WO1999038866A1 - Derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee et utilisation de derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee ou non marquee - Google Patents

Derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee et utilisation de derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee ou non marquee Download PDF

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WO1999038866A1
WO1999038866A1 PCT/DK1999/000044 DK9900044W WO9938866A1 WO 1999038866 A1 WO1999038866 A1 WO 1999038866A1 DK 9900044 W DK9900044 W DK 9900044W WO 9938866 A1 WO9938866 A1 WO 9938866A1
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Prior art keywords
compound
azabicyclo
labelled
oct
ene
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PCT/DK1999/000044
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English (en)
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WO1999038866A8 (fr
Inventor
Peter Moldt
Jørgen SCHEEL-KRÜGER
Elsebet Østergaard NIELSEN
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Neurosearch A/S
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Priority to EP99906069A priority Critical patent/EP1068204A1/fr
Priority to JP2000529334A priority patent/JP2002501921A/ja
Priority to AU26099/99A priority patent/AU2609999A/en
Publication of WO1999038866A1 publication Critical patent/WO1999038866A1/fr
Publication of WO1999038866A8 publication Critical patent/WO1999038866A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates to 8-azabicyclo[3.2.1]oct-2-ene derivatives in their labelled and unlabeiled form. Furthermore, the present invention relates to the use of said derivatives in their labelled or unlabeiled form in diagnostic methods, in particular for in vivo receptor imaging (neuroimaging).
  • WO 9713770 discloses 8-azabicyclo[3.2.1]oct-2-ene derivatives which are re-uptake inhibitors for the monoamine neurotransmitter serotonine (5-hydroxy- tryptamine, 5-HT) and therefore useful in the treatment of disorders or diseases which are caused, at least in part, by increase or decrease of the endogenous serotonine levels.
  • disorders or diseases are e.g., depression and related disorders, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit, hyperactivity disorder, obesity, anxiety and eating disorders.
  • Monoamine neurotransmitters i.e. serotonine, dopamine, and noradrenaline
  • the neurotransmitter molecules can diffuse through the cleft and then bind to specific receptor molecules (transporters) located in the postsynaptic cell membrane. Binding to these receptors results in polarisation of the cell, i.e. transduction of the stimulus.
  • the removal (or inactivation) of monoamine neurotransmitters from the synaptic cleft occurs mainly by a re-uptake mechanism into presynaptic nerve terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occurs.
  • Major depression is a common disorder, affecting approximately 1 in 6 individuals at some point in their lives.
  • the pathophysiology of depression is poorly understood so far, and several neurotransmitters have been implicated in the pathophysiology of major depression.
  • Inhibitors that block noradrenaline and serotonine re-uptake are currently used as pharmaceuticals in anti-depressant therapy.
  • Several lines of preclinical and clinical evidence indicate that an enhancement of serotonine-mediated neurotransmission might underlie the therapeutic effect of the most recent and currently used drugs in anti-depressant therapy, such as fluoxetine, citalopram and paroxetine [P. Blier & C de Montigney, TiPS (Review) 1994 15 220-225].
  • serotonine re-uptake inhibitors block the serotonine transporter within minutes after application whereas their full anti-depressant effect is seen only after three to four weeks of treatment, indicating that re-uptake inhibition per se is not responsible for the anti-depressant response, but rather that further adaptive changes underlie and/or contribute to their therapeutic effect [P. Willner, Int. Review of Psychiatry 1990 2 141-156].
  • the serotonergic neural system of the brain has been shown to influence a variety of physiologic functions, and disturbance of this system has been made responsible for a variety of diseases and disorders such as eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety.
  • depression and related disorders such as pseudodementia or Ganser's syndrome, migraine, pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of ageing, social phobia, attention deficit hyperactivity disorder (ADHD syndrome), chronic fatigue syndrome, premature ejaculation, erectile dysfunction, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
  • pseudodementia or Ganser's syndrome migraine, pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome
  • alcoholism tobacco abuse
  • panic disorder anxiety, post-traumatic syndrome
  • memory loss dementia of ageing
  • social phobia attention deficit hyperactivity disorder (ADHD syndrome)
  • chronic fatigue syndrome premature ejaculation
  • erectile dysfunction erectile dysfunction
  • anorexia nervosa disorders of sleep, autism, mutism or trichot
  • rCBF left dorsolateral prefrontal cortex, the left anterior cingulate cortex and the left angular gyms.
