HK1145316B

HK1145316B - Compounds for use in imaging, diagnosing, and/or treatment of diseases of the central nervous system or of tumors

Info

Publication number: HK1145316B
Application number: HK10111747.1A
Authority: HK
Inventors: L.莱曼; A.蒂勒; T.海因里希; T.布伦比; C．哈尔丁; B．古亚斯; S.纳格
Original assignee: 拜耳先灵医药股份有限公司
Priority date: 2007-10-26
Filing date: 2008-10-14
Publication date: 2017-06-02

Description

Compounds for imaging, diagnosing and/or treating central nervous system diseases or tumors

Technical Field

The invention relates to a marking or has been adapted to mark¹⁸Novel compounds labelled with F, methods for preparing such compounds, compositions comprising such compounds, kits comprising such compounds or compositions, and uses of such compounds, compositions or kits for diagnostic imaging by Positron Emission Tomography (PET).

Background

Molecular imaging has the potential to detect disease progression or treatment efficacy earlier than most conventional methods in the fields of oncology, neurology and cardiology. Among the several promising molecular imaging techniques that have been developed, such as optical imaging, MRI, SPECT and PET, PET is of particular interest for drug development because of its high sensitivity and ability to provide quantitative and dynamic data.

Positron emitting isotopes include, for example, carbon, iodine, nitrogen, and oxygen. These isotopes can replace their non-radioactive counterparts (counters) in the target compounds to form tracers for PET imaging that are biologically functional and chemically equivalent to the original molecules. Among these isotopes are, for example,¹⁸f is the most suitable marker isotope because its longer half-life (110min) allows diagnostic tracers to be prepared and biochemical processes to be subsequently studied, in addition, its low β + energy (634keV) is also advantageous.

Nucleophilic aromatic and aliphatic [ alpha ], [ alpha ]¹⁸F]-fluorine-fluorination reaction pair¹⁸F]Of particular importance are fluorine-labelled radiopharmaceuticals which are useful as in vivo imaging agents for targeting and imaging diseases such as solid tumors or encephalopathies. Application [2 ]¹⁸F]A very important technical goal in fluorine-labelled radiopharmaceuticals is the rapid preparation and administration of the radioactive compound, since¹⁸The F isotope has a short half-life of about only 110 minutes.

Monoamine oxidases (MAO, EC, 1.4.3.4) are a special class of amine oxidases. MAO exists in two forms: MAOA and MAOB (Med. Res. Rev.1984, 4, 323-358). The crystal structures of MAOA and MAOB complexed with ligands have been reported (j.med.chem.2004, 47, 1767-.

Studies of inhibitors selective for two isozymes have also been actively conducted (e.g., j.med. chem.2004, 47, 1767-. Selegiline (1) (biochem pharmacol.1972, 5, 393-408) and clorgyline (2) are potent inhibitors of monoamine oxidase, inducing irreversible inhibition of these enzymes. The L-isomer of selegiline (3) is a more potent inhibitor than the D-isomer.

Neuroprotection and other drug efficacy of inhibitors are also described (naturereviews neuroscience, 2006, 295-. MAOB inhibitors are used, for example, to increase DOPA levels in the CNS (progr. drug Res.1992, 38, 171-.

Fluorinated MAO inhibitors have been synthesized and evaluated biochemically (see: Kirk et al, supra). F-18 and C-11 labeled MAO inhibitors have been studied in vivo (journal of neurologic science, (2007), 255, 17-22; see: Methods2002, 27, 263-277). F-18 labeled selegiline and selegiline analogs 4-5 (int.J. radial.appl.Instrument.PartA, applied radiatissotopes, 1991, 42, 121, J.Med.chem.1990, 33, 2015-.

It would be desirable to have new F-18 labeled compounds and methods useful for imaging diseases accompanied by increased levels of MAO receptors, particularly to have available imaging agents and methods that are easily implemented and that are capable of imaging a level of astrocyte activation. This task is solved by the following invention:

■ the invention provides novel compounds of formula Ia and Ib if these compounds of formula Ia and Ib are not¹⁸F-labelled or¹⁹F-labelled but containing a suitable leaving group, they are then useful for the synthesis of formulae Ia and Ib¹⁸F-labelled or¹⁹Starting material for the F-labelled compound. Of formulae Ia and Ib¹⁹The F-labelled compound isTo give compounds of the formulae Ia and Ib¹⁸A standard control compound of F-labelled compound (as an identification tool and for quality testing). Hereinafter, suitable leaving groups are included and do not include¹⁸F or¹⁹The compounds of formulae Ia and Ib of F are also referred to as "precursor compounds having Ia or Ib". In addition, those include¹⁹Compounds of formulae Ia and Ib wherein F is not a suitable leaving group are also referred to as "having formula Ia or Ib¹⁹F standard control compound ". In addition, those include¹⁸F and compounds of the formulae Ia and Ib which do not contain a suitable leaving group are also referred to as "of the formulae Ia or Ib¹⁸F-labeled compound ".

■ the invention also provides a method of imaging a disease comprising administering a detectable amount of a compound of formula Ia or Ib¹⁸The F-labeled compound, or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, is introduced into the patient.

■ the present invention also provides compounds of formulae Ia and Ib¹⁸F-labelled or¹⁹An F-labelled compound for use as a medicament.

■ the present invention also provides diagnostic compositions comprising radiolabeled compounds, preferably of formulae Ia and Ib¹⁸An F-labelled compound and a pharmaceutically acceptable carrier or diluent.

■ Another aspect of the invention relates to compounds of the formulae Ia and Ib, in particular of the formulae Ia or Ib¹⁸F-or¹⁹Use of an F-labelled compound for the preparation of a medicament.

■ the invention also provides the synthesis of compounds of formulae Ia and Ib from precursor compounds of formulae Ia or Ib¹⁸Methods for F-labeled compounds.

■ the invention also provides the synthesis of compounds of formulae Ia and Ib from precursor compounds of formulae Ia or Ib¹⁹Methods for F-labeled compounds.

■ the invention also provides for the synthesis of compounds of formula Ia or Ib by reacting a compound of formula IV with a compound of formula VI¹⁸Method for F-labelled compounds. The compound of formula IV can be prepared by¹⁸F-or¹⁹F-fluorination of the compound of formula V.

■ the invention also provides a kit for preparing a radiopharmaceutical formulation, the kit comprising a closed vial containing a predetermined amount of a pharmaceutically acceptable carrier

A precursor compound having formula Ia or Ib, or

Compounds of formula V and VI.

■ the invention also provides kits for disease imaging. More specifically, the compounds of the invention are useful for imaging CNS diseases including, but not limited to, inflammatory and autoimmune, allergic, infectious and toxin-induced and ischemia-induced diseases, pharmacologically induced inflammation with pathophysiological relevance, neuroinflammation, neurodegenerative diseases. In another embodiment, the compounds of the invention are useful for imaging tissues, particularly tumors. Examples of inflammatory and autoimmune diseases are chronic inflammatory bowel disease (inflammatory bowel disease, crohn's disease, ulcerative colitis), arthritis, atheroma, atherosclerosis, inflammatory cardiomyopathy, pemphigus, asthma, multiple sclerosis, diabetes, type I insulin dependent diabetes mellitus, rheumatoid arthritis, lupus and other collagenous diseases, graves ' disease, hashimoto's disease, "graft-versus-host disease" and transplant rejection. Examples of allergic, infectious and toxin-induced and ischemia-induced diseases are: sarcoidosis, asthma, hypersensitivity pneumonitis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, toxic hepatic failure, ARDS (acute respiratory distress syndrome), eclampsia, cachexia, acute viral infections (such as mononucleosis, fulminant hepatitis), and organ damage following reperfusion. An example of a pharmacologically triggered pathophysiologically relevant inflammation is the "first dose response" following administration of an anti-T cell antibody such as OKT 3. An example of a systemic inflammatory response of unknown cause is eclampsia. Examples of neurodegenerative and neuroinflammatory diseases associated with astrocyte activation/MAO modulation are dementia, AIDS dementia, amyotrophic lateral sclerosis, encephalitis, neuropathic pain, creutzfeldt-jakob disease, down syndrome, diffuse Lewy body disease, huntington's disease, leukoencephalopathy, encephalopathy, septic encephalopathy, hepatic encephalopathy, multiple sclerosis, parkinson's disease, pick's disease, alzheimer's disease, frontotemporal dementia, hippocampal sclerosis, cerebral cysticercosis, epilepsy, stroke, cerebral ischemia, brain tumors, depression, schizophrenia, drug abuse. The invention therefore also relates to the use of the imaging compounds for the diagnosis of these diseases and for stratification (stratification) of therapy and therapy monitoring.

In a preferred embodiment, the compounds of the invention are used for imaging multiple sclerosis, alzheimer's disease, frontotemporal dementia, dementia with lewy bodies (dementias), cerebral poliosis, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, parkinson's disease, encephalopathy, brain tumors, depression, drug abuse, chronic inflammatory bowel disease, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically induced inflammation, systemic inflammation of unknown cause.

In a more preferred embodiment, the compounds of the invention are used for imaging multiple sclerosis, alzheimer's disease, amyotrophic lateral sclerosis, parkinson's disease, cerebral white matter disease, encephalopathy, epilepsy, brain tumors, drug abuse, chronic inflammatory bowel disease, atheroma, rheumatoid arthritis, pharmacologically triggered inflammation and unexplained systemic inflammation.

Detailed Description

In a first aspect, the present invention relates to compounds of formula Ia

Formula Ia

Or a compound of the formula Ib

Formula Ib

Wherein

W is selected from-C (U)¹)(U²) -C ≡ CH and cyclopropyl, U¹And U²Independently selected from hydrogen and deuterium;

a is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, e.g. furyl, (C)₁-G₁₀) Alkyl, G⁴-(C₂-C₄) Alkynyl group, G⁴-(C₁-C₄) Alkoxy group, (G)⁴-(C₁-C₄) Alkyl) aryl, (G)⁴-(C₁-C₄) Alkoxy) aryl, (G)⁴-(C₁-C₄) Alkyl) aryl and (G)⁴-(C₁-C₄) Alkoxy) aryl, heteroaryl is preferably furyl,

g in formula Ia and Ib¹、G²、G³And G⁴Independently and individually at each occurrence selected from hydrogen, (C)₁-C₄) Alkyl is preferably methyl, L and- (C)₁-C₆) An alkyl group-L having a structure represented by,

provided that G of formula Ia¹-G⁴Exactly one of which is selected from L and- (C)₁-C₆) alkyl-L, and

with the proviso that G of the formula Ib³And G⁴Exactly one of which is selected from L and- (C)₁-C₆) An alkyl group-L having a structure represented by,

l is a leaving group, or L is F, preferably¹⁸F or¹⁹F, wherein, preferably, if L is¹⁹F, then the compound comprises exactly one and sp³-hybridized carbon atom bound¹⁹The atomic number of F is greater than the atomic number of F,

in one embodiment, L is¹⁸F，

In a further embodiment of the process of the present invention,l is¹⁹F；

Wherein n is an integer from 0 to 6, preferably from 1 to 3, more preferably from 1 to 2,

and wherein m is an integer of 0 to 4, preferably 0 to 2, more preferably 0 to 1,

and wherein e and f are integers from 0 to 1, provided that at least one of e and f is 1,

including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures,

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof.

In one embodiment, W is-CH₂-C≡CH。

In one embodiment, a is selected from substituted or unsubstituted phenyl, substituted or unsubstituted furyl, (C)₁-C₄) Alkyl, G⁴-(C₃-C₄) Alkynyl group, G⁴-(C₁-C₃) Alkoxy group, (G)⁴-(C₁-C₃) Alkyl) phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl, wherein preferably A is selected from phenyl, furyl, (G)⁴-(C₁-C₃) Alkyl) phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl, preferably substituted phenyl, hydroxyphenyl, halophenyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl, wherein more preferably A is selected from phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl, hydroxyphenyl, fluorophenyl, methoxyphenyl, and methylphenyl. More preferably, the furyl group is furan-2-yl or furan-3-yl.

In one embodiment, G in formula Ia¹、G²、G³And G⁴And G in the formula Ib³And G⁴Independently and individually at each occurrence selected from hydrogen, (C)₁-C₄) Alkane (I) and its preparation methodThe radicals are preferably methyl, L and- (C)₁-C₄) An alkyl group-L having a structure represented by,

provided that G of formula Ia¹-G⁴Exactly one of and G of the formula Ib³-G⁴Exactly one of which is selected from L and- (C)₁-C₄) alkyl-L, wherein preferably G in formula Ia¹、G²、G³And G⁴And G in the formula Ib³And G⁴Independently and individually at each occurrence selected from the group consisting of hydrogen, methyl, L and- (C)₁-C₂) An alkyl group-L having a structure represented by,

provided that G of formula Ia¹-G⁴Exactly one of and G of the formula Ib³-G⁴Exactly one of which is selected from L and- (C)₁-C₂) alkyl-L, wherein G in formula Ia is more preferred¹、G²、G³And G⁴And G in the formula Ib³And G⁴Independently and individually at each occurrence, selected from the group consisting of hydrogen, methyl, L and-methyl-L,

provided that G of formula Ia¹-G⁴Exactly one of and G of the formula Ib³-G⁴Exactly one of which is selected from L and-methyl-L.

In one embodiment, L is a leaving group selected from halogen, in particular chlorine, bromine, iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy and (4-methoxyphenyl) sulfonyloxy.

Preferably, L is selected from the group consisting of chloro, bromo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, and (2,4, 6-triisopropylphenyl) sulfonyloxy.

