WO1996020940A1 - Nouveau compose a marquage radio-isotopique, melange comprenant ce compose et son procede de preparation - Google Patents

Nouveau compose a marquage radio-isotopique, melange comprenant ce compose et son procede de preparation Download PDF

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Publication number
WO1996020940A1
WO1996020940A1 PCT/FI1995/000686 FI9500686W WO9620940A1 WO 1996020940 A1 WO1996020940 A1 WO 1996020940A1 FI 9500686 W FI9500686 W FI 9500686W WO 9620940 A1 WO9620940 A1 WO 9620940A1
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WO
WIPO (PCT)
Prior art keywords
compound
exo
mixture
azabicyclo
octane
Prior art date
Application number
PCT/FI1995/000686
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English (en)
Inventor
Jörgen Bergman
Merja Haaparanta-Solin
Olof Solin
Original Assignee
Bergman Joergen
Haaparanta Solin Merja
Olof Solin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bergman Joergen, Haaparanta Solin Merja, Olof Solin filed Critical Bergman Joergen
Priority to EP95941100A priority Critical patent/EP0800523A1/fr
Priority to AU42617/96A priority patent/AU4261796A/en
Publication of WO1996020940A1 publication Critical patent/WO1996020940A1/fr

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Classifications

    • 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
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K51/0448—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil tropane or nortropane groups, e.g. cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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