  • depression is combined with cognitive impairment a decreased rCBF in the left medial prefrontal cortex and increased rCBF in the right cerebral vermis has been detected [Bench CJ, Friston KJ, Brown RG, Scott LC, Frackowiak RS & Dolan RJ: The anatomy of melancholia-focal abnormalities of cerebral blood flow in major depression; Psvchol- Med.
  • radioligands which have desirable properties for in vivo receptor imaging. These criteria include ease of labelling with positron-emitting radionucleotides, low rates of peripheral metabolism, high selectivity for brain regions holding the neuroreceptor of interest, and relatively high specific/non-specific binding ratios. Despite the development of a number of radioligands for the serotonine transporter, none of these compounds satisfactorily meet all the criteria desired for an ideal ligand.
  • the compounds and their derivatives of this invention are the first substances known that specifically bind to serotonine transporters. This allows for the first time to reliably determine the number of serotonine binding sites and related Kd values and the release of serotonine as well as the detection of changes in the serotonine metabolism in response to therapeutic drugs.
  • Fig. 1 shows a characteristic PET scan illustrating the unique and very specific uptake and labelling of serotonine nerve terminals (containing the serotonine reuptake transporter) by Compound (3-4) of the invention; A coronal (left), transaxial (centre) and sagittal (right) section of a pig brain labelled with Compound (3-4). Accumulation of the compound can be seen in the medial mesecephalon (the serotonergic Raphe nuclei) and in the diecephalon (the thalamus and basal ganglia).
  • This object is solved by providing a labelled or unlabeiled compounds derived from a compound having the formula (I): R"
  • This object is solved by providing a labelled compound derived from a compound having the formula (I):
  • R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2- hydroxyethyl; and R 4 is phenyl which may be substituted one or more times with substituents 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 substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3
  • halogen represents a fluorine, a chlorine, a bromine or a iodine atom.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C ⁇ s-alkyl), more preferred of from one to six carbon atoms (C 1 . 6 -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a C 1-4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • a haloalkyl group designates an alkyl as above, mono- or polysubstituted with halogen as above. This includes e.g. (X designates a halogen as above) CX 3 , CHX 2 , CH 2 X, CH 2 CX 3 , CH 2 CH 2 X, XCHCH 2 X,
  • Preferred groups are C 4 - haloalkyl containing one halogen; Especially preferred groups are -CH 2 F, -CH 2 I, -
  • a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3 . 7 -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly- enes.
  • the alkenyl group of the invention comprises of from two to six carbon atoms (C 2 . 6 -alkenyl), including at least one double bond.
  • the alkenyl group of the invention is ethenyl; 1- or 2- propenyl; or 1-, 2-, or 3-butenyl.
  • a haloalkenyl group designates a alkenyl group as above mono- or polysubstituted with halogen as above.
  • an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes.
  • the alkynyl group of the invention comprises of from two to six carbon atoms (C 2-6 -alkynyl), including at least one triple bond.
  • the alkynyl group of the invention is ethynyl, 1 ,2- or 2,3-propynyl, 1 ,2-,
  • haloalkynyl group is alkynyl as above substituted with one or more halogen as above. Examples are e.g. -C ⁇ C-CH 2 I, -
  • a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above.
  • Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.
  • alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
  • alkoxy-alkyl group designates an "alkyl-
  • O-aikyl-" group wherein alkyl is as defined above.
  • an amino group may be a primary (-NH 2 ), secondary (-NH-alkyl), or tertiary (-N(alkyl) 2 ) amino group, i.e. it may be substituted once or twice with an alkyl group as defined above.
  • a thioalkyl group is -alkyl-SH wherein alkyl is as defined above.
  • a thioalkenyl group is -alkenyl-SH wherein alkenyl is as defined above.
  • a thioalkynyl group is alkynyl-SH wherein alkynyl is as defined above.
  • alkynyl is as defined above.
  • preferred aromatic heterocyclic monocyclic groups of the invention include 1 ,3,2,4- or 1 ,3,4,5-dioxadiazolyl, dioxatriazinyl, dioxazinyl, 1 ,2,3-,
  • label stands for the binding of a marker to the compound of interest that will allow easy quantitative detection of said compound.
  • the labelled compound of the present invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from 11 C, 18 F, 15 0, 13 N, 123 l, 125 l, 131 l , 3 H and 99m Tc.
  • the fluorescent group of the compound of formula (I) can be selected from the group of naturally occurring fluorophores or chemically synthesized fluorescent groups, such as rhodamine, green fluorescent protein or fluorescein and its derivatives.
  • R is preferably hydrogen, an alkyl group having 1 to 6 C atoms, haloalkyl, haloalkenyl and R 4 is preferably a phenyl group which may be substituted one or more times.