Preferred "precursor compounds of the formula Ia or Ib" are

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -3-phenylpropyl ester, or

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -1-phenylpropyl ester, or

Methanesulfonic acid 3-furan-2 yl-2- (methylpropan-2-ynylamino) propyl ester, or

Methanesulfonic acid 1- (methylprop-2-ynylamino) indan-2-ester, or

Methanesulfonic acid 1- (methylpropan-2-ynylamino) -1, 2, 3, 4-tetrahydronaphthalen-2-yl ester, or

1-benzyl-2- (methylpropan-2-ynylamino) propyl methanesulfonate, or

Methanesulfonic acid 1- (methylpropan-2-ynylamino) -2-phenylethyl ester, or

Methanesulfonic acid 2- [ (2-furan-2-yl-1-methylethyl) prop-2-ynylamino ] ethyl ester, or

Methanesulfonic acid 2- [ (1-methyl-2-phenylethyl) prop-2-ynylamino ] ethyl ester, or

Methanesulfonic acid 2- [ prop-2-ynyl- (1, 2, 3, 4-tetrahydronaphthalen-1-yl) amino ] ethyl ester, or

Methanesulfonic acid 2- (indan-1-ylprop-2-ynylamino) ethyl ester, or

Methanesulfonic acid 2- {4- [2- (methylprop-2-ynylamino) propyl ] phenoxy } ethyl ester.

In one embodiment of the formulae Ia or Ib, L is not F, in particular not¹⁸F and is not¹⁹F; these are the "precursor compounds" described above.

In the general formula IIn another embodiment of a or Ib, L is¹⁸F, or, the mesyloxy group shown in any of the above specific precursor compounds is¹⁸F is replaced. These are of the formula Ia or Ib¹⁸F labeled compound.

In yet another embodiment of formula Ia or Ib, L is¹⁹F, or, the mesyloxy group shown in any of the above specific precursor compounds is¹⁹F is replaced. These are the "standard control compounds having formula Ia or Ib" described above.

L is a leaving group which is known or obvious to the person skilled in the art and is selected from, but not limited to, Synthesis (1982), p.85-125, Table 2 (p.86; (the last item of Table 2 requiring correction: "n-C₄F₉S(O)₂-O-perfluorobutanesulfonate (nonaflat) "instead of" n-C₄H₉S(O)₂-O-perfluorobutylsulfonate "), Carey and Sundberg, Organische Seynthese, (1995), page 279-281, Table 5.8; or those leaving groups described or named in Netscher, recentres, dev, org, chem, 2003, 7, 71-83, schemes 1,2, 10 and 15.

It should be clear that, wherever the term "aryl", "heteroaryl" or any other term is used in this specification to refer to an aromatic system, this also includes such aromatic systems being substituted with one or more suitable substituents such as OH, halogen, alkyl, NH₂、NO₂、SO₃Etc. are possible.

The term "aryl" as used herein alone or as part of another group, refers to a monocyclic or bicyclic aromatic group containing 6-12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl, which aromatic group itself may be substituted by one, two or three independently and individually selected from halogen, nitro, (C) and₁-C₆) Carbonyl, cyano, nitrile, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) A substituent of a sulfanyl group. As mentioned above, such "aryl" groups may additionally be substituted by one or several substituents.

As used herein, the term "heteroaryl" refers to a group containing 5 to 14 ring atoms sharing 6, 10 or 14 electrons П (π) in the ring system, and containing a carbon atom (which may be substituted by halogen, nitro, (C)₁-C₆) Carbonyl, cyano, nitrile, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy or (C)₁-C₆) Sulfanyl substituted) and 1,2, 3, or 4 oxygen, nitrogen, or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo [ b ]]Thienyl, naphtho [2, 3-b ]]Thienyl, thianthrenyl, furyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4 aH-carbazolyl, carbolinyl, phenanthridinyl, naphthyridinyl, phenanthridinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl.

Heteroaryl may be substituted by one, two or three independently and independently selected from halogen, nitro, (C)₁-C₆) Carbonyl, cyano, nitrile, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) And a substituent of a sulfanyl group. As mentioned above, such "heteroaryl" may be additionally substituted by one or several substituents.

In the inventionThe term "alkyl" as used herein after in the specification and in the claims, alone or as part of another group, refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. The alkyl groups may also be substituted by, for example, halogen atoms, hydroxy groups, C₁-C₄Alkoxy or C₆-C₁₂Aryl groups (which in turn may also be substituted, for example, by 1 to 3 halogen atoms). More preferably, alkyl is C₁-C₁₀Alkyl radical, C₁-C₆Alkyl or C₁-C₄An alkyl group.

As used hereinafter in the specification and in the claims, the term alkynyl is defined similarly as alkyl, but contains at least one carbon-carbon double or triple bond, respectively, and more preferably C₃-C₄Alkynyl.

The term "alkoxy (or alkyloxy)" as used hereinafter in the specification and in the claims, respectively, refers to an alkyl group attached by an oxygen atom, wherein the alkyl moiety is as defined above.

Whenever the term "substituted" is used, it is intended to indicate that one or more hydrogens on the indicated atom in the expression using "substituted" is replaced by a selection from the indicated group, provided that the normal valency of the indicated atom is not exceeded, and that the substitution forms a chemically stable compound, i.e., a compound that is sufficiently powerful to withstand isolation to a useful degree of purity from the reaction mixture and formulation into a pharmaceutical composition. The substituents may be selected from halogen atoms, hydroxyl groups, nitro groups, (C)₁-C₆) Carbonyl, cyano, nitrile, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) A sulfanyl group.

Of the formulae Ia or Ib¹⁸Preferred examples of F-labelled compounds are:

[ F-18] - (1-fluoromethyl-2-phenylethyl) methylpropane- [ F-18] - (2-fluoro-1-methyl-2-phenylethyl) methyl

2-alkynylaminoprop-2-ynylamine

[ F-18] - (1-fluoromethyl-2-furan-2-ylethyl) methyl [ F-18] - (2-fluoroindan-1-yl) methylprop-2-ynyl

Propen-2-ynylaminamines

[ F-18] - (2-fluoro-1, 2, 3, 4-tetrahydronaphthalen-1-yl) methylpropan-2-yne

Amine amines

[ F-18] - (3-fluoro-1, 2, 3, 4-tetrahydronaphthalen-1-yl) methylpropan-2-yne [ F-18] - (2-fluoro-1-methyl-3-phenylpropyl) methyl

Aminoprop-2-ynylamine

[ F-18] - (1-fluoro-2-phenylethyl) methylpropan-2-yne [ F-18] - (2-fluoroethyl) - (2-furan-2-yl-1-methylethyl)

Alkylamino) prop-2-ynylamine

[ F-18] -fluoromethyl- (1-methyl-2-phenylethyl) propane-2- [ F-18] - (2-fluoroethyl) - (1-methyl-2-phenylethyl)

Alkynylamine prop-2-ynylamine

[ F-18] - (2-fluoroethyl) prop-2-ynyl (1, 2, 3, 4-tetrahydronaphthalen-1-yl) [ F-18] - (2-fluoroethyl) indan-1-ylpropanone-

Amine 2-alkynylamines

[ F-18] - {2- [4- (2-fluoroethoxy) phenyl ] -1-methylethyl } methane

Prop-2-ynylamine

In a second aspect of the invention, there is provided a compound of formulae Ia and Ib¹⁸F-labelled compounds and of the formulae Ia and Ib¹⁹F standard control compound as a drug or medicament.

The invention also relates to compounds of the formulae Ia and Ib¹⁸F-labelled compounds and of the formulae Ia and Ib¹⁹Use of an F standard control compound for the manufacture of a medicament or medicament for use in therapy.

In a more preferred embodiment, the use relates to the treatment of CNS diseases. CNS diseases include, but are not limited to, inflammatory and autoimmune, allergic, infectious and toxin-induced, as well as ischemia-induced diseases, pharmacologically induced inflammation with pathophysiological relevance, neuroinflammation and neurodegenerative diseases.

More preferably, the CNS disease is selected from multiple sclerosis, alzheimer's disease, frontotemporal dementia, dementia with lewy bodies, leukoencephalopathy, epilepsy, neuropathic pain, amyotrophic lateral sclerosis, parkinson's disease, encephalopathy, brain tumors, depression, drug abuse, chronic inflammatory bowel disease, atheroma, atherosclerosis, arthritis, rheumatoid arthritis, pharmacologically induced inflammation, unexplained systemic inflammation.

The invention also relates to a method of treating a central nervous system disorder as defined above, comprising administering a suitable amount of a compound of formula Ia or Ib, preferably of formula Ia or Ib¹⁸F-labelled compounds, or suitable amounts of compounds of the formulae Ia or Ib¹⁹F step of introducing standard control compound into patient.

In a third aspect of the invention there is provided a compound of formula Ia or Ib¹⁸The F-labelled compounds are useful as diagnostic or imaging agents, preferably as imaging agents for PET applications. The invention also relates to compounds of the formula Ia or Ib¹⁸Use of an F-labelled compound for the preparation of an imaging agent.

In a more preferred embodiment, the use relates to imaging of CNS diseases. CNS diseases include, but are not limited to, inflammatory and autoimmune, allergic, infectious and toxin-induced and ischemia-induced diseases, pharmacologically induced inflammation with pathophysiological relevance, neuroinflammation, neurodegenerative diseases.

The invention also relates to an imaging method comprising administering a detectable amount of a compound of formula Ia or Ib¹⁸The steps of introducing an F-labelled compound into a patient and imaging said patient.

In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula Ia or Ib, preferably of formula Ia or Ib¹⁸F-labelled compounds or of formula Ia or Ib¹⁹F standard control compound, or a pharmaceutically acceptable salt of an inorganic or organic acid thereof, or a hydrate, complex, ester, amide, solvate or prodrug thereof. Preferably, the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or vehicle.

In a preferred embodiment, the pharmaceutical composition of the present invention comprises a compound of formula Ia or Ib, which is a pharmaceutically acceptable hydrate, complex, ester, amide, solvate or prodrug thereof.

As used hereinafter in the specification and claims of the present invention, the terms "inorganic acid" and "organic acid" refer to inorganic acids, including but not limited to: acids, such as carbonic acid, nitric acid, phosphoric acid, hydrochloric acid, perchloric acid or sulfuric acid, or acid salts thereof, such as potassium bisulfate; or suitable organic acids including, but not limited to: acids, such as aliphatic acids, alicyclic acids, aromatic acids, araliphatic acids, heterocyclic acids, carboxylic acids and sulfonic acids, examples of which include formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, methanesulfonic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, trifluoromethanesulfonic acid and sulfanilic acid.

In a fifth aspect of the invention, there is provided a radiopharmaceutical composition comprising a compound of formula Ia or Ib¹⁸An F-labeled compound or a pharmaceutically acceptable salt of an inorganic or organic acid thereof, a hydrate, complex, ester, amide, solvate or prodrug thereof.

Preferably, the pharmaceutical composition comprises a physiologically acceptable carrier, diluent, adjuvant or vehicle.

The compounds of the present invention, preferably the radiolabeled compounds of formula Ia or Ib provided herein, may be administered intravenously as a pharmaceutical composition for intravenous injection in any pharmaceutically acceptable carrier, e.g. in conventional media such as physiological saline medium, or in plasma medium. Such media may also contain conventional pharmaceutical materials such as pharmaceutically acceptable salts for regulating osmotic pressure, buffers, preservatives and the like. Among them, physiological saline solution and plasma are preferred media.

Suitable pharmaceutically acceptable carriers are known to those skilled in the art. In this regard, reference may be made to, for example, Remington's chromatography of pharmacy, 13 th edition, and J.of.pharmaceutical science & Technology, Vol.52, No.5, Sept-Oct, p.238-311, which are incorporated herein by reference.

Compounds of the formulae Ia and Ib according to the invention, preferably¹⁸The concentration of the F-labelled compound and the pharmaceutically acceptable carrier in, for example, an aqueous medium will vary with the particular field of use. When satisfactory visualization of the imaged target (e.g., tumor) is available, then a sufficient amount is present in the pharmaceutically acceptable carrier.

Compounds of the invention, in particular of the invention¹⁸F-radiolabelled compounds, i.e. of formula Ia or Ib as provided by the invention¹⁸The F-labelled compound may be administered intravenously as a pharmaceutical composition for intravenous injection in any pharmaceutically acceptable carrier, e.g. a conventional medium such as physiological saline medium, or in a plasma medium. Such media may also contain conventional pharmaceutical materials such as pharmaceutically acceptable salts for regulating osmotic pressure, buffers, preservatives and the like. Among them, physiological saline solution and plasma are preferred media. Suitable pharmaceutically acceptable carriers are known to those skilled in the art. In this regard, reference may be made to, for example, Remington's chromatography of pharmacy, 11 th edition, and j&Technology，Vol.52，No.5，Sept-Oct.，p.238-311.x

According to the invention, the radiolabeled compound of general chemical formula II is administered in a single injectable unit dose, either as a neutral composition or as a salt with a pharmaceutically acceptable counter ion. After radiolabelling according to the invention, the injectable solutions can be prepared using any conventional carrier known to those skilled in the art for diagnostic imaging of various organs, tumors, etc. Generally, the unit dose of diagnostic agent to be administered will have a radioactivity of from about 0.1mCi to about 100mCi, preferably 1mCi to 20 mCi. For radiotherapeutic agents, the therapeutic unit dose has a radioactivity of about 10mCi to 700mCi, preferably 50mCi to 400 mCi. The unit dose of solution to be injected is from about 0.01ml to about 30 ml. For diagnostic purposes, in vivo imaging of organs or diseases can be performed within minutes after intravenous administration. However, if desired, imaging is performed within hours or more after injection into the patient. In most cases, a sufficient dose will accumulate at the site to be imaged within about 0.1 hour, allowing a scintigraphic image to be obtained. Any conventional method of scintigraphic imaging for diagnostic purposes may be utilized in accordance with the present invention.

