 10 was achieved, and the aqueous phase was extracted with diethyl ether,
The organic phase is washed with water, dried over magnesium sulfate and then evaporated to an oil. The oil crystallizes on standing at room temperature. Ethanol (96%) solid
And 4M sodium hydroxide (5 ml) is added and the reaction mixture is heated at reflux overnight. Then a further 4 M sodium hydroxide (10 ml) is added and the reaction mixture is again heated at reflux overnight. An additional 4 M sodium hydroxide (10 ml) is added and the reaction mixture is heated at reflux for 4 hours. The reaction mixture is concentrated until no more ethanol remains. During the concentration, water is added to keep the volume of the solution almost constant. The resulting solution is extracted with diethyl ether. The organic phase is dried over magnesium sulfate and evaporated to a brown oil. The oil is separated by flash chromatography over silica gel (50 g) (dichloromethane / acetone / methanol, 4/1/1 (v / v)). The product fractions are concentrated to an oil. This oil was dissolved in ethanol (96%) and malonic acid (0.3 g, 0.29 mm
ol). The desired compound precipitates from this solution and is isolated by filtration. Yield 0.65 g (5.5%). 110-112 ° C. (±) -3- (4-Chlorophenyl) -8-azabicyclo [3.2.1] oct-2-emalonic acid salt (compound 2-3) (±) -3-in anhydrous 1,2-dichloroethane (20 ml) (4-chlorophenyl) -8-
Methyl-8-azabicyclo [3.2.1] oct-2-ene (compound 2-2) (2 g, 8
. Under a nitrogen atmosphere, 1-chloroethyl chloroformate (1.25 ml, 11.6 g) is added to the stirred solution having 5 mol). The reaction mixture was heated at reflux overnight, 1-chloroethyl chloroformate (1 ml, 9.3 mmol) was added,
The mixture is again heated at reflux overnight. The reaction mixture is concentrated to dryness to an oil, which is dissolved in methanol (25 ml). The solution was heated at reflux for 2 hours,
It is then concentrated to dryness to give an oil. Dissolve the residue in water and add concentrated NH ₄ OH until a pH = 10 is achieved. The aqueous phase is extracted with diethyl ether. The organic phase is dried over magnesium sulfate and then concentrated to dryness. The residue is chromatographed over silica gel (dichloromethane / acetone / methanol (4 /
1/1, v / v)). The product fractions were concentrated to an oil which was dissolved in ethanol (96%) and malonic acid (0.55 g, 5%) in ethanol (96%).
. 3 mmol) are added. The solution is concentrated to an oil, which is triturated in diethyl ether. The desired compound precipitates as a powder and is isolated by filtration. Yield (1.32 g, 48%). 136-138 ° C.

The following compound is similarly prepared: (±) -3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2
-Ene (compound 3-3) Melting point: 131.4-132.8 ° C. (±) -3- (4-Fluorophenyl) -8-azabicyclo [3.2.1] oct-2-emalonic acid salt (compound 4-3) (±) -3- (4-fluorophenyl) -8-methyl -8- Azabicyclo [3.2.1] oct
The target compound is prepared from 2-ene (compound 4-2) (1.6 g, 7.37 mol) and 1-chloroethyl chloroformate (1.2 ml, 1.6 g, 11 mmol). The free base of the target compound is dissolved in isopropanol, and malonic acid (0.4
3 g, 4.1 mmol) are added. The desired compound precipitates from this solution and is isolated by filtration. Yield 1.14 g (50%). 132.2-132.6
° C. The following compound is prepared analogously: (±) -3-phenyl-8-azabicyclo [3.2.1] oct-2-ene (compound 5-3)
(±) -3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene (compound 6-3) (±) -3- (4-methoxyphenyl) -8-azabicyclo [3.2 .1] oct-2-ene (compound 7-3) preparation of example 4 preparation [labeled compound of formula (I)] ^[11 C] methyl iodide produced: ^[11 C] carbon dioxide, GEMedicalSystemsPETtrace
Prepared by 14N (p, a) ¹¹ C nuclear reaction using a nitrogen gas target produced by cyclotron and 16 MeV protons.