  • the substituents are preferably selected from I, F, Cl, CF 3 , CH 3 , and OCH 3 .
  • Preferred compounds of the invention are:
  • R represents a haloalkenyl such as 1-iodo-prop-1-en-3-yl, wherein the iodine is a radioactive isotope of iodine and R 4 represents phenyl substituted with Cl F, CH 3 , CF 3 , Cl, H; or R 4 represents 3,4-dichlorophenyl.
  • R represents a haloalkyl such as methyliodine, ethyliodine, propyliodine, methylflouride, ethylfluoride, propylfluoride wherein the halogen is optionally a radioactive isotope of iodine or fluoride and R 4 represents phenyl substituted with Cl F, CH 3 , CF 3 , Cl, H; or R 4 represents 3,4-dichlorophenyl.
  • R represents a haloalkyl such as methyliodine, ethyliodine, propyliodine, methylflouride, ethylfluoride, propylfluoride wherein the halogen is optionally a radioactive isotope of iodine or fluoride and R 4 represents phenyl substituted with Cl F, CH 3 , CF 3 , Cl, H; or R 4 represents 3,4-dichloroph
  • R represents a alkylthio-derivative such as thiomethyl, ethylthio, propylthio, butylthio and R 4 represents phenyl substituted with F, CH 3 , CF 3 , Cl, H; or R 4 represents 3,4- dichlorophenyl;.
  • R represents a alkylthio-derivative such as thiomethyl, ethylthio, propylthio, butylthio and R 4 represents phenyl substituted with F, CH 3 , CF 3 , Cl, H; or R 4 represents 3,4- dichlorophenyl;.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts.
  • the compounds of formula (I) may also be resolved by the formation of diastereomeric amides by reaction of the compounds of formula (I) with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the compounds of formula (I) e.g. with an optically active chloroformate.
  • optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid
  • optically active chloroformate an optically active chloroformate.
  • the labelled compounds of the invention may be prepared in numerous ways.
  • the labelled compounds of the invention and their pharmaceutically acceptable derivatives may thus be prepared by any method known in the art for the preparation of compounds of analogous structure, provided that a label, preferably a radionuclide, is incorporated by suitable means.
  • the labelled compounds of the present invention can be prepared in the same way as the unlabeiled compounds of formula (I) except that at least one of the materials used for the preparation of the compounds of formula (I) comprises a label, preferably a radionuclide, which label is inserted into the final compound.
  • a group of an unlabeiled compound of formula (I) can be exchanged by a labelled group, thereby forming a labelled compound of formula (I).
  • the unlabeiled compounds of formula (I) can for example be prepared according to the methods disclosed in WO 97/13770, for example as in the following scheme (1).
  • the processes in the reaction scheme above are carried out in conventional manner.
  • the dehydration of the alcohol is affected using acids such as hydrochloric or sulphuric acid or other conventional dehydrating agents such as for example P 2 0 5 or SOCI 2 .
  • An unlabeiled compound of formula (I) can be converted to another unlabeiled compound of formula (I) using conventional methods.
  • the products of the reactions described herein can be isolated by conventional means, such as extraction, crystallisation, distillation and/or chromatography.
  • the labelled compounds of formula (I) can generally be prepared in the same way as described above for the unlabeiled compounds of formula (I).
  • any of the materials used for the preparation of the unlabeiled compound of formula (I) can be labelled, preferably by a radionuclide, in such a way that the label is incorporated into the finally prepared labelled compound of formula (I).
  • Said labelled materials are either commercially available or can be prepared by using commercially available labelling agents.
  • labelling agents which can be used in the preparation of the labelled compounds of the present invention is [ 11 C]0 2 , 18 F , and Nal with different isotopes of Iodine.
  • [C 11 ]0 2 may be converted to a [ 11 C]-methylating agent, such as [ 11 C]H 3 I or [ 11 C]-methyl triflate.
  • Labelled compounds containing e.g. [ 125 l ] labelled 1-iodoprop-1-en-3-yl as substituent on N-8 may be prepared as described in the art [Elmaleh, et al.; J. Nucl. Med. 1996 37 1197-1202] .
  • Labelled compounds containing e.g. [ 18 F] -alkyl substituted N-8 may be prepared as described in the art, e.g. in WO 96/39198.
  • labelled compounds of the present invention can, for example, be prepared by using labelled compounds R X in the reaction shown in scheme (1) above, wherein R 4 and X are as defined above, except that R 4 contains a label.