The term "prodrug" as used hereinafter in the description and in the claims of the present invention refers to any covalently linked compound which releases the active parent drug of formula Ia or Ib, preferably Ia or Ib¹⁸F labeled compound.

As used throughout this document, the term "prodrug" refers to pharmaceutically acceptable derivatives, such as esters, amides and phosphates, such that the resulting biotransformation product of the derivative in vivo is the active drug as defined in the compounds of formula (I). The reference Goodman and Gilman (the pharmacological basis of therapeutics, 8 th edition, McGraw-HiM, int. Ed.1992, "biotransformations of drugs", p13-15) generally describes prodrugs, which is incorporated herein. Prodrugs of the compounds of the present invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Prodrugs of compounds of the present invention include compounds wherein, for example, a hydroxy group, such as on an asymmetric carbon atom, or an amino group, is attached to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxy or free amino group, respectively.

Typical examples of prodrugs are described, for example, in WO99/33795, WO99/33815, WO99/33793 and WO99/33792, all of which are incorporated herein by reference.

Prodrugs are characterized by excellent water solubility, increased bioavailability, and are readily metabolized in vivo into active inhibitors.

In a sixth aspect, the present invention relates to compounds of formula Ia or Ib, wherein L is¹⁹F, with the proviso that such a compound comprises exactly one and sp³-hybridized carbon atom bound¹⁹And (3) an F atom.

The term "sp³-hybrid carbon atom "means a carbon atom other than the above [ F-19]In addition to the fluorine atom, it is also linked to three other atoms via single chemical bonds, so that the carbon atom has a total of four linking ligands.

Preferably wherein L is¹⁹The compounds of formula Ia or Ib of F are:

(1-fluoromethyl-2-phenylethyl) methylprop-2-ynyl (2-fluoro-1-methyl-2-phenylethyl) methylprop-2-yne

Aminoamines

(1-fluoromethyl-2-furan-2-ylethyl) methylpropan-2- (2-fluoroindan-1-yl) methylpropan-2-ynylamine

Alkynylamines

(2-fluoro-1, 2, 3, 4-tetrahydronaphthalen-1-yl) methylpropan-2-ynylamine (3-fluoro-1, 2, 3, 4-tetrahydronaphthalen-1-yl) methylpropan-2-ynylamine

(2-fluoro-1-methyl-3-phenylpropyl) methylpropan-2-yne

Amine amines

(1-fluoro-2-phenylethyl) methylpropan-2-ynylamine (2-fluoroethyl) - (2-furan-2-yl-1-methylethyl) propanone-

2-alkynylamines

Fluoromethyl- (1-methyl-2-phenylethyl) prop-2-ynylamine (2-fluoroethyl) - (1-methyl-2-phenylethyl) prop-2-yne

Amine amines

(2-fluoroethyl) prop-2-ynyl (1, 2, 3, 4-tetrahydronaphthalen-1-yl) amine (2-fluoroethyl) indan-1-ylprop-2-ynyl

Amines as pesticides

{2- [4- (2-fluoroethoxy) phenyl ] -1-methylethyl } methylpropane-2-

Alkynylamines

If a chiral center or another form of an isomeric center is present in the compounds of the present invention, all forms of these isomers, including enantiomers and diastereomers, are covered herein. Compounds containing chiral centers may be used in the form of a racemic mixture or in the form of an enantiomerically enriched mixture, or alternatively, the racemic mixture may be separated using known techniques and the individual enantiomers may be used individually. In the case of compounds having unsaturated carbon-carbon bond double bonds, both cis and trans isomers are within the scope of the present invention. Where a compound may exist in tautomeric forms (such as keto-enol tautomers), each tautomeric form, whether existing in equilibrium or one form predominates, is included within the scope of the invention.

When referring to a compound of formula (la) of the present invention as such and any pharmaceutical composition thereof, the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of the present invention, unless otherwise indicated. Prodrugs are any covalently linked compounds which release the active parent drug of formula Ia or Ib.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

In a seventh aspect, the invention relates to a method for obtaining wherein L is¹⁸F or¹⁹F, formula Ia or Ib.

Surprisingly, two methods for obtaining such compounds were identified.

In a first embodiment, a precursor compound of formula Ia or Ib (where L is a leaving group as defined above) is reacted with a F-fluorinating agent.

Preferably, the F-fluorinating agent is a compound comprising F-anions, preferably a compound selected from the group consisting of 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]Hexacosane KF, i.e. the crown ether salts Kryptofix KF, HF, KHF₂Tetraalkylammonium salts of CsF, NaF, and F such as [, ]¹⁸F]A compound of tetrabutylammonium fluoride, and wherein F ═¹⁸F or¹⁹F。

More particularly with respect to formulae Ia and Ib¹⁸F-labelled compounds for obtaining compounds of formula Ia or Ib¹⁸A first embodiment of the method for radiolabeling an F-labelled compound comprises the steps of:

by fluorinating agents¹⁸F-radiolabelling a compound of formula Ia or Ib, having a suitable leaving group, to obtain a compound of formula Ia or Ib¹⁸F-labelled compound.

As used herein, the term "radiolabeled" molecule generally means that the molecule will be¹⁸F-atoms are introduced into the molecule.

The F-fluorinating agent is as defined above, wherein F ═¹⁸F。

In a second embodiment, the synthesis is such that L is¹⁸F or¹⁹The process for the preparation of compounds of formula Ia and Ib of F comprises the following steps:

fluorination of compounds of formula V with F-fluorinating agents F

Formula V

To give a compound of the formula IV

Formula IV

-substitution of said compound of formula IV with a compound of formula VI

Formula VI

Wherein F is¹⁸F or¹⁹F，

a is an integer of 0 to 4, preferably 0 to 2, more preferably 0 to 1,

b is a leaving group, preferably halogen, in particular chlorine, bromine, iodine, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy and (4-methoxyphenyl) sulfonyloxy,

W²is W as defined in any one of claims 1-2 and hereinbefore,

A²is selected from R¹²-O-aryl, R¹²-O-heteroaryl, aryl, heteroaryl, e.g. furyl, (C)₁-C₁₀) Alkyl, (C)₂-C₄) Alkynyl, (C)₁-C₄) Alkoxy group, ((C)₁-C₄) Alkoxy) aryl, ((C)₁-C₄) Alkyl) aryl groups, and (c) alkyl) aryl groups,

wherein R is⁹And R¹⁰Independently and individually at each occurrence selected from (C)₁-C₆) An alkyl group and hydrogen,

wherein R is¹¹Is selected from (C)₁-C₆) Alkyl and R¹²，

Wherein R is¹²Is a hydrogen atom, and is,

wherein d is an integer of 0 to 4, preferably 0 to 2, more preferably 0 to 1, and

wherein the F-fluorinating agent is as defined above,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹²。

Preferably, B is selected from the group consisting of iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy and perfluorobutylsulfonyloxy.

Preferably, A²Is selected from R¹²-O-phenyl, furyl, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkynyl, (C)₁-C₃) Alkoxy and substituted phenyl, more preferably selected from R¹²-O-phenyl, furyl, ((C)₁-C₃) Alkoxy) phenyl, hydroxyphenyl, halophenyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl, even more preferably selected from R¹²-O-phenyl, furanyl, hydroxyphenyl, fluorophenyl, methoxyphenyl and methylphenyl.

Preferably, R⁹And R¹⁰Independently and individually at each occurrence selected from (C)₁-C4) alkyl and hydrogen, preferably selected from methyl and hydrogen.

Preferably, R¹¹Is selected from (C)₁-C₄) Alkyl and R¹²Preferably selected from methyl and R¹²。

More particularly for obtaining formula Ia or Ib¹⁸A second embodiment of the method for radiolabeling an F-labelled compound comprises the steps of:

by fluorinating agents¹⁸F radiolabelling a compound of formula V to give a compound of IV, and

-substituting a compound of formula IV with a compound of formula VI.

Of formula IV¹⁸The F-labelled compound is

Or pharmaceutically acceptable inorganic acid salt or organic acid salt thereof, hydrate, complex, ester, amide, solvate or prodrug thereof,

wherein

B is a leaving group;

said leaving group B is known or evident to the person skilled in the art and is selected from, but not limited to, Synthesis (1982), p.85-125, Table 2 (p.86; (the last item of Table 2 requiring a correction: "n-C₄F₉S(O)₂-O-perfluorobutylsulfonate "instead of" n-C₄H₉S(O)₂-O-perfluorobutylsulfonate "), Carey and Sundberg, Organische Seynthese, (1995), page 279-281, Table 5.8; or those leaving groups described or named in Netscher, recentres.dev.org.chem., 2003, 7, 71-83, schemes 1,2, 10 and 15;

in a more preferred embodiment, B is selected from the following:

a) the amount of iodine is such that,

b) the bromine is added to the reaction mixture,

c) the chlorine is added to the reaction mixture in the presence of chlorine,

d) a mesyloxy group, which is a group having a sulfonyl group,

e) a tosyloxy group,

f) trifluoromethylsulfonyloxy and

g) a perfluorobutylsulfonyloxy group;

a is an integer of 0 to 4, preferably a is an integer of 0 to 2, more preferably a is an integer of 0 to 1.

The compound of formula V is

wherein

B is as defined above for the compound of formula IV, and

a is as defined above for the compound of formula IV,

the fluorinating agent is as defined above.

The compound of the formula VI is

Or pharmaceutically acceptable salts of inorganic or organic acids thereof, their hydrates, complexes, esters, amides, solvates or prodrugs thereof.

Wherein A is²Is selected from the following

a)R¹²-O-aryl and

b)R¹²-O-heteroaryl;

c) an aryl group, a heteroaryl group,

d) (ii) a heteroaryl group, wherein,

e)(C₁-C₁₀) An alkyl group, a carboxyl group,

f)C₂-C₄) An alkynyl group,

g)(C₁-C₄) An alkoxy group,

h)((C₁-C₄) Alkoxy) aryl groups, in which the alkyl groups are,

i)((C₁-C₄) Alkyl) aryl and (b) an alkyl) aryl and,

j)((C₁-C₄) Alkoxy) aryl;

in a preferred embodiment, A²Selected from the following:

a)R¹²-an O-phenyl group, which is,

b) a phenyl group,

c) a furyl group, a thienyl group,

d)(C₁-C4) an alkyl group,

e)(C₃-C₄) An alkynyl group,

f)(C₁-C₃) Alkoxy and

g) substituted phenyl;

in a preferred embodiment, A²Selected from the following:

a)R¹²-an O-phenyl group, which is,

b) a phenyl group,

c) a furyl group, a thienyl group,

d)((C₁-C₃) Alkoxy) phenyl groups, in which the phenyl groups are linked,

e) hydroxy phenyl

f) A halogenated phenyl group,

g) a group consisting of a methoxyphenyl group and a substituted phenyl group,

h) a dimethoxy phenyl group,

i) trifluoromethyl phenyl and

j)((C₁-C₄) Alkyl) phenyl;

in an even more preferred embodiment, A²Selected from the following:

a)R¹²-an O-phenyl group, which is,

b) a phenyl group,

c) a furyl group, a thienyl group,

d) a hydroxyl phenyl group,

e) fluorophenyl group

f) Methoxyphenyl and

g) a methyl phenyl group;

W²is selected from the following

a)-C(U³)(U⁴) -C ≡ CH and

b) a cyclopropyl group;

in a more preferred embodiment, W²is-CH₂-C≡CH；

U³And U⁴Independently and individually selected from the following

a) Hydrogen and

b) deuterium;

in a preferred embodiment, U³And U⁴Is hydrogen;

R⁹and R¹⁰Is independently selected from

a)(C₁-C₆) Alkyl radicals and

b) hydrogen;

in a preferred embodiment, R⁹And R¹⁰Is independently selected from

a)(C₁-C₄) Alkyl radicals and

b) hydrogen;

in a more preferred embodiment, R⁹And R¹⁰Is independently selected from

a) Methyl and

b) hydrogen;

R¹¹is selected from the following

a)(C₁-C₆) Alkyl radicals and

b)R¹²；

in a preferred embodiment, R¹¹Selected from the following:

a)(C₁-C₄) Alkyl radicals and

b)R¹²；

in a preferred embodiment, R¹¹Selected from the following:

a) methyl and

b)R¹²；

d is an integer from 0 to 4, m is an integer from 0 to 2 in preferred embodiments, and from 0 to 1 in more preferred embodiments;

R¹²is hydrogen;

with the proviso that the compound of formula VI contains exactly one R¹²。

In a preferred embodiment, the fluorinating agent is a fluorine radioisotope derivative. More preferably, the fluoro radioisotope derivative is¹⁸And F derivative. More preferably, the¹⁸The F derivative is 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]Hexacosane K¹⁸F (crown ether salt Kryptofix K)¹⁸F)、K¹⁸F、H¹⁸F、KH¹⁸F₂、Cs¹⁸F、Na¹⁸F or¹⁸A tetraalkylammonium salt of F (e.g., [2 ]¹⁸F]Tetrabutylammonium fluoride). More preferably, the fluorinating agent is K¹⁸F、H¹⁸F or KH¹⁸F₂Most preferably K¹⁸F(¹⁸F fluoride anion).