[ ¹¹ C] Carbon dioxide is removed from the target in a stream of nitrogen gas and then captured by a 4 molecular sieve. With heating, [ ¹¹ C] O ₂ is released and passed through a solution of LiAlH ₄ in anhydrous tetrahydrofuran (THF; 300 μl). At the completion of the [ ¹¹ C] O ₂ transfer, the THF is evaporated and 1 ml of hydroiodic acid is added. 160
While heating to ° C., the resulting [ ¹¹ C] methyl iodide is distilled in a stream of nitrogen gas and placed in a reaction vial containing the labeled precursor. Synthesis and purification of [ ¹¹ C] -labeled (±) 8-methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2-ene (compound 3-4) Free amine (±) -3- (4-Trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2-ene (Compound 3-3) (1 mg) in the form of dimethyl sulfoxide (DMSO; 300 μl) And then reacted with [ ¹¹ C] methyl iodide and heated at 130 ° C. for 5 minutes. Then the resulting ^N-[11 C] methyl-labeled ^[11 C] compounds purified by HPLC. Removal of the HPLC solvent was performed by [ ¹¹ C] labeled (±) 8-methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2
.1] achieved by heating the fraction containing octo-2-ene under reduced pressure. The labeled product is then formulated in saline or water (10 ml) to give 0.2
Place in sterile vial through 2 μm membrane filter. Synthesis and purification of [ ¹¹ C] -labeled (±) -3- (3,4-dichlorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene (Compound 1-4) (± ) -3- (3,4-Dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-emmalonate (Compound 1-3) was dissolved in DMSO (300 μl), and NaO was added thereto.
H 0.5 mg is added. The resulting mixture is then reacted with [ ¹¹ C] methyl iodide while heating at 130 ° C. for 5 minutes. Purification is performed in the same manner as in the purification of compound 3-4.

The following compounds are similarly prepared and purified. [ ¹¹ C] labeled (±) -3- (4-chlorophenyl) -8-methyl-8-azabicyclo
[3.2.1] Oct-2-ene (Compound 2-4) The target compound was treated with (±) -3- (4-chlorophenyl) -8-azabicyclo in DMSO.
[3.2.1] Oct-2-emmalonate (compound 2-3), prepared from NaOH and [ ¹¹ C] methyl iodide, and purified as shown in compound 1-4. [ ¹¹ C] -labeled (±) -3- (4-fluorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2-ene (compound 4-4) (±) -3- (4-Fluorophenyl) -8-azabicyclo [3.2.1] oct-2-emalonic acid salt (compound 4-3), NaOH and [ ¹¹ C]
Prepared from methyl iodide and purified as shown in compounds 1-4.

The following compounds can be prepared analogously: [ ¹¹ C] -labeled (±) -3-phenyl-8-methyl-8-azabicyclo [3.2.1] oct-2-ene (Compound 5) -4) [ ¹¹ C] -labeled (±) -3- (4-methylphenyl) -8-methyl-8-azabicyclo
[3.2.1] Oct-2-ene (Compound 6-4) [ ¹¹ C] -labeled (±) -3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [3.2.1] oct- 2-ene (Compound 7-4) The labeled product is synthesized within 30 minutes. Compounds 1-4, 2-
Measured for 4,3-4 and 4-4: Radiochemical purity:> 98%. Representative mass of compounds 1-4, 2-4, 3-4 and 4-4 in the final product: 30-60 nmol in 10 ml of preparation. Representative radioactivity of the final product: 1-4 GBq. Representative relative activity: 30-100 GBq / μmol. Example 5 In Vivo Administration of [ ¹¹ C] -Labeled (±) 8-Methyl-3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2-ene (Compound 3-4) Compound (3-4) is used as a marker for the number of serotonin transporter sites. The binding of the labeled compound (3-4) to the serotonin transporter site is measured as described below. Experimental animals Three female pigs (Hampshire x Yorkshire x Duroc x Landrace hybrid) weighing 39-44 kg are used as test animals. The animals are housed separately in a thermostated (20 ° C.) animal community under natural light conditions. Pigs have free access to water, but have no food 24 hours before the experiment.