  • R 4 X are those, wherein R 4 is selected from [ 11 C]H 3 -substituted phenyl, benzyl, heteroaryl and naphthyl groups, [ 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]0-substituted phenyl, benzyl, heteroaryl and naphthyl groups, [ 18 F]- substituted phenyl, benzyl, heteroaryl and naphthyl groups, [ 18 F] 3 C-sub
  • an unlabeiled compound of formula (I) can be converted to a labelled compound of formula (I) by using a labelling agent.
  • [ 11 C]H 3 -group can, for example, be prepared by reacting a free amine compound of formula (I), i.e. wherein R is H and R 4 is as defined above, with a [ 11 C]-methylating agent, preferably with [ 11 C]H 3 I or [ 11 C]-methyl triflate, or another suitable leaving group as exemplified below.
  • a [ 11 C] labelled groups R can be introduced, e.g. by reacting said free amine compound of formula (I) with a [ 11 C] labelled alkylating agent optionally derivatised with a suitable leaving group (LG), such as [ 11 C]-cyclohexyl triflate or any other cycloalkyl alkylating agent.
  • LG suitable leaving group
  • R representing alkyl substituted with [ 125 l]; alkenyl substituted with [ 125 l]; e.g. 1-[ 125 l]-prop-1-en-3-yl as described in the art, 1-[ 125 l]-but-1- en-3-yl; and alkynyl substituted with [ 125 l] or alkyl substituted with [ 18 F], alkenyl substituted with [ 18 F], alkynyl substituted with [ 18 F]; Standard leaving groups for use in these types of reaction are known in the art and a few examples are mentioned below.
  • the reaction may proceed through intermediate compounds such as the trialkyl tin derivatives, which is displaced by addition of Na[ 125 l] or [ 18 F].
  • labelled groups can be introduced to the R group e.g. by derivatising said free amine compound of formula (I), to contain a suitable leaving group, attached to a alkyl chain of suitable length.
  • the leaving group can then be displaced by a labelled nucleofile.
  • the leaving group being e.g.
  • esters of sulphuric and sulfonic acids in general such as mesylate, tosylate, brosylate, nosylate, triflate, nonaflates, tresylates; Esters of nitrous acid, and inorganic ester leaving groups such as ROPO(OH) 2 , ROB(OH) 2 halogen, conjugate acid of alcohol, ether, quarternary amines, tertiary sulphides, trialkyl tin derivatives etc., all known in the art; Performing the reaction in a suitable solvent, preferable polar, aprotic solvent and preferably essential free of water, with a labelled agent, acting as a nucleofile.
  • a suitable solvent preferable polar, aprotic solvent and preferably essential free of water
  • auxiliary agent of the form M + X " , M + being e.g. 4,7,13,16,21 ,24-hexaoxa-1 , 10- diazabicyclo [8.8.8] hexacosane, alkali metal ions, tetraalkyammonium etc. as described in the art, and X " being e.g. carbonate, bicarbonate, hydroxide, formate or another counter ion, capable of dissolving radionuclides. Such compounds are known in the art.
  • the compounds of formula(l) can represent substituents capable of co-ordinating to a metal complex.
  • a metal could be positron emitting isotopes of Tc whereby the complete complex formation is radiolabelled and suitable for diagnostic use [Meegall S, et al.; Bioconiu ⁇ ate Chem. 1996 7 421-429].
  • substituents are e.g. alkylthio, alkenylthio, and alkynylthio.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a diagnostically effective amount of the labelled compound of formula (I) or mixtures thereof together with at least one pharmaceutically acceptable carrier or diluent, wherein the labelled compound of formula (I) is defined as disclosed above.
  • the carrier or diluent must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof and is not specifically limited.
  • compositions include those suitable for parenteral administration, including intramuscular, sub-cutaneous and intravenous administration. Intravenous injection is the preferred way of administration.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the labelled compounds of the present invention may thus be formulated for parenteral administration (e.g. by injection) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile, pyrogen-free water
  • Aqueous solutions suitable for oral use can be prepared by dissolving the labelled compound of the present invention in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided labelled compound of the present invention in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • these preparations may, for example, contain colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, and/or solubilizing agents.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the labelled compound of the present invention in a suitable powder base, such as lactose, starch, starch derivatives such as hydroxyp ropy I methyl cellulose and polyvinylpyrrolidone (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxyp ropy I methyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatine or blister packs.
  • compositions are tablets or capsules for oral administration and liquids for intravenous administration.