The radiofluorination reaction may be carried out, for example, in conventional reaction vessels (such as Wheaton vials) or in microreactors known to those skilled in the art. The reaction can be heated by conventional means such as an oil bath, heating block or microwaves. The radiofluorination reaction was carried out in dimethylformamide with potassium carbonate as base and "kryptofix" as crown ether. However, other solvents known to the skilled person may also be used. These possible conditions include, but are not limited to: dimethyl sulfoxide and acetonitrile as solvents, and tetraalkylammonium and tetraalkylphosphonium carbonates as bases. Water and/or alcohol may participate in such a reaction as a co-solvent. The radiation fluorination reaction is carried out for 1 to 60 minutes. The preferred reaction time is 5 to 50 minutes. More preferably, the reaction time is 10 to 40 min. This and other conditions for this radiofluorination are known to the person skilled in the art (Coenen, Fluorine-18Labeling methods: Features and Possibiliityou basic reactions, (2006), in Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-the drivingForcein molecular imaging. Springer, Berlin Heidelberg, pp.15-50). The radiofluorination can be carried out in a "hot cell" and/or by using modules (see: Krasikowa, Synthesis modules and molecular Imformation nF-18labeling (2006), Schubiger P.A., Friebe M., Lehmann L., (eds), PET-Chemistry-the driving formation molecular imaging. Springer, Berlin Heidelberg, pp.289-316), which allow automated or semi-automated synthesis.

In addition, the present invention provides a composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or diluent.

In one embodiment, the compound is¹⁸F-labelled compound.

In another embodiment, the compound is¹⁹F-labelled compound.

In yet another embodiment, the compound is a precursor compound.

The invention also provides compounds of the invention, preferably of the invention¹⁸F-or¹⁹An F-labelled compound, or a composition of the invention, for use as a medicament or diagnostic agent or imaging agent.

The invention also provides compounds of the invention, preferably of the invention¹⁸F-or¹⁹Use of F-labelled Compounds, Or compositions of the invention, for the preparation ofUse of a medicament for the treatment and/or diagnosis and/or imaging of a Central Nervous System (CNS) disease.

The invention also provides compounds of the formulae Ia or Ib¹⁸F-labelled compounds or compositions comprising such compounds for use as diagnostic or imaging agents, particularly for central nervous system diseases.

The invention also provides a kit comprising a closed vial containing a predetermined amount of a compound

a) The compound is a precursor compound of formula Ia or Ib, or

b) A compound of formula V as defined above and a compound of formula VI.

The present invention also provides a method for detecting the presence of monoamine oxidase in a patient, in particular for imaging a central nervous system disorder in a patient, comprising:

will measure a detectable amount of the present invention¹⁸Introducing an F-labelled compound or a composition comprising such a compound into a patient,

and detecting the compound or the composition by Positron Emission Tomography (PET).

The present invention also provides a method of treating a central nervous system disorder comprising administering a suitable amount of a compound of the present invention, preferably of the present invention¹⁸F-or¹⁹A step of introducing the F-labeled compound into the patient.

Synthesis of Compounds

According to said fluorine atom (F-19 or F-18) or said leaving group (control G)¹-G⁴) Different synthetic strategies are possible for the carbon atom of the attached compound of formula Ia: (the following numbers are "1)" to "4)".

1) Fluorine atom (F-19 or F-18) or leaving group (control G)³) Nitrogen atom attached to the center via a linker:

a series of different, suitable omega-substituted 1- (alkyl) alkylamines (a1) (see scheme 1) are commercially available. They are used, for example, as starting materials for alkylation with propargyl bromide. Alternatively, the ω -substituted 2-bromoalkanes (a2) can be used as electrophiles in chemical reactions with propargylamine or cyclobutylamine.

Compound A3 can be alkylated with [ F-18] - ω -fluoroalkyl bromide (a6) produced from the corresponding triflate (a7) to give compound a 4. Compound A3 can also be alkylated with omega-functionalized building blocks to give A5, so that the latter leaving group (V) of A5 is then converted into the [ F-18] atom of compound A4.

A specific example of this process in scheme 1 is shown in scheme 2: release of ammonium salt 6(Sigma) by alkaline water extraction gave the corresponding free amine (7). Compound 7 is then alkylated with [ F-18] -2-fluoroethyl bromide (Bioorg.Med.chem.; 13; 20; 2005; 5779-.

2) Fluorine atom (F-19 or F-18) or leaving group (control substituent G)¹) Nitrogen atom attached to the center at position α -:

route 3

Compound B2 may be obtained by alkylating an amino alcohol, many examples of which are known in the literature, with, for example, propargyl bromide (see B1, scheme 3), or which is commercially available. Introduction of a leaving group (mesyloxy as shown, but other leaving groups are also possible) can be caused by standard methods to give compound B3. Substitution of the leaving group of compound B3 by a fluorinating agent gives compound B4.

A specific example of the synthesis of scheme 3 is shown in scheme 4:

compound 9 was N-alkylated with propargyl bromide (see J.organomet. chem.; 317; 1986; 93-104). The reaction can be carried out in dimethylformamide and potassium carbonate in dimethylformamide (e.g., org. Lett.; 8; 14; 2006; 2945-. But other bases (including but not limited to cesium carbonate or sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tetra-alkylammonium hydroxide, sodium hydride) and other solvents (including but not limited to acetone, tetrahydrofuran) that are eventually mixed with water are also possible. Then, the resulting alcohol 10 is converted into compound 11 by using, for example, methanesulfonyl chloride, triethylamine and dichloromethane. Other possible solvents and bases include, but are not limited to, dichloroethane, diethyl ether, ethyl acetate, diisopropylethylamine, DABCO, and the like. In some cases, mesylate 11 happens to be used as an intermediate, which forms the corresponding "in situ" aziridine. This derivative (not shown) is then opened by the presence of a chloride anion nucleophile in solution to give the appropriate chloro precursor molecule (control scheme 11, compounds 42 and 43). Therefore, it is also conceivable that other mesylating (mesylating) reagents, such as methanesulfonic anhydride (see, for example, Tetrahedron; 63; 25; 2007; 5470-5476), produce a mesylate ester which is a stable derivative. However, chloro precursor compounds 42 and 43 are also suitable for producing F-18 labeled molecules (control scheme 11, compounds 13 and 39. subsequently, the radiofluorination of compound 11 is carried out in dimethylformamide with potassium carbonate as the base and "kryptofix" as the crown ether to give compound 13. however, other solvents well known to the skilled artisan may also be used. Compound 12 can also be obtained from compound 10 by treatment with DAST in dichloromethane. This method is known to the person skilled in the art (e.g. J.Med.chem.; 49; 8; 2006; 2496-.

3) Fluorine atom (F-19 or F-18) or leaving group (control substituent G)²) Nitrogen atom attached to the center at position β -:

the process is similar to that described in 2). The skilled worker can start from an amino alcohol C1 (known from the literature or commercially available). Amino and alcohol groups can be protected (not shown in scheme 5, but exemplified in scheme 6).

C1 can be alkylated with, for example, propargyl bromide to give compound C2. Introduction of a leaving group (mesyloxy as shown, but other leaving groups are also possible) can be caused by standard methods to give compound C3. Substitution of the leaving group of compound C3 by a fluorinating agent gives compound C4.

Route 5

A specific example of this process (scheme 5) is shown in scheme 6. The amino alcohol 13(Aldrich) protected as a cyclic carbamate is alkylated with a propargyl halide such as propargyl bromide (Aldrich) by methods known to those skilled in the art (see J.org.chem.; 71; 13; (2006); 5023-5026.). The reaction can be carried out, for example, in DMF or THF using a strong base such as sodium hydride to give oxazolidinone 14. Compound 14 can be reduced with lithium aluminum hydride to give alcohol 15 (analogous to j. carbohydr. chem.; 24; 2; (2005); 187-. Alcohol 15 can be converted to mesylate 16 by standard methods including, for example, methanesulfonyl chloride in dichloromethane and triethylamine as a base. Triflate 16 was used as a precursor for radiofluorination. Thus, the conversion to compound 17 was carried out using potassium fluoride and a solution of "kryptofix" in acetonitrile. Compound 18 was used as a standard control compound for the radiofluorination reaction. Mesylate 16 may also be converted to non-radioactive fluoride 16. Suitable reagents for this reaction are potassium fluoride and "kryptofix" in acetonitrile. Optionally, the reaction mixture is heated by microwave techniques. Alternatively, compound 16 can also be obtained from compound 15 by treatment with DAST in dichloromethane. This method is known to the person skilled in the art (e.g. J.Med.chem.; 49; 8; 2006; 2496-.

4) Fluorine atom (F-19 or F-18) or leaving group (control substituent G)⁴) Nitrogen atom attached to the center at the ω -position:

route 7

Compound D2 can be obtained by alkylating an amino alcohol, many examples of which are known in the literature, with, for example, propargyl bromide (see D1, scheme 7 (the hydroxyl functionality can optionally be protected; "spacer" according to substituent a in formula Ia) to give compound D2, or which is commercially available, by standard methods resulting in the introduction of a leaving group (the methanesulfonyloxy group shown, but other leaving groups are also possible) to give compound D3, by substituting the leaving group of compound D3 with a fluorinating agent to give compound D4.

A specific example of this process is shown in scheme 8: methyl ester 19(Pharmazie (1997), 52, 12, 937) is reduced to the corresponding alcohol by using sodium borohydride (e.g. Tetrahedron; 63; 9; 2007; 2000-. The protecting group for the amino group is then removed by dissolving the intermediate in meoh (aq) and alkali metal (sodium or potassium) carbonate (e.g., j. org. chem., 53, (1988), 3108). Alkylation of the amino group of compound 20 (e.g., org. Lett.; 8; 14; 2006; 2945-2947) with propargyl bromide in DMF and potassium carbonate affords compound 21. Alcohol 21 is converted to the corresponding mesylate 22, and mesylate 22 is fluorinated to 23 and 24 by use of a fluorinating agent.

Route 8

An example of the synthesis of a compound of formula Ib is shown in scheme 10:

compound 25 is alkylated with sodium hydride (as a base) in DMF by using propargyl bromide (see, e.g., j. org. chem.; 71; 13; (2006); 5023-. Deprotection of the Boc-protected amine 26 with trifluoroacetic acid or other acid affords compound 27. Alkylation of the secondary amine (27) with [ F-18] fluoroethyl bromide (control scheme 1, A6) affords compound (32). Compound 27 can also be alkylated with 2- (2-tetrahydropyranyloxy) ethyl bromide (Aldrich) and potassium carbonate in DMF. The protecting group (THP) is removed using an acid (e.g. toluene sulfonic acid in dichloromethane) and the alcohol (29) is then converted to the mesylate 30 using methanesulfonyl chloride and triethylamine in dichloromethane. Compound 30 is converted to compound 31 or compound 32 using F-19 and F-18 fluorinating agents. Optionally, compound 29 can be converted to compound 31 by using DAST in dichloromethane.

Another example of the synthesis of compounds of formula Ib is shown in scheme 10: compound 32(j.am. chem. so.; EN; 129; 3; 2007; 562-568) is alkylated with propargyl bromide and sodium hydride in DMF (see, e.g., j.org. chem.; 71; 13; (2007); 5023-5026). The Tces and TBDMS groups were removed using a Zn-Cu couple (J.Am.chem.Soc.; 129; 3; 2007; 562-568) and hydrogen chloride. Alkylation of secondary amine 34 with methyl iodide in acetonitrile and sodium carbonate affords compound 35. Alcohol 35 was converted to the corresponding triflate 36 by using trifluoromethylsulfonyl chloride and triethylamine as a base. Trifluoromethanesulfonate 36 is converted to [ F-18] fluoro derivative 37 using typical [ F-18] fluorinating agents. Alcohol 35 can also be converted to fluoride 38 using a DBU solution of perfluorobutylsulfonyl chloride (tetrahedron letters, Vol.36, No.15, pp.2611-2614, 1995).

The object of the present invention was to find improved F-18 labelled compounds compared to the current state of the art, which can be used to detect reactive astrocytes by PET imaging targeting monoamine oxidase B. Because the data of the present invention prove that when the alpha-¹¹C]Selegiline (control compound 3) and Compound 5(, (B)¹⁸F]FHMP; NuclearMedicine biology, Vol.26, pp111-116, (1999), supra¹⁸F]Compound 13 surprisingly shows improved metabolic stability.

On human brain sections obtained from patients with Alzheimer's disease and normal controls, the standard protocol was used to investigate¹⁸F]Binding of compound 13. Briefly, tissues were cut at a thickness of 18 μm in Cryostat (Leica, Germany), placed on slides for thawing, and held at-20 ℃ for at least 48 hours prior to use. Thereafter, the slide glass was taken out and left at room temperature. The sections were washed with 25mM HEPES buffer for 5min in 25mM HEPES/0.1% BSA at room temperature in a humidified chamber with 10 Bq/. mu.l¹⁸F]Compound 13 was incubated for 60min and then washed 5 more times, each for 2min in 25mM HEPES/0.1% BSA. Sections were immersed twice in ice cold distilled water, then dried at room temperature and exposed to P overnighthospor Imanger plate (FUJIBAS 5000.) for detection of signal specificity, sections were immunohistochemically stained with anti-GFAP antibody to detect reactive astrocytes using standard protocols after exposure to excess (10 μ M) of selegiline, pargyline (both for MAOB) and clogiline (for MAOA), respectively using the binding protocol described above for detection β of amyloid plaques using BAY949172 (RoweCC et al, LancetNeutol 2008; 7: 129-¹⁸F]The specificity of compound 13 for MAOB is shown in FIGS. 1 and 2, FIGS. 3 and 4 demonstrate the relationship of the radioactive signal to the underlying pathology, β amyloid plaques (FIG. 3) and reactive astrocytes (FIG. 4), respectively.