Pigs were treated with midazolam (0.5 mg / kg) and ketamine HCl (10 mg / kg)
Sedated by intramuscular injection of. After 10 to 15 minutes, a catheter is inserted into the ear vein and
Through which midazolam (0.25 mg / kg) and ketamine HCl (5 mg / k)
The mixture of g) is administered. Then incubate the pig,_Two/ N_TwoA in O
Anesthetize with sofran. Catheter [Avanti (registered trademark) size 4F-
7F] is surgically inserted into the femoral artery and vein. Isotonic salt solution (about 100cm ^Five / H) and 5% glucose (about 20 cm^Three/ H) intravenously throughout the experiment
Intravenous administration. Maintain body temperature within normal range (39.0-39.4 ° C) with automatic temperature control
And the physiological factors (ie, blood pressure, heart rate and exhaled CO2)_Two) Continuously monitor
You. Hematocrit and whole blood acid-base parameters (ie pH, pCO_Two , PO_Two, HCO_ThreeAnd O_TwoSaturation) and take appropriate measures to prevent disturbance during fluid balance.
Location (eg, force ventilation)
And / or changes in injection rate).PET imaging (neuroimaging) Pigs are swallowed using custom made head-holding equipment.
I slept on my side in the canner (Siemens ECAT EXACT HR)
Check by state. Hepari distribution and binding of compound (3-4) in pig brain
Intravenous dose of approximately 10 μg of the solution and then immediately intravenously into the catheter.
Check by shooting and flowing. The scan starts with injection of compound (3-4),
28 frames (6 × 10 seconds, 4 × 30 seconds, 7 × 1 minute, 5 × 2 minutes and 5 × 10 minutes)
Consists of Under control conditions, no further injections are made during the scan. Antidepressant
To determine if agents affect brain binding, kinetics and distribution of tracer compounds
For intravenous injection of 5 mg / kg under the conditions of antidepressant treatment, the compound (3-4)
Administer 20 minutes after injection.

FIG. 1 shows a coronal section (left), a transverse section (center) and a sagittal section (right) of a pig brain labeled with the compound (3-4). Accumulation of this compound is visible in the raphe nucleus and in the thalamus. For the determination of the total plasma radioactivity concentration of the blood sample compound (3-4), the following number of times: 18
Twenty-eight serial arterial blood samples (1-2 ml) are collected from pigs at x10 seconds, 4x30 seconds, 5x1 minute, 7x5 minutes, and 1x15 minutes. The total plasma radioactivity was measured and the metabolic correction was adjusted to 0.5, 2, 10,
Perform with 200 μl plasma obtained from samples taken at 30 and 60 minutes (200 μl plasma made alkaline with 10 μl of 50% NaOH and 400 μl of ethyl acetate added thereto).

Remove the 200 μl of the organic phase and measure the amount of ¹¹ C radioactivity. At the beginning of the scan, the ¹¹ C count is decay corrected and multiplied by the dilution factor to obtain plasma levels of non-metabolized compound (3-4) per cm ³ of plasma. The arterial sample obtained after infusion of citalopram is used for HPLC evaluation of the concentration of citalopram in plasma. Metabolite analysis Acetonitrile (0.05 ml) is added to plasma samples for metabolite analysis. After centrifugation, the supernatant was filled into a 1 ml injection loop,
Chromatographic separation is performed under the above analytical HPLC conditions. Unfilled compound (3-4)
Is determined by integration of the emission peak corresponding to compound (3-4) with respect to the sum of all radiometric analyses. A biexponential fitting of this data to total plasma activity concentration results in a metabolite-corrected input function. From the metabolite-corrected plasma time-activity curve, the metabolic rate of compound (3-4) is measured by adjusting the polyline curve based on the expression of plasma metabolites. Identification of seven brain regions of pharmacokinetic analysis problem using neuroanatomical catalog of pig brain (Yoshika
wa T; Atlasof the brains ofdomesticanimals;
Pennsylvania State University Press, University of Park, Penn.
, 1968). For each region, the radioactivity concentration is calculated in a series of frames, corrected for radioactivity decay of ¹¹ C (20.3 min) and plotted against time. Notational data is expressed in terms of standard uptake value (SUV). That is, [radioactivity in ROI (Bq / cc) × body weight (g) / injected radioactivity (Bq)]. Normalization of this data is performed by dividing the SUVs obtained at a specific time in the ROI by the SUVs in the cerebellum, ie, the area without the neuronal serotonin transporter. The cerebellum (CB) is also used as a reference area for measuring the binding potential. Calculate the binding potential (BP) as follows:

[0104]

[Outside 1] The pharmacokinetic parameters of the two-component model were evaluated using custom-made software based on the words of Gjedde and Wrong [Gje dde A & Wrond DF: Modeling neurore.
sceptor binding of radioligands in vi
vo. Quantitative imaging; Neurorecept
tors, Neurotransmitters, and Enzymes; Frost JJ and Wagner, Jr. HN
(Eds.), Raven press, New York, 1991 51-7.
9], K ₁ is a single tissue fraction of the tracer from the circulation (Singletissuecom
represents the unidirectional exclusion to K.partment, where K ₂ is the actual rate constant for exclusion from the brain for the cerebellum. On the other hand, assuming that the equilibrium between the tissue fraction of the solution and the bound tissue fraction is fast such that a single tissue fraction results, K ₂ ｀ is the apparent exclusion from the single tissue fraction. It is a rate constant. The K ₁ / K ₂ ｀ ratio is called the apparent partition value and represents the binding of the compound in the ROI. Example 6 In Vitro Diagnosis Reincorporation of Serotonin into Platelets: Platelet-rich plasma is obtained by centrifuging blood samples at 200 xg for 10 minutes at 20 ° C. The platelet pellet is hemolyzed and homogenized to prepare a platelet membrane according to the method of Plenge and Mellerup [Plenge P
& Mellerup ET: [ ³ H] Citaloprambind t
o brain and platelet membranes of hu
man and rat; Neurochem. 1991 56 24
8-252].

Aliquots of 500 μl membrane suspension were added to 25 μl of [ ³ H] -X, mixed,
Incubate for 60 minutes at 2 ° C. Non-specific binding is determined using paroxetine (1 μM, final concentration). After incubation, add this sample to 5 ml of ice-cold buffer and pour directly onto Whatman GF / C fiber filter under suction,
Immediately wash with 5 ml of ice-cold buffer.

The amount of radioactivity on the filter is measured with a conventional liquid scintillation counter.
Using 5-6 concentrates of [ ³ H] -X in the incubation mixture,
The density of binding sites (Bmax) is determined by chard analysis.

Add 375 μl of PRP (platelet rich plasma) to an Eppendorf tube containing 25 μl [ ¹⁴ C] -5HT and incubate at 37 ° C. for 12 (±) 1 minute. Incubate each sample in triplicate. Incubate 400 μl of ice cold stop solution (100 mM NaCl solution containing 40 mM EDTA)
And add 200 μl aliquots into scintillation vials prepared for radioactivity counting. The remaining incubation mixture is quickly centrifuged at> 1500 × g for 2 minutes. After centrifugation, a 200 μl aliquot of the supernatant is removed and added to a scintillation vial. Add 10 ml of scintillation liquid to each bottle and count on a liquid scintillation counter for 5 minutes. Triplicate measurements are made on each sample. [ ¹⁴ C] for each sample
Percent uptake of 5HT is calculated from the average of triplicate counts.

FIG. 1 is a characteristic PET scan showing only one very specific uptake and labeling the serotonin nerve endings (with the serotonin reuptake transporter) with compound (3-4). .