Definitions

  • the invention relates to a novel 18 F-labelled compound useful in studying anomalies in the dopaminergic neurotransmission of brain in neurological and psychiatric diseases.
  • Tropane derivatives labelled with radioisotopes have been previously used as selective tracers for dopamine transporter, e.g. in the diagnosis or study of the Parkinson's disease, misuse of some narcotic substances, and schizophrenia.
  • 2 ⁇ -carbomethoxy-3 ⁇ -(4-fluorophenyl)- tropane labelled with C isotope or [ ⁇ j- ⁇ -CFT or [ n C]WIN 35,428 or 8-(methyl- n C)-3-(4-fluorophenyl)-8- azabicyclo[3.2.l]octane-2-carboxylic acid methyl ester, [lR-(exo, exo)], has been used in PET studies in humans (1,2), (PET .Positron Emission Tomography).
  • Iodoisotope I 12 3 decays through so-called single gamma emission and consequently this isotope cannot be used in PET studies.
  • i8 F isotope (like n C isotope) decays through positron emission ( ⁇ +) creating a directed beam which in turn makes PET imaging possible.
  • radioactivity the amount of radionuclide per mass of the substance
  • the molecules in question are generally very toxic so that they cannot be used in large quantities. For example, about 20 nmol (5.5 ⁇ g) of 2 ⁇ -carbomethoxy-3 ⁇ -(4-fluoro ⁇ phenyl)tropane labelled with U C isotope was injected to the patients and this quantity of the substance was not observed to have any adverse effects (1). Furthermore, the radiochemical synthesis of the tracer must be rapid owing to the half life of 18 F isotope.
  • the solvatized F ion is dried and activated with a cryptand.
  • the negatively charged F ion produced is an efficient nucleophilic fluorination reagent.
  • the obtained [ F]CH 3 F gas is chromatographically purified and transferred to a reaction chamber with the carrier gas mixture (noble gas / fluorine gas).
  • the gas mixture is subjected to a high voltage.
  • the electric discharge gaseous F 2 is produced wherein part of the F-atoms are 18 F isotopes.
  • This 18 F-labelled F 2 gas is highly reactive but unlike the fluorine gas obtained by the previous methods it also has a very high specific radioactivity.
  • Classical methods produce fluorine gas with a specific radioactivity of 3-10 mCi/ ⁇ mol whereas this new method produces fluorine gas with a specific radioactivity of over 100 mCi/ ⁇ mol, preferably about 1500 mCi/ ⁇ mol.
  • the high specific radioactivity 18F-fluorine gas prepared by the above method has been used for fluorine labelling of L-dopa (7) .
  • the invention also relates to mixtures of the compound (I) with the corresponding non-radioactive compound (II),
  • the invention further relates to a method for producing the compound (I) and its mixtures with the compound (II)
  • Formula (I) covers all stereoisomers of the compound.
  • Literature knows the following stereoisomers of the corresponding non-radioactive compound (II): a) 3-(4- fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2- carboxylic acid methyl ester, [lR-(exo, exo)]-, (reference 8), b) 3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]- octane-2-carboxylic acid methyl ester, [lR-(2-exo,3- endo)]-, (reference 9), c) 3-(4-fluorophenyl)-8-methyl-8- azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester, [lS-(2-endo,3-exo) ]-, (reference 8), d) 3-(4-fluoro ⁇ phenyl)
  • the formula (I) includes particularly the stereoisomers [lR-(exo, exo)]-, [lR-(2- exo,3-endo)]-, [lS-(2-endo,3-exo)]-, [IS-(exo, exo)]-, and [lR-(2-endo, 3-exo)]- of. the compound 3-(4-fluorophenyl- 18F)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl ester.
  • the compound (I) is advantageously 3-(4-fluoro- phenyl-18F)-8-methyl-8-azabicyclo[3.2.1]octane-2-carbox- ylic acid methyl ester, [lR-(exo, exo)]- or [ 18 F]-2 ⁇ - carbomethoxy-3fi-(4-fluorophenyl)tropane.
  • the compound (II) is a substance (code WIN 35428) patented by Sterling Drug, Inc. in 1972 and it is known as a very selective tracer of dopamine transporter.
  • a mixture comprising the compounds according to the formulas (I) and (II) must comprise the compound (I) in such an amount that the specific radioactivity of the mixture at the time of injection is at least 25 mCi/ ⁇ mol.
  • the specific radioactivity at the time of injection is preferably at least about 100 mCi/ ⁇ mol. Very good imaging results are obtained if the corresponding value is at least about 250 mCi/ ⁇ mol.
  • a compound according to the formula (I) and its mixture with a compound of the formula (II) is prepared so that a compound of the formula (III)
  • M is Sn, Hg or Si
  • R l f R 2 , and R 3 which may be the same or different groups , are Ci-C ⁇ -alkyl or phenyl groups , are reacted either
  • the compound according to formula (III) is preferably 3- (4-trimethylstannylphenyl)-8-methyl-8-azabicyclo[3.2.1]- octane-2-carboxylic acid methyl ester, [lR-(exo, exo)]- or 2 ⁇ -carbomethoxy-3 ⁇ -(4-trimethylstannylphenyl)tropane, which is a commercially available substance.
  • An example of another substance according to formula (III) known in literature is a compound where M is Sn and R R 2 , and R 3 are butyl groups (11).
  • the reagent [ 18 F]F 2 or [ 18 F]CH 3 COOF) has a certain minimum specific radioactivity in the beginning of the synthesis of the tracer. Specific radioactivity diminishes as a function of time due to radioactive decay.
  • the fluorine gas should comprise 18F isotope in such an amount that the specific radioactivity of the gas is at least about 100 mCi/ ⁇ mol, however, preferably at least about 1000 mCi/ ⁇ mol. If on the other hand radioactive acetylhypofluorite or [ F]CH 3 C00F is used, the reagent
  • the compound CH 3 C00 F must comprise the compound CH 3 C00 F in such an amount that the specific radioactivity of the mixture is at least about 50 mCi/ ⁇ mol, however, preferably at least about 500 mCi/ ⁇ mol.
  • Kryptofix 222 (4, 7, 13, 16, 21, 24 - Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane)
  • K 2 C0 3 potassium carbonate
  • glacial acetic acid CH 3 C00H
  • ammonium acetate CH 3 C00NH 4
  • Merck methyl iodide
  • CH 3 I methyl iodide
  • acetonitrile from Aldrich
  • Freon 11 CFC1 3
  • the labelling precursor or 2 ⁇ -carbo- methoxy-3 ⁇ -(4-trimethylstannylphenyl)tropane was purchased from Research Biochemicals Inc. in vials each containing 50 ⁇ g of the substance. In all tests, the labelling reac ⁇ tion was made in the same one ml vials in which the labelling precursor was supplied.
  • [ 18 F]-fluoride was prepared by irradiating 400 ⁇ l 18 0-enriched water (94 %, Isotec, Inc.) in an open silver chamber with protons (10-12 ⁇ A, 16 MeV, 60-90 min) using the Abo Akademi 103 cm isochronous cyclotron.
  • the solvatized [ 18 F]F " was transferred through silicon tubes into a reaction flask in the radiocheraistry laboratory.
  • [ F]F 2 was passed directly into a vial containing 50 ⁇ g of 2 ⁇ -carbomethoxy-3 ⁇ -(4-trimethylstannylphenyl)tropane dissolved in 0.6 ml of Freon 11. The gas was bubbled until the solvent had evaporated. The solid residue was dissolved in one ml of the mobile phase of the high pressure liquid chromatograph and injected onto the liquid chromatograph column for purification. The purified end product was collected from the column outlet. The end product was chromatographically identified by comparing it with a reference standard (WIN 35,428, Research Biochemicals Int.). The specific radioactivity of the obtained product was about 400 mCi/ ⁇ mol.
  • the [ 18F]acetylhypofluorite in acetic acid was passed into a vial containing 50 ⁇ g of 2 ⁇ -carbomethoxy-3 ⁇ -(4-tri- methylstannylphenyl)tropane.
  • the desired end product was purified and identified as above.
  • the specific radioactivity of the obtained product was about 400 mCi/ ⁇ mol.
  • striatum basic ganglia
  • cerebellum little brain which has a small number of such sites.
  • GRR 12935 RBI
  • Fig. 2 shows that the inactive medicament has already saturated the reuptake sites of dopamine and no specific [ 18 F]CFT accumulation can be seen.
  • Other rats were in a corresponding way given medicament which had strong affinity for serotonin transporter (citalopram). Similar displacement is not observed though citalopram affects the [ 18 F]CFT metabolism in the rat liver.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention se rapporte à un nouveau composé chimique ayant la formule structurelle (I). Le composé (I) est utilisé dans le diagnostic des maladies dopaminergiques telles que la maladie de Parkinson et la schizophrénie. L'invention se rapporte également à des mélanges du composé (I) avec le composé non radioactif correspondant, aux procédés de préparation du composé (I) et à ses mélanges.
PCT/FI1995/000686 1994-12-30 1995-12-18 Nouveau compose a marquage radio-isotopique, melange comprenant ce compose et son procede de preparation WO1996020940A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95941100A EP0800523A1 (fr) 1994-12-30 1995-12-18 Nouveau compose a marquage radio-isotopique, melange comprenant ce compose et son procede de preparation
AU42617/96A AU4261796A (en) 1994-12-30 1995-12-18 A novel radioisotope labelled compound, a mixture comprising said compound and a method for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI946172 1994-12-30
FI946172A FI96603C (fi) 1994-12-30 1994-12-30 Uusi radioisotoopilla leimattu yhdiste, yhdistettä sisältävä seos sekä menetelmä niiden valmistamiseksi