In NMRI mice weighing 25-31.5g, the 2 [ alpha ] protein was studied at 5 time points¹⁸F]Biodistribution of compound 13.3 mice were used at each time point. Each mouse is injected with 0.178MBq 2¹⁸F]Compound 13. After each time point, mice were sacrificed and organs were removed and measured with a gamma counter. The result is decay corrected. As shown in fig. 5, the compounds showed high initial brain uptake of radioactivity (7.5 ± 0.04% ID/g at 2 min.i.) and high initial clearance of radioactivity from the brain (2.10 ± 0.33% ID/g at 30 min.i.), dropping to 1.34 ± 0.26% ID/g after 4 hours.

The term "2" was tested in a cynomolgus monkey¹⁸F]Compound 13. Respectively mixing 155MBq [2 ], [ solution of ]¹¹C]Selegiline and 178MBq [ solution of ] Selegiline¹⁸F]Compound 13 was injected into the same monkey. Comparing by calculating a Standard absorption value (SUV) monitoring time Activity Curve¹⁸F]Compound 13 and [2 ]¹¹C]A compound is provided. Plasma radioactivity curves were monitored over time. As can be seen from a comparison of the curves for the parent compound in FIGS. 8 and 9, at the time points of 30 and 45min, [2 ]¹⁸F]The plasma radioactivity of Compound 13 is approximately the observed value of [ alpha ], [ alpha¹¹C]2 times the plasma radioactivity of selegiline. Furthermore, metabolites that appeared in plasma over time were monitored for both ligands (fig. 8 and 9). As can be seen by comparing FIG. 8 with FIG. 9, the term¹⁸F]Compound 13 [2 ]¹¹C]Selegiline is more stable. Phase angle 2¹¹C]About 25% of the selegiline, a [ sic ], [ solution of¹⁸F]Metabolite b of compound 13 was produced at a level of about 10%. Example (b)For example, at the time point of 30min, the metabolite b is only [2 ]¹¹C]One third of what is observed with selegiline. Apparently, with the reported rapid decomposition into polar [2 ]¹⁸F]Compound 13 is also more suitable for in vivo imaging than compound 5, which is a labeled metabolite.

[¹⁸F]Absorption and enrichment ratio of Compound 13 in a specific site such as the striatum¹¹C]Selegiline was about 10% higher (fig. 10).

Further blocking experiments in monkeys showed that staining was specific in monkey brain.

Preferred precursor molecules having the formula Ia are

(2S) -2- [ methyl (prop-2-yn-1-yl) amino ] -3-phenylpropyl methanesulfonate,

4-Methylbenzenesulfonic acid (2S) -2- [ methyl (prop-2-yn-1-yl) amino ] -3-phenylpropyl ester,

n- [ (2S) -1-chloro-3-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine,

(2S) -3- (furan-2-yl) -2- [ methyl (prop-2-yn-1-yl) amino ] propyl methanesulfonate,

4-Methylbenzenesulfonic acid (2S) -3- (furan-2-yl) -2- [ methyl (prop-2-yn-1-yl) amino ] propyl ester,

n- [ (2S) -1-chloro-3- (furan-2-yl) prop-2-yl ] -N-methylprop-2-yn-1-amine.

Preferred precursor molecules not covered by formula Ib are

(3aS, 8aR) -3- (prop-2-yn-1-yl) -3, 3a, 8, 8 a-tetrahydroindeno [1, 2-d ] [1, 2, 3] oxathiazole 2, 2-dioxide and

(3aS, 8aS) -3- (prop-2-yn-1-yl) -3, 3a, 8, 8 a-tetrahydroindeno [1, 2-d ] [1, 2, 3] oxathiazole 2, 2-dioxide.

Of the formulae Ia or Ib¹⁸Preferred examples of F-labelled compounds are

N-[(2S)-1-(¹⁸F) Fluoro-3-phenylprop-2-yl]-N-methylpropan-2-yn-1-amine

N-[(2S)-1-(¹⁸F) Fluoro-3- (furan-2-yl) propan-2-yl]-N-methylpropan-2-yn-1-amine

[(1S，2R)-2-(¹⁸F) fluoro-N- (prop-2-yn-1-yl) -2, 3-dihydro-1H-inden-1-amine

(1S，2S)-2-(¹⁸F) fluoro-N- (prop-2-yn-1-yl) -2, 3-dihydro-1H-inden-1-amine

Compound 10 can be converted to a mixture of fluorides 12 and 41, while compound 41 is the rearranged reaction product (scheme 11). Fluorides 12 and 41 can be separated on the column (control TLC fig. 15). In some cases, alcohol 10 is converted with methanesulfonyl chloride to form a mixture of chlorides 42 and 43, which are suitable precursor compound pairs that are radiofluorinated to F-18 labeled compounds 13 and 39. F-18 labeled compounds 13 and 39 can be separated on an HPLC column (compare FIGS. 11 and 12) and studied separately.

Alcohol 10 can also be converted to mesylate 44 using toluene sulfonic anhydride. This derivative is also a suitable precursor for radiolabelling compound 13.

Derivative 15 can be converted to compound 18 by using DAST (see scheme 12). Conversion of compound 15 to chloride 45 was achieved using methanesulfonyl chloride. Chloride 45 is a suitable precursor molecule for radiofluorination to compound 46 (compare figure 14).

Route 12

The diastereomer of compound 18 is compound 47, which is synthesized from (1R, 2R) pseudoephedrine 48 via alcohol 49 in two steps. Conversion of alcohol 49 synthesized from (1R, 2R) pseudoephedrine to fluoride 47 by alkylation with propargyl bromide was achieved by using DAST. Compound 49 may also be converted to precursor molecule 50 using methanesulfonyl chloride.

Route 13

Compound 8 is the product of radioactive chlorinated chloride 52. The precursor chloride is obtained from alcohol 51 by using methanesulfonyl chloride. F-18 labeled fluoride 8 cold control (coldreference) compound (53) is also shown in scheme 14 and can be synthesized from alcohol 51 using DAST.

An example of the synthesis of a [ F-18] labeled compound of formula Ib is shown in scheme 15:

route 15

By using SO₂Cl₂(cf. tetrahedron Analyzer (1990), 1, 12, 877-. Mitsonobu reaction using prop-2-yn-1-ol, triphenylphosphine and dipropylene-2-ester of (E) -diazene-1, 2-dicarboxylate to form precursor compound 56, followed by oxidation of ammonium with tetrabutyl ammonium hydroxide [2 ], [¹⁸F]Fluorination followed by deprotection of the sulfate moiety (control F-19 analog 57) converts precursor compound 56 to compound 58. A similar procedure also gave the corresponding F-19 derivative 59 (cf. Posakony et al, Synthesis (2002), 6, 766-770)。

Further, the present invention relates to

1. A compound of formula Ia

Formula Ia

Or a compound of the formula Ib

Formula Ib

Wherein

a is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, e.g. furyl, (C)₁-C₁₀) Alkyl, G⁴-(C₂-C₄) Alkynyl group, G⁴-(C₁-C₄) Alkoxy group, (G)⁴-(C₁-C₄) Alkyl) aryl, (G)⁴-(C₁-C₄) Alkoxy) aryl, (G)⁴-(C₁-C₄) Alkyl) aryl and (G)⁴-(C₁-C₄) Alkoxy) aryl, wherein the heteroaryl is preferably furyl,

and wherein e and f are integers from 0 to 1, provided that at least one of e and f is 1, including all isomeric forms of said compounds, including but not limited to enantiomers and diastereomers and racemic mixtures,

2. The compound of item 1, wherein W is-CH₂-C≡CH。

3. A compound according to any one of items 1 to 2, wherein a is selected from substituted or unsubstituted phenyl, substituted or unsubstituted furyl, in particular furan-2-yl, furan-3-yl, (C)₁-C₄) Alkyl, G⁴-(C₃-C₄) Alkynyl group, G⁴-(C₁-C₃) Alkoxy group, (G)⁴-(C₁-C₃) Alkyl) phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl.

4. A compound of item 3, wherein A is selected from substituted or unsubstituted phenyl, substituted or unsubstituted furyl, (G)⁴-(C₁-C₃) Alkyl) phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl, hydroxyphenyl, halophenyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl。

5. The compound of item 4, wherein A is selected from substituted or unsubstituted phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl, hydroxyphenyl, fluorophenyl, methoxyphenyl, and methylphenyl.

6. A compound of any one of the preceding, wherein G in formula Ia¹、G²、G³And G⁴And G of the formula Ib³And G⁴Independently and individually at each occurrence selected from hydrogen, (C)₁-C₄) Alkyl is preferably methyl, L and- (C)₁-C₄) An alkyl group-L having a structure represented by,

provided that G of formula Ia¹-G⁴Exactly one of and G of the formula Ib³-G⁴Exactly one of which is selected from L and- (C)₁-C₄) alkyl-L.

7. The compound of item 6, wherein G in formula Ia¹、G²、G³And G⁴And G of the formula Ib³And G⁴Independently and individually at each occurrence selected from the group consisting of hydrogen, methyl, L and- (C)₁-C₂) An alkyl group-L having a structure represented by,

provided that G of formula Ia¹-G⁴Exactly one of and G of the formula Ib³-G⁴Exactly one of which is selected from L and- (C)₁-C₂) alkyl-L.

8. The compound of item 7, wherein G in formula Ia¹、G²、G³And G⁴And G of the formula Ib³And G⁴Independently and individually at each occurrence, selected from the group consisting of hydrogen, methyl, L and-methyl-L,

9. A compound of any one of the preceding, wherein L is a leaving group selected from halogen, in particular chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethylsulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy and (4-methoxyphenyl) sulfonyloxy.

10. The compound of item 9, wherein L is selected from the group consisting of chloro, bromo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, and (2,4, 6-triisopropylphenyl) sulfonyloxy.

11. A compound of any one of the preceding which is

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -3-phenylpropyl ester, or

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -1-phenylpropyl ester, or

Methanesulfonic acid 1- (methylprop-2-ynylamino) indan-2-ester, or

1-benzyl-2- (methylpropan-2-ynylamino) propyl methanesulfonate, or

Methanesulfonic acid 1- (methylpropan-2-ynylamino) -2-phenylethyl ester, or

Methanesulfonic acid 2- (indan-1-ylprop-2-ynylamino) ethyl ester, or

Methanesulfonic acid 2- {4- [2- (methylpropan-2-ynylamino) propyl ] phenoxy } ethyl ester, or

(2S) -2- [ methyl (prop-2-yn-1-yl) amino ] -3-phenylpropanesulfonic acid, or

4-methylbenzenesulfonic acid (2S) -2- [ methyl (prop-2-yn-1-yl) amino ] -3-phenylpropyl ester, or

N- [ (2S) -1-chloro-3-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine, or

(2S) -3- (furan-2-yl) -2- [ methyl (prop-2-yn-1-yl) amino ] propyl methanesulfonate, or

4-methylbenzenesulfonic acid (2S) -3- (furan-2-yl) -2- [ methyl (prop-2-yn-1-yl) amino ] propyl ester, or

N- [ (2S) -1-chloro-3- (furan-2-yl) prop-2-yl ] -N-methylprop-2-yn-1-amine.

12. A compound according to any one of items 1 to 10, wherein L is not F, in particular not¹⁸F and is not¹⁹F。

13. The compound of any one of items 1 to 11, wherein L is¹⁸F, or, wherein the methanesulfonyloxy, chloro and toluenesulfonyloxy groups in any of the compounds shown in item 11 are substituted with¹⁸F is replaced.

14. The compound of any one of items 1 to 11, wherein L is¹⁹F, or, wherein the methanesulfonyloxy, chloro and toluenesulfonyloxy groups in any of the compounds shown in item 11 are substituted with¹⁹F is replaced.

15. A method for synthesizing a compound defined in item 13 or 14, wherein the compound of item 9 or 12 is reacted with a compound wherein F ═¹⁸F or¹⁹F-fluorinating agent reaction of F.

16. The process of item 15, wherein the F-fluorinating agent is a compound comprising an F-anion, preferably selected from the group consisting of 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8]Hexacosane KF, i.e. the crown ether salts Kryptofix KF, HF, KHF₂Tetraalkylammonium salts of CsF, NaF, and F such as [, ]¹⁸F]A compound of tetrabutylammonium fluoride, and wherein F ═¹⁸F or¹⁹F。

17. A method of synthesizing a compound defined in item 13 or 14, comprising the steps of:

fluorination of compounds of formula V with F-fluorinating agents F

Formula V

To obtain the compound of the formula IV,

formula IV

-substitution of said compound of formula IV with a compound of formula VI

Formula VI

Wherein F is¹⁸F or¹⁹F，

a is an integer of 0 to 4, preferably 0 to 2, more preferably 0 to 1,

and wherein W²Is W as defined in any one of items 1 to 2,

wherein A is²Is selected from R¹²-O-aryl, R¹²-O-heteroaryl, aryl, heteroaryl, e.g. furyl, (C)₁-C₁₀) Alkyl, (C)₂-C₄) Alkynyl, (C)₁-C₄) Alkoxy group, ((C)₁-C₄) Alkoxy) aryl, ((C)₁-C₄) Alkyl) aryl groups, and (c) alkyl) aryl groups,

whereinR⁹And R¹⁰Independently and individually at each occurrence selected from (C)₁-C₆) An alkyl group and hydrogen,

wherein R is¹¹Is selected from (C)₁-C₆) Alkyl and R¹²，

Wherein R is¹²Is a hydrogen atom, and is,

wherein the F-fluorinating agent is as defined in item 16,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹²。

18. The method of item 17, wherein B is selected from the group consisting of iodo, bromo, chloro, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, and perfluorobutylsulfonyloxy.