[Procedural Amendment] Submission of translation of Article 34 Amendment of the Patent Cooperation Treaty

[Submission date] April 8, 2000 (200.4.8)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

Embedded image Wherein R is hydrogen or alkyl; R ⁴ is phenyl, which is substituted one or more times by a substituent selected from the group consisting of halogen and CF ₃ ; is there. A labeled compound derived from the compound represented by｝, any enantiomer thereof, any mixture thereof, or a pharmaceutically acceptable salt thereof.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE , KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Nielsen Elsebeth Aestergoel DK-2750 Barelup, Denmark , Pederstrup Bay 93, Neurother Ace Actiesel Skab F-term (reference) 4C064 AA01 CC01 DD09 EE01 FF03 GG03 4C085 HH03 JJ02 KA29 KB56

Claims (27)

[Claims] 1. A compound of the general formula (I) Wherein R is hydrogen, alkyl, haloalkyl, thioalkyl, alkenyl, thioalkenyl, haloalkenyl, alkynyl, thioalkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R ⁴ is phenyl} It is substituted one or more times with a substituent selected from the group consisting of halogen, CF ₃ , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl. 3,4-methylenedioxyphenyl; benzyl, which may be halogen, CF ₃ , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and Selected from the group consisting of aryl Heteroaryl, which may be substituted one or more times by a substituted substituent; halogen, CF ₃ , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino Na, nitro, heteroaryl and aryl, which may be substituted one or more times with a substituent selected from the group consisting of: naphthyl, which is halogen, CF ₃ , CN, alkoxy, cycloal It may be substituted one or more times by a substituent selected from the group consisting of oxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or a fluorescent group. A labeled compound derived from the compound represented by｝, any enantiomer thereof, any mixture thereof, or a pharmaceutically acceptable salt thereof. 2. The labeled compound according to claim 1, which contains at least one radionuclide. Wherein the radionuclide is ^{11 C, 18 F, 15 O} , 13 N, 123 I, 12 5 I, 131 I, selected from ³ H and the group consisting of ^99m Tc, labeled according to claim 2, wherein Compound. 4. R is an alkyl group having 1 to 6 carbon atoms and R ⁴ is phenyl, which is selected from the group consisting of Cl, I, F, CF ₃ , CH ₃ and OCH _3. Which may be substituted once or more times by a substituted group,
A labeled compound according to claim 1. 5. A (±) -3- (3,4-dichlorophenyl)-labeled with at least one radionuclide selected from the group consisting of [ ¹¹ C], [ ¹⁸ F] and [ ¹³ N]. 8-methyl-8-azabicyclo [3.2.1] oct
2-ene; (±) -3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-chlorophenyl) -8-methyl-8 -Azabicyclo [3.2.1] octo-2-
Ene; (±) -3- (4-chlorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3-phenyl-8-methyl-8-azabicyclo [3.2.1] oct- 2-ene; (±) -3-phenyl-8-azabicyclo [3.2.1] octo-2-ene; (±) -3- (4-methylphenyl) -8-methyl-8-azabicyclo [3.2.1 ] Oct-2
Ene; (±) -3- (4-methylphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-methoxyphenyl) -8-methyl-8-azabicyclo [ 3.2.1] Oct-2
-Ene; (±) -3- (4-methoxyphenyl) -8-azabicyclo [3.2.1] oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-methyl-8 -Azabicyclo [3.2.1
] Oct-2-ene; (±) -3- (4-trifluoromethylphenyl) -8-azabicyclo [3.2.1] oct-2
-Ene; (±) -3- (4-fluorophenyl) -8-methyl-8-azabicyclo [3.2.1] oct-2
Or (±) -3- (4-fluorophenyl) -8-azabicyclo [3.2.1] oct-2-ene; or a pharmaceutically acceptable salt of the labeled compound. A labeled compound according to any one of claims 1 to 4. 6. Pharmaceutical preparation comprising a diagnostically effective amount of a labeled compound according to any of claims 1 to 5 together with at least one pharmaceutically acceptable carrier or diluent. object. 7. A compound of formula (I) according to any of claims 1 to 5, or any enantiomer thereof, in a labeled or unlabeled form in a blood sample. Adding the body or any mixture thereof, or a pharmaceutically acceptable salt thereof, and (b) determining the amount of the compound of formula (I) bound to the predetermined portion of the blood sample; (C) A method for measuring the level of a monoamine neurotransmitter reuptake site in a blood sample, comprising the step of calculating the level of a monoamine neurotransmitter reuptake site from the data obtained in step (b). 8. The method according to claim 7, wherein the level of the 5-HT reuptake site is calculated. 9. The method of claim 7, wherein the predetermined portion of the blood sample used in step (b) is platelets. 10. The compound according to claim 7, wherein the compound represented by the formula (I) added in the step (a) is the labeled compound according to any one of claims 2 to 5. The described method. 11. The compound of formula (I) added in step (a) is a compound which can be detected by spectroscopy, in particular UV-spectroscopy and / or fluorescence spectroscopy.