  • Suitable dosage ranges are in the range of from about 0.1 ng to about 100 ⁇ g of the labelled compounds of the present invention, administered in an appropriate dose, dependent as usual upon the exact mode and form of administration, the type of diagnosis, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • the second object of the present invention is attained in a first embodiment of the invention by a method for determining the level of monoamine neurotransmitter re-uptake sites in a blood sample, said method comprising the steps of
  • this method is also referred to as the "in-vitro method" of the present invention.
  • the in-vitro method especially allows to accurately calculate the serotonine re-uptake sites in a cellular fraction obtained in step (b).
  • the predetermined part of the blood sample is preferably a blood fraction that contains the blood platelets.
  • step (2) of the in-vitro method of the present invention a labelled or unlabeiled compound of formula (I) or any of its enantiomers or a mixture thereof, or a pharmaceutically acceptable salt thereof is added to a blood sample.
  • the compound of formula (I) added in step (a) is selected depending on the method of measuring the amount of the compound of formula (I) bound to said predetermined part of the blood sample used in step (b) of the in-vitro method of the invention.
  • a compound of formula (I) used in step (a) of the above mentioned method is a labelled compound of the present invention
  • this compound is preferably labelled with at least one radionuclide.
  • Preferred radionuclides are those described above.
  • R and R 4 are as defined above, and preferred groups R and R 4 are as defined above. Additionally, R 4 being a fluorescent group is preferred.
  • the compound of formula (I) may also be used in unlabeiled form. In this case, R and R 4 are as defined above, and preferred groups R and R 4 are as defined above. Additionally, R 4 being a fluorescent group is preferred.
  • the labelled or unlabeiled compound of formula (I) added in step (a) of the in vitro-method of the present invention can be detected by a suitable spectroscopic method, in particular UV spectroscopy and/or fluorescence spectroscopy.
  • step (c) of the in-vitro method of the present invention the level of the monoamine neurotransmitter re-uptake sites can be calculated from the data obtained in step (b) by using, for example, Scatchard Plot Analysis.
  • the second object of the present invention is solved by a method for the non-invasive determination of the distribution of a tracer compound inside a whole, intact living animal or human body using a physical detection method, wherein the tracer compound is a compound of formula (I) or any of its enantiomers and any mixture thereof, or a pharmaceutically acceptable salt thereof in its labelled or unlabeiled form.
  • this method is also referred to as "in-vivo method" of the present invention.
  • the physical method for detecting said tracer compound of formula (I) in the in-vivo method of the present invention is preferably selected from Position
  • PET Emission Tomography
  • PET Single Photon Imaging Computed Tomography
  • MRI Magnetic resonance Imaging
  • CAT Computed Axial X-ray Tomography
  • the tracer compound of formula (I) can be selected in accordance with the detection method chosen.
  • the compound of formula (I) as described above can be used in labelled form or in unlabeiled form.
  • a labelled compound of formula (I) is used in the in-vivo method of the present invention, it is preferably labelled with a radionuclide, which is preferably selected from 11 C, 18 F, 15 0, 13 N, 23 l, 125 l, 131 l and 3 H.
  • a radionuclide which is preferably selected from 11 C, 18 F, 15 0, 13 N, 23 l, 125 l, 131 l and 3 H.
  • an unlabeiled compound of formula (I) is used in the in-vivo method of the present invention, said compound preferably contains at least one 19 F containing substituent.
  • Especially preferred unlabeiled compounds of formula (I) are those, wherein R 4 is a phenyl group containing at least one substituent selected from
  • Examples of physical detection methods which can be used for detecting unlabeled compounds of formula (I) are HPLC and Mass spectroscopy.
  • the compound of formula (I) or any of its enantiomers or any mixtures thereof in labelled or unlabeiled form can be used as a diagnostic agent for the diagnosis of a disorder or disease of a living animal body, including a human, which disorder or disease is responsive to the inhibition of monoamine neurotransmitter reuptake in the central nervous system. Especially preferred is the use of these compounds for the diagnosis of a disorder or disease which is responsive to the inhibition of serotonine neurotransmitter re-uptake.
  • said labelled or unlabeiled compound of formula (I) can be used for diagnosing a disorder or disease which is depression or a related disorder, such as pseudodementia or Ganser's syndrome, obsessive compulsive disorder, panic disorder, memory deficit, attention deficit hyperactivity disorder (ADHD syndrome), obesity, anxiety and eating disorder.
  • a diagnostically effective amount of a labelled or unlabeiled compound of formula (I) is administered to a living body, including a human.
  • the labelled or unlabeiled compound of formula (I) can be administered as such, it is preferably administered in the form of a pharmaceutical composition.