19. The method according to any one of items 17 to 18, wherein A²Is selected from R¹²-O-phenyl, furyl, (C)₁-C₄) Alkyl, (C)₃-C₄) Alkynyl, (C)₁-C₃) Alkoxy and substituted phenyl, more preferably selected from R¹²-O-phenyl, furyl, ((C)₁-C₃) Alkoxy) phenyl, hydroxyphenyl, halophenyl, methoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl, even more preferably selected from R¹²-O-phenyl, furanyl, hydroxyphenyl, fluorophenyl, methoxyphenyl and methylphenyl.

20. The method of any one of items 17 to 19, wherein R⁹And R¹⁰Independently and individually at each occurrence selected from (C)₁-C₄) Alkyl and hydrogen, preferably selected from methyl and hydrogen.

21. The method of any one of items 17 to 20, wherein R¹¹Is selected from (C)₁-C₄) Alkyl and R¹²Preferably selected from methyl and R¹²。

22. A pharmaceutical composition comprising a compound of any one of items 1-14 and a pharmaceutically acceptable carrier or diluent.

23. The composition of item 22, wherein the compound is a compound of item 13.

24. The composition of item 22, wherein the compound is a compound of item 14.

25. The composition of item 22, wherein the compound is a compound of item 12.

26. A compound according to any one of claims 1 to 14, preferably a compound according to any one of claims 13 or 14, or a composition according to any one of claims 22, 23, 24 or 25 for use as a medicament or diagnostic agent or imaging agent.

27. Use of a compound according to any one of items 1 to 14, preferably a compound according to item 13 or 14, or a composition according to any one of items 22, 23, 24 or 25, for the preparation of a medicament for the treatment and/or diagnosis and/or imaging of a Central Nervous System (CNS) disease.

28. The compound of item 13 or the composition of item 23 for use as a diagnostic or imaging agent, particularly for a central nervous system disorder.

29. Kit comprising a closed vial containing a predetermined quantity of

a) A compound of item 12 or

b) Compounds of formulae V and VI as defined in any one of claims 17 to 21.

30. A method for detecting the presence of monoamine oxidase in a patient, in particular for imaging a disease of the central nervous system in a patient, comprising:

introducing a detectable amount of the compound of item 13 or the composition of item 23 into the patient,

31. A method of treating a central nervous system disorder comprising the step of introducing into a patient a suitable amount of a compound according to any one of items 1 to 14, preferably a compound according to item 13 or 14.

Drawings

FIG. 1: used on human brain slices of four brains from a patient diagnosed with Alzheimer's disease¹⁸F](A) autoradiographic signals after exposure to PhosphorImager plate Note that the dark spots in the tissue sections correspond to regions with β amyloid plaques (see example in FIG. 3.) the (B) and (C) signals can be blocked by selegiline and pargyline, respectively, indicating that¹⁸F]Specificity of compound 13 for MAOB.

FIG. 2: used on human brain slices of four brains from a patient diagnosed with Alzheimer's disease¹⁸F](A) autoradiographic signals after exposure to PhosphorImager plate Note that the dark spots in the tissue sections correspond to regions with β amyloid plaques (see example in FIG. 3.) the (B) signal can be completely blocked by selegiline, but not by clogiline as seen in (C), indicating that¹⁸F]Specificity of compound 13 for MAOB.

FIG. 3: tissue samples from three brains of a patient suffering from Alzheimer's disease, which are treated for¹⁸F]Compound 13 autoradiography, then bound to amyloid detection substance BAY949172 (A) and (B) labeled squares in brain sections are shown at higher magnification in (a), (B) illustrate the potential β amyloidosis (C) two squares, (a) and (B), labeled in brain sections and shown at higher magnification in (a ') and (B') (C) and (d) indicate β amyloidosis in regions indicated at higher magnificationLoad (load). Squares (b) have no specific signal in autoradiography nor show BAY949172 binding (d).

FIG. 4: the correspondence of autoradiographic signals to reactive astrocytes was demonstrated. (A) On a section of the brain from a patient with AD, display [2 ]¹⁸F]Compound 13 binds. (B) The squares marked in a are displayed at a higher magnification. The GFAP immunoreactivity within this region, which indicates reactive astrocytes, is shown in (C).

FIG. 5: detected by a gamma detector¹⁸F]Brain and blood distribution of compound 13 is shown in a4 hour time frame.

FIG. 6: shows that the value is within 120min¹¹C]Time activity curves of selegiline (C-11 labeled Compound 3) in cynomolgus monkey brain, expressed as standard absorption values (SUV%).

FIG. 7: shows that the value is within 120min¹⁸F]Time activity curve of compound 13 in cynomolgus monkey brain, expressed as standard absorption value (SUV%).

FIG. 8: term [2 ]¹¹C]Selegiline (C-11 labeled Compound 3) is metabolized in vivo in cynomolgus monkeys. Display parent compound [ alpha ], [ alpha¹¹C]Selegiline (C-11 labeled Compound 3) and metabolites a and b.

FIG. 9: term [2 ]¹⁸F]Compound 13 is metabolized in vivo in cynomolgus monkeys. The parent compound (C-11 labeled Compound 3) is shown along with metabolites a and b.

FIG. 10: injection (A)¹¹C]Selegiline (C-11 labeled Compound 3) and (B)¹⁸F]After compound 13, three planes (cross-section, coronal and sagittal) of the brain of the same cynomolgus monkey were imaged. (C) (a), [2 ]¹¹C]Selegiline (C-11 labeled Compound 3) and (b)¹⁸F]Time activity profile of compound 13 in the striatum and cerebellum of monkey brain.

FIG. 11 radiochromatograms of crude product (compounds 13 and 39 from 42 and 43) on ACE5-C18-HL250mm × 10mm column, Advancedchromtography technologies; cat No.: ACE 321-2510; isocratic, 35% acetonitrile in 0.1% trifluoroacetic acid, flow rate: 4 ml/min; t is t_R＝17.5min。

FIG. 12: analytical chromatogram of Compound 13 on reverse phase HPLC, on a μ -Bondapakc-18column (300X3.9mm, 10 μm; Watersignstrents), MeCN-H₃PO₄(0.01M) (15: 85v/v) was used as the elution solvent, flow rate 2mL/min the eluate was monitored by UV absorption detector (. lamda. 214nm) in series with radioactivity detector (β -flow; Beckman, Fullerton, Calif.).

FIG. 13: analytical chromatogram of Compound 8 on reverse phase HPLC, on a μ -Bondapakc-18column (300X3.9mm, 10 μm; Watersignstrents), MeCN-H₃PO₄(0.01M) (15: 85v/v) was used as the elution solvent, flow rate 2mL/min the eluate was monitored by UV absorption detector (. lamda. 214nm) in series with radioactivity detector (β -flow; Beckman, Fullerton, Calif.).

FIG. 14: analytical chromatogram of Compound 40 on reverse phase HPLC, on a μ -Bondapakc-18column (300X3.9mm, 10 μm; Watersignstrents), MeCN-H₃PO₄(0.01M) (15: 85v/v) was used as the elution solvent, flow rate 2mL/min the eluate was monitored by UV absorption detector (. lamda. 214nm) in series with radioactivity detector (β -flow; Beckman, Fullerton, Calif.).

FIG. 15: TLC analysis of the fluorination reactions of compounds 12 and 41 from compound 10 (silica gel, latent phosphomolybdic acid bath (divanbath); ethyl acetate: hexane: 1: 2). (a) The method comprises the following steps Starting material (10) of the reaction (with impurities ("circled")). (b) The method comprises the following steps Column fractions containing predominantly compound 41. (c) The method comprises the following steps Column fractions containing compounds 12 and 41. (d) The method comprises the following steps Column fractions containing predominantly compound 12. (e) The method comprises the following steps Column fractions containing compounds 12 and 41.

Experiment:

the general method comprises the following steps:

a: fluorination with non-radioactive [ F-19] fluorides

To a solution of 0.25mmol of the starting material in 0.5ml of acetonitrile were added 16mg (0.27mmol) of potassium fluoride and 104mg (1.1eq.) of kryptofix. The reaction mixture was heated by microwave (130 ℃, 15min) and cooled to room temperature. The reaction mixture was diluted with 10ml of diethyl ether and 10ml of water. The organic phase was separated. The aqueous phase is extracted 3 times with 10ml of diethyl ether. The combined organic phases were washed with brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

B: fluorination with radioactive [ F-18] fluorides

To a Wheaton vial (5ml) containing 2.5mg of kryptofix (2.2.2 cryptand) and 0.5mg of potassium carbonate in 0.75ml of acetonitrile was added fluorine-containing water (0.5-2.5GBq, 200-. The solvent was removed by heating at 120 ℃ for 10 minutes under a stream of nitrogen. Anhydrous MeCN (1ml) was added and then evaporated as before. This step is repeated again. A solution of the starting material (2mg) in 0.70ml of anhydrous MeCN was added. Heating at 110 deg.C for 30 min. The crude reaction mixture was analyzed using analytical HPLC: ACE3-C1850mm × 4,6 mm; solvent gradient: start switch from 5% aqueous acetonitrile to 95% aqueous acetonitrile over 7min, flow rate: 2 ml/min. The expected F-18 labeled product was confirmed on analytical HPLC by co-injection with the corresponding non-radioactive F-19 fluorine standard (standard). The crude product was purified by preparative HPLC column (50-400 MBq): the desired product (15-200MBq) was obtained and confirmed again on analytical HPLC by co-injection with non-radioactive F-19 fluorine standards.

C: fluorination with [ F-18] fluorides

Angle [ alpha ], [ beta¹⁸F]Fluoride in Fulong¹⁸O]The solution in water was quickly passed through a Sep-PakQMA cartridge (lightcartridge) (with K)₂CO₃[0.5M，10mL]18M. OMEGA H2O, 15mL pretreatment) to isolate [2 ], [2 ]¹⁸F]Fluoride, then with K₂CO₃A solution of (7. mu. mol), Kryptofix2.2.2 (130. mu. mol) in water (18 M.OMEGA., 43. mu.L) and acetonitrile (2mL) was eluted from the column. The solvent was evaporated at 160 ℃ under a continuous nitrogen flow, leaving a yellow residue¹⁸F]F^-/K₂CO₃/K_2.2.2. The residue was then cooled to 25 ℃ and a solution of the precursor (. about.0.01 mmol,. about.2 mg) in DMSO (600. mu.L) was added. The closed reaction vessel was heated at 120 ℃ for 20min and then cooled to room temperature. The reaction mixture was diluted conventionally with water to a total volume of 5mL and then purified by HPLC.

For example, F-18 labeled compounds 13, 39, 8 and 40 were also purified by reverse phase HPLC on a μ -Bondapakc-18column (300X7.8mm, 10 μm; Watersignmatters), MeCN-H₃PO₄(0.01M) (15: 85v/v) was used as the elution solvent at a flow rate of 4mL/min (compare FIGS. 11, 12, 13 and 14). The eluate was monitored by a UV absorption detector (λ 214nm) in series with a GM tube radioactivity detector. Fractions of the desired compound were collected and then evaporated to dryness. The residue was dissolved in sterile disodium phosphate buffer solution (PBS; pH 7.4; 10mL) and filtered through a sterile filter (0.22 μm; Millipore, Bedford, MA) to give [ alpha ], [ beta¹⁸F]Sterile, pyrogenic (pyrogenic) solutions of radioligand. The radiochemical purity of each radioligand, MeCN-H, was analyzed by reverse phase HPLC on a μ -BondaPak C-18column (300X3.9mm, 10 μm; Watersinums)₃PO₄(0.01M) (15: 85v/v) was used as the elution solvent, flow rate 2 mL/min. the eluate was monitored by UV absorption detector (. lamda. times.214 nm) in series with a radioactivity detector (β -flow; Beckman, Fullerton, Calif.) the radiochemical purity of all three compounds was > 99%, or, the collected HPLC fractions were diluted with 40mL water and then fixed on a Sep-Pakplus C18 column (Waters) and the column was washed with 5mL water and eluted with 1mL ethanol, releasing the product, which also was > 99% radiochemical purity.

Stability and radiochemical yield were analyzed by HPLC and TLC on silica gel. TLC plates were scanned with AR-2000imagingScanner and analyzed with Winscann 2.2 software. The incorporation (incorporation) yield of the fluorination reaction was 40% to 70%. The radiochemical purity of all three radioligands was greater than 99%. During the experiment, the radioligand was found to be stable in PBS buffer. Radiochemical purity > 99% by HPLC and TLC at 3 hours after formulation in PBS. Alternatively, also by preparative HPLC columns andmethod (see FIG. 11) for separating compounds 13 and 39 ACE5-C18-HL250mm × 10mm, advanced Chromotography technologies, Cat. No. ACE321-2510, isocratic 35% acetonitrile in 0.1% trifluoroacetic acid at a flow rate of 4ml/min, t_R17.5 min. The collected HPLC fractions were diluted with 40ml of water and then immobilized on a Sep-PakPlusC18 column (Waters), which was then washed with 5ml of water and eluted with 1ml of ethanol, releasing Compound 13 with radiochemical purity > 99%. The desired product 13 was characterized on analytical HPLC by co-injection with a non-radioactive F-19 fluorine standard 12.