The method according to claim 7. 12. A compound of the formula (I) added in the step (a), wherein
R is an alkyl group having 1 to 6 carbon atoms, R ⁴ is phenyl ─── This Cl, I, F, by a substituent selected from the group consisting of CF _3, CH ₃ and OCH ₃ 1 Or a fluorescent group which may be substituted one or more times. ) Is in the form of its unlabeled compound. 13. A method for non-invasively measuring the distribution of a tracer compound in a complete, intact animal or human body by a physical detection method, wherein the tracer compound is in a labeled or unlabeled form. Formula (I) according to any one of claims 1 to 5.
Or a mixture thereof, or a pharmaceutically acceptable salt thereof. 14. The method according to claim 1, wherein the physical detection method is PET, SPECT, MRS, MRI, CAT.
14. The method of claim 13, wherein the method is selected from the group consisting of: or a combination thereof. 15. The method according to claim 13, wherein the compound represented by the formula (I) is the labeled compound according to any one of claims 2 to 5. 16. A compound of formula (I) wherein R is an alkyl group having 1 to 6 carbon atoms and R ⁴ is phenyl, which is Cl, I, F, CF ₃ , which is optionally substituted one or more times by a substituent selected from the group consisting of CH ₃ and OCH ₃ ) is present in the form of its unlabelled compound. Or the method of 14. 17. A method for the manufacture of a diagnostic agent for the diagnosis of a disorder or disease in living organisms, including humans, wherein said disorder or disease responds to inhibition of monoamine neurotransmitter reuptake in the central nervous system. Or a method of using a compound of formula (I) according to any one of claims 1 to 5 or any enantiomer thereof or any mixture thereof in unlabeled form. 18. The method according to claim 17, wherein the monoamine neurotransmitter is serotonin. 19. The disorder or disease is depression or a related disorder, such as pseudo dementia or Ganser syndrome, impulse compulsive disorder, panic disorder, memory deficits, attention-deprivation, hyperactivity disorder, obesity, anxiety and eating disorders. The use according to claim 17 or 18, wherein 20. The use according to any one of claims 17 to 19, wherein the compound represented by the formula (I) is the labeled compound according to any one of claims 2 to 5. 21. A compound of the formula (I) wherein R is an alkyl group having 1 to 6 carbon atoms and R ⁴ is phenyl, which is Cl, I, F, CF ₃ , or a fluorescent group optionally substituted one or more times by a substituent selected from the group consisting of CH ₃ and OCH ₃ ) is present in the form of its unlabeled compound; Use according to any one of claims 17 to 19. 22. A method of diagnosing a disorder or disease of a living body of a human or animal, wherein the disorder or disease is responsive to inhibition of monoamine neurotransmitter reuptake, comprising: (a) the labeled or labeled Administering to said organism a diagnostically effective amount of a compound of formula (I) according to any one of claims 1 to 5 in a non-existent form; (C) comparing the obtained data with control data. 23. The method for detecting a physical condition is PET, SPECT, MRS, MRI, CA.
23. The method of claim 22, wherein the method is selected from the group consisting of T or a combination thereof. 24. The method according to claim 22, wherein said part of the organism is the brain and / or other parts of the central nervous system. 25. An assay kit containing the formulation of claim 6 in a unit dosage form in a suitable container. 26. The assay kit according to claim 25, further comprising a stabilizer. 27. An assay kit having a pharmaceutical formulation comprising a diagnostically effective amount of an unlabeled compound of formula (I) together with at least one pharmaceutically acceptable carrier or diluent. The above assay kit, further comprising a stabilizer.