  • a labelled compound of formula (I) is administered in the form of a pharmaceutical composition
  • the pharmaceutical composition of the present invention as described above can be used.
  • a pharmaceutical composition which differs from the above described pharmaceutical composition of the present invention in that it contains an unlabeiled compound of formula (I) instead of the labelled compound of formula (I).
  • the diagnostically effective amount of the labelled or unlabeiled compound of formula (I) to be administered before conducting the in-vivo method for the present invention is within a range of from 0.1 ng to 100 ⁇ g per kg body weight, preferably within a range of from 1 ng to 10 ⁇ g per kg body weight.
  • the distribution of said labelled or unlabeiled compound of formula (I) can be determined by a physical method in the body or any desired part thereof.
  • the distribution in a part of the nervous system, especially preferred in the brain is determined.
  • the extent of disease can be evaluated e.g. by a physician, preferably a neurologist.
  • Said evaluation can especially be effected by comparing the data obtained from the in-vivo method of the present invention with control data.
  • Said control data may, for example, be obtained from a control group of individuals. This group consists either of healthy individuals or of individuals who suffer from one of the above mentioned disorders or diseases.
  • the present invention further provides a method of diagnosis of a disorder or disease of a living human or animal body, which disorder or disease is responsive to the inhibition or monoamine neurotransmitter re-uptake, comprising the steps of (a) administering to said body a diagnostically effective amount of a compound of formula (I) in its labelled or unlabeiled form,
  • the pharmaceutical composition which is preferably used in the in-vitro method of the present invention, can be provided in the form of an assay kit system wherein said pharmaceutical composition comprises either a labelled or unlabeiled compound of formula (I) in unit-dosage form in a suitable container.
  • said unit dosage is adjusted to be sufficient for analysing one blood sample according to the in-vitro method of the invention.
  • said assay kit of the present invention can further comprise a stabilising composition.
  • the stabilising composition can be selected from antioxidants, such as ascorbic acid, or from buffers of weak acid- base composition e.g. phosphate buffers or from various types of cyclodextrins e.g.
  • the compounds and their derivatives of this invention are the first substances known that specifically bind to serotonine transporters. This allows for the first time to reliably determine the number of serotonine binding sites and related Kd values and the release of serotonine as well as the detection of changes in the serotonine metabolism in response to therapeutic drugs. Furthermore, a labelled compound of formula (I) may also be used in the analysis and adjustment of the treatment of patients having a lower level of serotonine re-uptake as compared to the normal level with serotonine uptake inhibitors.
  • the compounds of the invention can be employed to assess whether the dosage of serotonine re-uptake inhibitors given is sufficient to occupy a high number of the serotonine transporter sites thereby blocking the re-uptake of serotonine and extending their presence and action within the synaptic cleft.
  • the labelled compound of the invention can likewise be used to investigate whether an unnecessary high dose is given thereby blocking too many serotonine transporter sites and/or increasing the risk of unwanted side-effects. If a compound is given in a sufficient dose whereby maximal blocking of serotonine re-uptake is achieved, then higher doses will only increase the risk of side effects.
  • Fig. 1 is a characteristic PET scan showing the unique and very specific uptake and labelling of serotonine nerve terminals (containing the serotonine reuptake transporter) by Compound (3-4).
  • the resulting solution was stirred for another 30 minutes at -70°C followed by addition of a solution of 8- methyl-8-azabicyclo[3.2.1]octan-3-one (50 g, 0.36 mol) in anhydrous tetrahydrofuran (360 ml). The temperature was kept below -50°C during the addition which took approximately one hour. The resulting solution was stirred at -50°C for two hours followed by addition of water (215 ml) over 15 minutes and 4 M HCI (360 ml) over 25 minutes. The temperature reached -20°C by the end of the addition. The organic phase was discharged and the aqueous phase was washed once with diethyl ether (500 ml).
  • the title compound was prepared from 4-bromochlorobenzene (15.4 g, 81 mmol), n-butyllithium in hexane (31 ml 2.5 M; 78 mmol) and 8-methyl-8- azabicyclo[3.2.1]-octan-3-one (5 g, 36 mmol). Yield 5.7 g (63%) as a white solid, m.p. 186.3-187°C.
  • the title compound was prepared from 4-bromotoluene (13.9 g, 81.4 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 78 mmol) and 8-methyl-8-azabicyclo[3.2.1]- octan-3-one (5 g, 35.9 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 3.5 g (42%) as a white solid, m.p. 247-249°C.