D: alkylation of NH-carbamates with [ F-18] labelled prosthetic groups

To a suspension of 1ml of anhydrous Tetrahydrofuran (THF) and 7.7mmol of sodium hydride washed with hexane, a solution of 7mmol of the starting material in 1ml of THF was added dropwise. The reaction mixture was stirred for 20 min. A tetrahydrofuran solution of the prepared [ F-18] fluoroalkyl bromide (100-. The reaction was heated to 50 ℃ and held for 20 min. The vigorous reaction mixture was cooled to room temperature. The crude reaction mixture was analyzed using analytical HPLC. The desired F-18 labeled product was confirmed by co-injection with a non-radioactive F-19 fluorine standard on analytical HPLC.

E: fluorination with [ F-18] fluoride using tetrabutylammonium hydroxide and subsequent deprotection

See also: med. chem.2007, 50, 1028-1040.

Will 2¹⁸F]Fluoride was transferred to a Vacutainer that had been previously treated with tetrabutylammonium hydroxide (2 microliters). By azeotropic distillation with acetonitrile (0.75mL, 3 times), N₂And heat ((refer to Nucl. Med. biol.2003, 30, 397-)) to remove¹⁸O]H₂And O. The precursor (3.0. mu. mol) was added to the vessel and dissolved in DMSO (400. mu.l). The resulting mixture was heated by microwave radiation (20sec, 3 times). Passing the crude mixture through a reactor having CH₃CN (3mL) in a silica pipet column (50mg) and then the volatile organics were removed under reduced pressure. Comprises¹⁸F]Vials of crude mixtures of productsIs dissolved in CH₃CN (500microL) and treated with 4N sulfuric acid (0.5 ml.) the resulting mixture is heated by microwave radiation (20sec, 3 times.) the desired product is isolated by preparative HPLC columns and methods ACE5-C18-HL250mm × 10mm, advanced dChromatographic technologies; Cat. No. ACE 321-2510; isocratic, 35% acetonitrile in 0.1% trifluoroacetic acid at a flow rate of 4 ml/min.) the collected HPLC fractions are diluted with 40ml water and then fixed on a Sep-PakPlus C18 column (Waters) and the column is then washed with 5ml water and eluted with 1ml ethanol releasing compound 13 with radiochemical purity > 99%. on analytical HPLC, the desired product 13 is characterized by co-injection with non-radioactive F-19 fluorine standard 12.

F: alkylated NH-carbamates

To a stirred suspension of 20ml of anhydrous DMF and 11mmol of sodium hydride washed with hexane, a solution of 10mmol of the starting material in 5ml of DMF is added dropwise at 0 ℃. The reaction mixture was stirred for 20 min. 15mmol of alkylating agent diluted in 5ml of tetrahydrofuran are added dropwise to the stirred suspension. The reaction mixture was stirred for 16-10 hours. The reaction mixture was poured into a vigorously stirred mixture of ice-water and diethyl ether. The organic phase was separated. The aqueous phase is extracted 3 times with 30ml of diethyl ether. The combined organic phases were washed with brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

G: alkylation of NH-amines with [ F-18] labelled prosthetic groups

To a solution of 2mg of secondary amine (starting material) and 3mg of potassium carbonate in 0,7ml of dimethylformamide was added a solution of the [ F-18] fluoro-alkylating agent (about 200-1000MBq) prepared according to the literature protocol in dimethylformamide. The reaction mixture was heated to 110 ℃ and held for 20 min. The reaction mixture was cooled to room temperature. The desired F-18 labeled product was confirmed by co-injection with a non-radioactive F-19 fluorine standard on analytical HPLC. The crude product (about 50-400MBq) was purified by preparative HPLC column. The desired product (about 15-200MBq) was obtained and confirmed again on analytical HPLC by co-injection with non-radioactive F-19 fluorine standards.

H: alkylated NH-amines (secondary amines) or phenols

To a stirred solution of 2mmol of starting material and 0.415g (3mmol) of potassium carbonate in 6ml of dimethylformamide was added 2.5mmol of alkylating agent. The reaction mixture was heated to 110 ℃ by microwave and held for 15 min. The solvent in the reaction mixture was evaporated. Water (8ml) and diethyl ether or a dichloromethane/isopropanol mixture (1: 10-8ml) were added. The organic phase was separated. The aqueous phase is extracted 3 times with 30ml of diethyl ether. The combined organic phases were washed with water (about 5ml, twice), brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

I: conversion of alcohol to the corresponding O-sulfonate (mode 1)

To a solution of 0.5mmol of starting material and 0.103g (0.8mmol) of diisopropylethylamine in 1.5ml of dichloromethane is added dropwise a solution of methanesulfonyl chloride or methanesulfonic anhydride in 0.1ml of dichloromethane at-10 ℃. The stirred reaction mixture was warmed to room temperature over 4, 5h and diluted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, water and brine. The organic phase was dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate-hexane gradient).

K: conversion of alcohol to the corresponding 0-sulfonate (mode 2)

A solution of 3mmol of starting material in 5ml of dichloromethane and 5ml of pyridine is added dropwise (3.3mmol) at-10 ℃ to a solution of arylsulfonyl chloride in 3ml of dichloromethane. The stirred reaction mixture was warmed to room temperature over 4, 5h and diluted with dichloromethane. The organic phase was washed with 0.5N sulfuric acid (three times), saturated sodium bicarbonate solution, water and brine. The organic phase was dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate-hexane gradient).

M: deprotection of acid labile protecting groups (scheme 1)

A solution of 5mmol of starting material in an aqueous trifluoroacetic acid-dichloromethane mixture (1: 1) is stirred for 4 to 7 hours. The reaction mixture was evaporated. The residue was dissolved in dichloromethane and the solution was evaporated again. The last step was repeated three times. The residue was purified by column chromatography (dichloromethane-pentane gradient, amino phase).

N: deprotection of acid labile protecting groups (scheme 2)

(according to J.Am.chem.Soc., 6644, 92, (1970))

To a stirred solution of 0.5mmol of starting material in 1ml of ethanol at 0 deg.C was added 1ml of 3N aqueous hydrochloric acid. The solution was stirred at room temperature for 16 h. The reaction was treated with aqueous NaOH (4N) until pH 9.5. The ethanol was evaporated. Water (10ml) and dichloromethane-isopropanol (10 ml; 1: 10) were added. The organic phase was separated. The aqueous phase was extracted 3 times with 10ml dichloromethane-isopropanol (10: 1). The combined organic phases were washed with brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ether-pentane gradient, or by preparative HPLC.

P: reduction of acids to alcohols by mixed anhydride processes

According to journal of medicinal chemistry, 2006, vol.49, No.15, p.4544, compound 94.

To a stirred solution of 11mmol of carboxylic acid (starting material) and triethylamine (1.9mL, 14mmol) in THF (300mL) at-5 deg.C was added ethyl chloroformate (13mL, 14 mmol). The mixture was stirred for 20 minutes, then sodium borohydride (1.72g, 44mmol) and methanol (32mL) were added successively. The mixture was stirred at-5 ℃ for 30 minutes, then saturated NH was added₄Cl solution to stop the reaction. The mixture was extracted with Et2O (ca 50ml), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography (hexane/AcOEt 1/1) of the residue afforded the desired product.

Q: reduction of oxazolidinones to N-methyl aminoalcohols

To a stirred solution of 5mmol of starting material (oxazolidinone) in 10ml THF at 0 deg.C was added 10mmol lithium aluminum hydride. The reaction suspension was stirred at room temperature for 4 h. The vigorously stirred reaction mixture was treated dropwise with 10ml of 1mNaOH (water) solution. The reaction mixture was stirred for 30min and then filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (ethyl acetate/hexane gradient).

S: reduction of esters to alcohols

To a solution of 15mmol (555mg) NaBH4 in 15ml water/THF (1: 1) was added dropwise 10mmol of the ester (starting material) dissolved in 20ml THF. The reaction mixture was stirred for 4 hours. The reaction mixture was poured into a stirred ice-cold mixture of water and diethyl ether (200ml, 1: 1). The organic phase was separated. The aqueous phase is extracted 3 times with 10ml of diethyl ether. The combined organic phases were washed with brine and then dried over magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography with an ethyl acetate-hexane gradient.

T: conversion of alcohols to the corresponding triflates

According to chem.eur.j. (2007), 13, 115-:

pyridine (0.25ml, 3.13mmol) and Tf₂O (0.32ml, 1.88mmol) was added to CH of the starting material (1.34mmol) continuously at-20 deg.C₂Cl₂(50mL) and the resulting mixture was stirred at this temperature for 1 h. Transferring the pink solution to a container containing KHSO₄Aqueous solution (30mL, 10%) and ice in a separatory funnel. By CH₂Cl₂Extracting the aqueous layer with Na₂SO₄The combined organic layers were dried and then the solvent was carefully evaporated while keeping the temperature at 0 ℃. The desired product was filtered through a silica bed using ethyl acetate hexane solvent mixture.

U: reduction of mesylate to alkane

Like org.lett.; 2004; 6(24) pp 4439-4442:

lithium aluminum hydride (65mg) was added to a solution of the starting material (0.5mmol) in dehydrated ether (20mL) at 0 ℃ and stirred at the same temperature for 24 hours. 0.263ml of 2M NaOH solution was added at-10 ℃ and then the reaction mixture was stirred at room temperature for 30min and then filtered. The filtrate was concentrated and the residue was used without further purification.

V: fluorinated secondary alcohols (DBU/NfF):

according to tetrahedron letters, Vol.36, No.15, pp.2611-2614, 1995:

to a cooled solution of secondary alcohol (2.5mmol) and DBU (1.12mL, 7.5mmol) in toluene (20mmol) at 0 deg.C under stirring C was added₄F₉SO₂F (perfluorobutanesulfonyl fluoride) (1.13g, 3.75 mmol). After 1h at 0 ℃ the reaction mixture was evaporated in vacuo and the residue was chromatographed on a silica gel column with a hexane/ethyl acetate gradient.

For the following examples, at 400MHz, 600 MHz: (¹H) 100MHz and 151 MHz: (¹³C) The NMR spectrum was recorded on an NMR meter.¹HNMR with CDCl₃(¹H7.26) as an internal standard,¹³CNMR with CDCl₃(¹³C77.20) as internal standard. Liquid Chromatography (LC) was performed using a Merck-Hitachi gradient pump and a Merck-Hitachi, L-4000 variable wavelength UV detector. mu-Bondapak C-18column (300X7.8mm, 10 μm; waters instruments) was used at a flow rate of 2 ml/min. LC-MS was performed using a WatersQuattra-TofPremiermax, tandem WatersAcquisyUPLC instrument. The ionization mode used was electrospray positive ion ionization (ESI +). Analytical TLC was performed on 0.25 silica gel plates.

All solvents and chemicals were obtained from commercial sources and were used without further purification.

Example 1

a) Synthesis of tert-butyl ((S) -1-hydroxymethyl-2-phenylethyl) methylcarbamate (1a)

Reduction of (S) -2- (tert-butoxycarbonylmethylamino) -3-phenylpropionic acid (Fluka) according to general procedure P gave compound 1a in 80% yield (8.8mmol, 2.34 g).

MS-ESI：266(M⁺+1，100)。

Elemental analysis:

theoretical value: c67.90% H8.74% N5.28%

Measurement values: c67.87% H8.72% N5.27%

b) Synthesis of (S) -2-methylamino-3-phenylpropan-1-ol (1b)

Deprotection of compound 1a according to general procedure M gave compound 1b in 77% yield (630mg, 3.8 mmol).

MS-ESI：166(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.69% H9.15% N8.48%

Measurement values: c72.66% H9.13% N8.47%

c) Synthesis of (S) -2- (methylprop-2-ynylamino) -3-phenylprop-1-ol (1c)

Compound 1c was synthesized according to general procedure H from starting material 1b using 2.5mmol of propargyl bromide (298 mg). The expected compound is obtained in 60% yield (243mg, 1.2 mmol).

MS-ESI：204(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.81% H8.43% N6.89%

Measurement values: c76.77% H8.42% N6.88%

d) Synthesis of (S) -2- (methylpropan-2-ynylamino) -3-phenylpropyl methanesulfonate (1d)

Compound 1d was synthesized by general procedure I from starting material 1c in 91% yield (126mg, 0.45 mmol).

MS-ESI：282(M⁺+1，100)。

Elemental analysis:

theoretical value: c59.76% H6.81% N4.98%

Measurement values: c59.78% H6.82% N4.99%

e) Synthesis of ((S) -1-fluoromethyl-2-phenylethyl) methylpropan-2-ynylamine (1e)

Compound 1e was synthesized by general procedure a from starting material 1d in 48% yield (24mg, 0.12 mmol).

MS-ESI：206(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.07% H7.86% N6.82%

Measurement values: c76.04% H7.85% N6.83%

f) Synthesis of ((S) -, [2 ]¹⁸F]1-fluoromethyl-2-phenylethyl) methylpropan-2-ynylamine (1e)

Compound 1f was prepared from compound 1e by general method B. The desired 254MBq product 1e (decay corrected) was obtained from 1.12GBqF-18 fluoride.

g) Synthesis of (2S) -2- (methylamino) -3-phenylpropan-1-ol (1b)

To a solution of N-methyl-L-phenylalanine (Sigma, 10g, 55.8mmol) in anhydrous THF (600mL) at-5 deg.C was added 3.18g (83.7mmol) of lithium aluminum hydride. The reaction mixture was stirred overnight and then cooled to-5 ℃. An additional 2.12g (55.8mmol) of lithium aluminum hydride was added. The reaction mixture was refluxed overnight and then cooled to-5 ℃. To the mixture was added dropwise 21.5ml of NaOH solution (2N) and stirred at room temperature for another 30 min. The mixture was filtered and the filter cake was washed with diethyl ether (50 mL). Filtrate is MgSO 2₄Drying and removal of the solvent under reduced pressure gave product 1b as a pale yellow solid.