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Publication Number Publication Date
WO1996020940A1 true WO1996020940A1 (fr) 1996-07-11

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EP (1) EP0800523A1 (fr)
AU (1) AU4261796A (fr)
CA (1) CA2206954A1 (fr)
FI (1) FI96603C (fr)
WO (1) WO1996020940A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038866A1 (fr) * 1998-01-28 1999-08-05 Neurosearch A/S 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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009814A1 (fr) * 1991-11-15 1993-05-27 Research Triangle Institute Ligands de liaison de recepteur de cocaine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009814A1 (fr) * 1991-11-15 1993-05-27 Research Triangle Institute Ligands de liaison de recepteur de cocaine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. MED. CHEM., Volume 36, 1993, ROBERT H. MACH et al., "F-Labeled Benzamides for Studying the Dopamine D2 Receptor With Positron Emission Tomography", pages 3707-3720. *
J. NEUROCHEM., Volume 62, 1994, S. JOHN GATLEY et al., "Studies With Differentially Labeled (11C)Cocaine, (11C)Norcocaine, (11C)Benzoylecgonine and (11C)- and 4'-(18F)Fluorococaine to Probe the Extent to Which (11C)Cocaine Metabolites Contribute to PET Images of the ....", pages 1154-1162. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038866A1 (fr) * 1998-01-28 1999-08-05 Neurosearch A/S 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

Also Published As

Publication number Publication date
FI946172A0 (fi) 1994-12-30
CA2206954A1 (fr) 1996-07-11
EP0800523A1 (fr) 1997-10-15
FI96603B (fi) 1996-04-15
AU4261796A (en) 1996-07-24
FI96603C (fi) 1996-07-25

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