  • the title compound was prepared from 4-bromoanisole (15.1 g, 80.5 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 77.9 mmol) and 8-methyl-8-azabicyclo- [3.2.1]octan-3-one (5 g, 36 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 2.1 g (24%), m.p. 161.8-162.3°C.
  • the title compound was prepared from 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). The free base of the title compound was dissolved in ethanol (96%) and malonic acid (1.17 g, 11.2 mmol) in ethanol (96%) was added. The solution was concentrated to dryness, and the residue was trituated in diethyl ether. The title compound precipitated as a powder and was finally isolated by filtration. Yield 3.9 g (60%), m.p. 106.7-107.8°C.
  • the title compound was prepared from 8-methyl-3-phenyl-8- azabicyclo[3.2.1]octan-3-ol (8 g, 37 mmol), glacial acetic acid (25 mL) and concentrated hydrochloric acid (8 mL).
  • the title compound was prepared from ( ⁇ )-3-(4-fluorophenyl)-8-methyl-8- azabicyclo[3.2.1]oct-2-ene (Compound 4-2) (1.6 g, 7.37 mmol) and 1-chloroethyl chloroformate (1.2 ml, 1.6g, 11 mmol).
  • the free base of the title compound was dissolved in isopropanol and malonic acid (0.43g, 4.1 mmol) was added.
  • the title compound precipitated from this solution and was isolated by filtration. Yield 1.14 g (50%) m.p. 132.2-132.6°C.
  • Carbon dioxide was prepared by the 14N(p,a) 11 C nuclear reaction using a nitrogen gas target and 16 MeV protons produced by a GE Medical Systems PETtrace cyclotron.
  • Typical mass of compounds 1-4, 2-4, 3-4 and 4-4 in the final product 30-60 nmol in a 10 ml formulation.
  • Typical radioactivity of final product 1-4 GBq.
  • Typical specific activity 30 - 100 GBq/ ⁇ mol.
  • Compound (3-4) was used as a marker for the number of serotonine transporter sites.
  • the binding of labelled compound (3-4) to the serotonine transporter sites was measured as follows.
  • test animals three female pigs (Hampshire x Yorkshire x Duroc x Landrace crossbred) weighing 39 to 44 kg were used. They were housed singularly in a thermostatically controlled (20°C) animal colony with natural lighting conditions. The pigs had free access to water but were deprived of food for 24 hours prior to experiments.
  • Pigs were sedated with an i.m. injection of Midazolam (0.5 mg/kg) and Ketamine HCI (10 mg/kg). After 10 to 15 minutes a catheter was installed in an ear vein through which a mixture of Midazolam (0.25 mg/kg) and Ketamine (5 mg/kg) was administered. The pigs were then incubated and anaesthetised with Isoflourane in 0 2 /N 2 0. Catheters (Avanti® size 4F-7F) were surgically installed in a femoral artery and vein. Infusions of isotonic saline (ca. 100 cm 5 /h) and 5% of glucose (ca. 20 cm 3 /h) were administered i.v. throughout the experiments.
  • Body temperature was thermostatically maintained in the normal range (39.0-39.4°C) and physiological functions (i.e. blood pressure, heart rate and expired air C0 2 ) were monitored continuously.
  • Hematocrit and whole blood acid-base parameters i.e. pH, pC0 2 , p0 2 , HC0 3 and 0 2 saturation
  • disturbances in body fluid balance were corrected by appropriate procedures (e.g. force ventilation and/or changes in infusion rates).
  • EXACT HR EXACT HR using a custom-made head-holding device.
  • the regional distribution and binding of Compound (3-4) in pig brain was studied by administering an i.v. dose of ca. 10 ⁇ g followed immediately by an i.v. injection of heparin solution to flush the catheter. Scanning began on injection of Compound (3-4) and consisted of 28 frames
  • an intravenous dose of 5 mg/kg was administered at 20 minutes after injection of Compound (3-4) in order to determine whether the antidepressant drug influenced the cerebral binding, kinetics and distribution of the tracer compound.
  • Fig. 1 shows a coronal (left), transaxial (centre) and sagittal (right) section of a pig brain labelled with Compound (3-4). Accumulation of the compound can be seen in the serotonergic Raphe nuclei and the thalamus.
  • Acetonitrile (0.05 ml) was added to plasma samples for metabolite analysis.
  • the amount of uncharged Compound (3-4) was determined by integration of the radiopeak corresponding to Compound (3-4) in relation to the sum of all radioanalytes. Biexponential fitting of the data to the total plasma radioactivity concentration was performed to generate a metabolite-corrected input function.
  • the rate of metabolism of Compound (3-4) was determined by multilinear curve-fitting based on the appearance of plasma metabolites from the metabolite-corrected plasma time-activity curve.
  • ROIs Seven brain regions of interest (ROIs) were identified using a neuroanatomical atlas of the pig brain [Yoshikawa T; Atlas of the brains of domestic animals: Pennsylvania State University Press, University Park, Penn., 1968]. For each region, radioactivity concentrations were calculated for the sequence of frames, were corrected for the radioactive decay of 1 C (20.3 min), and were plotted versus time. The data for illustrations were expressed in terms of standard uptake values (SUV), i.e. [radioactivity in ROI (Bq/cc) X body weight (g)/injected dose of radioactivity (Bq)].
  • SUV standard uptake values
  • K ⁇ expresses the unidirectional clearance of the tracer from the circulation to the single tissue compartment
  • k 2 in the case of the cerebellum is the true rate constant for clearance from the brain
  • k 2 is an apparent rate constant of clearance from the single tissue compartment, assuming that equilibration between tissue compartments of solution and of binding are so rapid that a single compartment results.
  • the K ⁇ /k 2 ratio is termed the apparent partition volume and expresses the binding of the compound in the ROI.
  • Platelet-rich plasma was obtained by centrifugation of blood samples at 200 x g for 10 min at 20° C. Platelet membranes were prepared by lysis and homogenisation of the platelet pellet following the method of Plenge and Mellerup
  • the amount of radioactivity on the filters were determined by conventional liquid scintillation counting. Five to six concentrations of [ 3 H]-X were used in the incubation mixture to determine the density of binding sites (Bmax) by Scatchard analysis.
  • Fig. 1 is a characteristic PET scan showing the unique and very specific uptake and labelling of serotonine nerve terminals (containing the serotonine reuptake transporter) by Compound (3-4).

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Abstract

L'invention concerne des dérivés de 8-azabicyclo[3.2.1]oct-2-ène sous leur forme marquée. L'invention concerne, en outre, l'utilisation desdits dérivés sous leur forme marquée ou non marquée lors de diagnostics, plus particulièrement lors d'imagerie de récepteurs in vivo (neuro-imagerie)
PCT/DK1999/000044 1998-01-28 1999-01-28 Derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee et utilisation de derives de 8-azabicyclo[3.2.1]oct-2-ene sous forme marquee ou non marquee WO1999038866A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP99906069A EP1068204A1 (fr) 1998-01-28 1999-01-28 Derives de 8-azabicyclo 3.2.1]oct-2-ene sous forme marquee et utilisation de derives de 8-azabicyclo 3.2.1]oct-2-ene sous forme marquee ou non marquee
JP2000529334A JP2002501921A (ja) 1998-01-28 1999-01-28 標識された形での８−アザビシクロ［３．２．１］オクト−２−エン誘導体及び標識された及び標識されていない形での８−アザビシクロ［３．２．１］オクト−２−エン誘導体の使用方法
AU26099/99A AU2609999A (en) 1998-01-28 1999-01-28 8-azabicyclo(3.2.1)oct-2-ene derivatives in labelled and use of 8-azabicyclo(3.2.1)oct-2-ene derivatives in labelled and unlabelled form

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DK12598 1998-01-28
DK0125/98 1998-01-28

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WO2000044746A1 (fr) * 1999-01-28 2000-08-03 Neurosearch A/S Nouveaux derives d'azabicyclo et leur utilisation
WO2002030405A2 (fr) * 2000-10-13 2002-04-18 Neurosearch A/S Traitement de troubles affectifs par l'action combinee d'un agoniste du recepteur nicotinique et d'une substance monoaminergique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044746A1 (fr) * 1999-01-28 2000-08-03 Neurosearch A/S Nouveaux derives d'azabicyclo et leur utilisation
US6617459B2 (en) 1999-01-28 2003-09-09 Neurosearch A/S Azabicyclo derivatives and their use
WO2002030405A2 (fr) * 2000-10-13 2002-04-18 Neurosearch A/S Traitement de troubles affectifs par l'action combinee d'un agoniste du recepteur nicotinique et d'une substance monoaminergique
WO2002030405A3 (fr) * 2000-10-13 2002-09-06 Neurosearch As Traitement de troubles affectifs par l'action combinee d'un agoniste du recepteur nicotinique et d'une substance monoaminergique
US7307087B2 (en) 2000-10-13 2007-12-11 Neurosearch A/S Treatment of affective disorders by the combined action of a nicotinic receptor agonist and a monoaminergic substance

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