MS-ESI：204(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.69% H9.15% N8.48%

Measurement values: c72.65% H9.13% N8.45%

h) Synthesis of a mixture of N- [ (2S) -1-chloro-3-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine (1h) and N- (2-chloro-3-phenylpropyl) -N-methylprop-2-yn-1-amine (1i)

A solution of 1c (100mg, 0.49mmol) and triethylamine (1.0mmol) in THF (2ml) was stirred at room temperature for 30 min. Methanesulfonyl chloride (0.60mmol) was added dropwise to the stirred mixture at-7 ℃ and then the reaction mixture was stirred at room temperature for another 30 min. Adding saturated Na₂CO₃The solution (1mL) was stirred for an additional 30 min. The organic layer was partitioned between CH2Cl2(15ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed over MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 3: 1) and then analyzed by NMR, HPLC and LC-MS. The final product was obtained as a mixture of 1h and 1 i.

1h：

¹HNMR (600MHz, chloroform-d) ppm2.21(t, J ═ 2.38Hz, 1H)2.38(s, 3H)2.73(d, J ═ 6.97Hz, 2H)2.95(dd, J ═ 14.31, 8.07Hz, 1H)3.23(dd, J ═ 14.31, 4.77Hz, 1H)3.43(dd, J ═ 10.45, 2.38Hz, 2H)4.10-4.18(m, 1H)7.28-7.35(m, 5H)

¹³CNMR (151MHz, chloroform-d) ppm34.77(1C)38.29(1C)43.58(1C)44.24(s, 1C)64.28(1C)7337(1C)79.24(1C)126.38(1C)128.54(1C)129.24(1C)138.86(1C)

1i

¹³CNMR (151MHz, chloroform-d) ppm42.08(1C)42.33(1C)45.94(1C)60.43(1C)61.52(1C)73.49(1C)77.98(1C)126.76(1C)128.33(1C)129.50(1C)138.94(1C)

i) Synthesis of N- [ (2S) -1-fluoro-3-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine (1e) and N- (2-fluoro-3-phenylpropyl) -N-methylprop-2-yn-1-amine (1k)

DAST (2.0mmol) was added dropwise to a stirred solution of 1c (300mg, 1.48mmol) in dichloromethane (5mL) at-5 deg.C and the reaction mixture was stirred at the same temperature for an additional 20 min. Saturated sodium carbonate solution (4.0mL) was added to terminate the untreated DAST. The organic layer was partitioned between CH2Cl2(25ml) and water (15 ml). The organic phase was separated, washed with brine (10ml) and MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/ether 3: 1) to give 1e and 1k as isolated products (control TLC: FIG. 15).

1e：

¹HNMR (600MHz, chloroform-d) ppm2.27(t, 1H)2.52(s, 3H)2.74(dd, J ═ 13.39, 10.09Hz, 1H)2.97-3.03(m, 1H)3.03-3.14(m, 1H)3.53(t, J ═ 2.75Hz, 2H)4.38(ddd, J ═ 47.32, 10.09, 4.95Hz, 1H)4.51(ddd, J ═ 48.05, 10.27, 2.57Hz, 1H).

¹³CNMR (151MHz, chloroform-d) ppm32.91(d, J ═ 6.13Hz, 1C)38.20(d, J ═ 1.67Hz, 1C)43.94(d, J ═ 2.23Hz, 1C)63.83(d, J ═ 17.54Hz, 1C)72.83(1C)80.15(s, 1C)82.27(d, J ═ 172.08Hz, 1C)126.31(1C)128.51(1C)129.24(1C)139.01(1C).

1k：

¹HNMR (600MHz, chloroform-d) ppm2.21(t, J ═ 2.38Hz, 1H)2.37(s, 3H)2.59-2.72(m, 2H)2.90-3.01(m, 2H)3.41(dd, J ═ 4.95, 2.38Hz, 2H)4.75-4.89(m, 1H)7.20-7.32(m, 5H).

³CNMR (151MHz, chloroform-d) ppm39.66(d, J-21.44 Hz, 1C)42.40(d, J-1.39 Hz, 1C)46.30(d, J-1.67 Hz, 1C)58.53(d, J-20.88 Hz, 1C)73.37(s, 1C)78.22(s, 1C)92.84(d, J-173.19 Hz, 1C)126.63(1C)128.45(1C)129.37(1C)136.85(d, J-4.46 Hz, 1C).

j) Synthesis of N- [ (2S) -1-, (¹⁸F) Fluoro-3-phenylprop-2-yl]-N-methylpropan-2-yn-1-amine (1f) and N- [2-, (¹⁸F) Fluoro-3-phenylpropyl]-N-methylpropan-2-yn-1-amine(1m)

Crude products 1f and 1m were obtained according to general procedure C. The products 1f and 1m were isolated according to general procedure C and studied separately after HPLC separation (control HPLC chromatograms fig. 11 and fig. 12).

Example 2

a) Synthesis of (4R, 5S) -4-methyl-5-phenyl-3-prop-2-ynyloxazolidin-2-one (2a)

Compound 2a was synthesized according to general method F from (4R, 5S) - (+) -4-methyl-5-phenyl-2-oxazolidinone (Aldrich) using 15mmol (1.79g) of propargyl bromide (Aldrich). Compound 2a was obtained in 76% yield (7.6mmol, 1.61 g).

MS-ESI：216(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.54% H6.09% N6.51%

Measurement values: c72.52% H6.11% N6.52%

b) Synthesis of (1S, 2R) -2- (methylprop-2-ynylamino) -1-phenylprop-1-ol (2b)

Compound 2b was synthesized by general method Q from starting material 2a in 89% yield (0.91g, 0.45 mmol).

MS-ESI：204(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.81% H8.43% N6.89%

Measurement values: c76.82% H8.41% N6.88%

c) Synthesis of (1S, 2R) -2- (methylpropan-2-ynylamino) -1-phenylpropyl methanesulfonate (2c)

Compound 2c was synthesized by general method T from starting material 2b in 78% yield (352mg, 1.05 mmol).

MS-ESI：336(M⁺+1，100)。

Elemental analysis:

theoretical value: c50.14% H4.81% N4.18%

Measurement values: c50.17% H4.82% N4.16%

d) Synthesis of ((1R, 2R) -, (1R, 2R) -, (2R) -, (2R) -, (2R) -, (2R) -¹⁸F]-2-fluoro-1-methyl-2-phenylethyl) methylpropan-2-ynylamine (2d)

Compound 2d was prepared from compound 2c by general method B. The desired 198MBq product 2d (decay corrected) was obtained from 1.09GBqF-18 fluoride.

e) Synthesis of ((1R, 2R) -2-fluoro-1-methyl-2-phenylethyl) methylpropan-2-ynylamine (2e)

Compound 2e was synthesized by general method V from starting material 2b in 58% yield (297mg, 1.45 mmol).

MS-ESI：206(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.07% H7.86% N6.82%

Measurement values: c76.04% H7.84% N6.83%

f) Synthesis of N- [ (1R, 2R) -1-chloro-1-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine (2f)

A solution of 2b (120mg, 0.54mmol) and triethylamine (1.0mmol) in THF (2ml) was stirred at room temperature for 30 min. Methanesulfonyl chloride (0.60mmol) was added dropwise to the stirred mixture at-7 ℃ and then the reaction mixture was stirred at room temperature for another 30 min. Adding saturated Na₂CO₃The solution (1mL) was stirred for an additional 30 min. Placing the organic layer in CH₂Cl₂(15ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed over MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 3: 1).

MS-ESI：221(M⁺35Cl+1，82)。

Elemental analysis:

theoretical value: c70.42% H7.27% Cl15.99% N6.32%

Measurement values: c70.38% H7.25% Cl15.97% N6.30%

g synthesizing N- [ (1S, 2R) -1-, (¹⁸F) Fluoro-1-phenylprop-2-yl]-N-methylpropan-2-yn-1-amine (2g)

The desired product (2g) was obtained from 2f according to general procedure C.

Example 3

a) Synthesis of 4-furan-2-ylmethyl-3-prop-2-ynyloxazolidin-2-one (3a)

Compound 3a was synthesized according to general procedure F (4mmol scale) from starting material 4-furan-2-ylmethyloxazolin-2-one (j.am.chem.soc.; 125; 42; 2003; 12694-. Using 6mmol of propargyl bromide as alkylating agent gave the desired compound 3a in 60% yield (2.4 mmol).

MS-ESI：205(M⁺+1，100)。

Elemental analysis:

theoretical value: c64.38% H5.40% N6.83%

Measurement values: c64.41% H5.41% N6.82%

b) Synthesis of 3-furan-2-yl-2- (methylpropan-2-ynylamino) propan-1-ol (3b)

Compound 3b was synthesized by general procedure Q (half scale) from starting material 3a in 70% yield (338mg, 1.75 mmol).

MS-ESI：194(M⁺+1，100)。

Elemental analysis:

theoretical value: c68.37% H7.82% N7.25%

Measurement values: c68.37% H7.81% N7.26%

c) Methanesulfonic acid 3-furan-2-yl-2- (methylpropan-2-ynylamino) propyl ester (3c)

Compound 3c was synthesized by general procedure I, starting from material 3b, in 88% yield (120mg, 0.44 mmol).

MS-ESI：272(M⁺+1，100)。

Elemental analysis:

theoretical value: c53.12% H6.32% N5.16%

Measurement values: c53.15% H6.34% N5.18%

d) Synthesis of 1-fluoromethyl-2-furan-2-ylethyl) methylpropan-2-ynylamine (3d)

Compound 3d was synthesized by general procedure a from starting material 3c in 61% yield (29.9mg, 0.153 mmol).

MS-ESI：196(M⁺+1，100)。

Elemental analysis:

theoretical value: c67.67% H7.23% N7.17%

Measurement values: c67.67% H7.23% N7.18%

e) Synthesis of (1-fluoromethyl-2-furan-2-ylethyl) methylpropan-2-ynylamine (3e)

Compound 3e was synthesized by general method A from starting material 3c using F-18 fluoride 0.96 GBq. The desired compound (124MBq) was obtained.

Example 4

a) Synthesis of (S) -4-benzyl-3-prop-2-ynyloxazolidin-2-one (4a)

Compound 4a was synthesized by general method F from starting (S) -4-benzyloxazolidin-2-one (Aldrich) in 72% yield (1.58g, 7.2 mmol).

MS-ESI：216(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.54% H6.09% N6.51%

Measurement values: c72.51% H6.08% N6.53%

b) (S) -2- (methylprop-2-ynylamino) -3-phenylprop-1-ol (4b)

Compound 4b was synthesized from 4a by general method Q in 68% yield (690mg, 3.4 mmol).

MS-ESI：204(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.81% H8.43% N6.89%

Measurement values: c76.78% H8.41% N6.90%

c) 4-Bromobenzenesulfonic acid (S) -2- (methylpropan-2-ynylamino) -3-phenylpropyl ester (4c)

Compound 4c was synthesized from 4b p-bromobenzenesulfonyl chloride by general method K in 47% yield (1.58g (690mg, 1.41 mmol).

MS-ESI：424(M^{+ bromine isotope}80+1，76)。

Elemental analysis: c54.03% H4.77% N3.32%

Measurement values: c54.03% H4.77% N3.32%

Example 5

a) Synthesis of (S) -4- [4- (2-methoxymethoxyethoxy) benzyl ] oxazolidin-2-one (5a)

Compound 5a was synthesized by general method H from (S) - (-) -4- (4-hydroxybenzyl) -2-oxazolidinone (Tetrahedron; EN; 57; 39; 2001; 8313-propanoic 8322) and 2-bromoethylmethoxymethyl ether (Aldrich) on a 10-fold scale in 77% yield (15.4mmol, 4.33 g).

MS-ESI：282(M⁺+1，100)。

Elemental analysis:

theoretical value: c59.78% H6.81% N4.98%

Measurement values: c59.81% H6.83% N4.97%

b) Synthesis of (S) -4- [4- (2-methoxymethoxyethoxy) benzyl ] -3-prop-2-ynyloxazolidin-2-one (5b)

Compound 5b was synthesized by general method F from compound 5a in 65% yield (6.5mmol, 2.07 g).

MS-ESI：320(M⁺+1，100)。

Elemental analysis:

theoretical value: c63.94% H6.63% N4.39%

Measurement values: c63.92% H6.64% N4.40%

c) Synthesis of (S) -3- [4- (2-methoxymethoxyethoxy) phenyl ] -2- (methylpropan-2-ynylamino) propan-1-ol (5c)

Compound 5c was synthesized by general method Q from compound 5b in 74% yield (3.7mmol, 1.14 g).

MS-ESI：308(M⁺+1，100)。

Elemental analysis:

theoretical value: c66.43% H8.20% N4.56%

Measurement values: c66.46% H8.21% N4.55%

d) Synthesis of { (R) -2- [4- (2-methoxymethoxyethoxy) phenyl ] -1-methylethyl } methylpropan-2-ynylamine (5d)

Compound 5d was synthesized from compound 5c by general methods I (on a 5-fold scale) and U, in 81% yield after two steps (2.02mmol, 589 mg).

MS-ESI：292(M⁺+1，100)。

Elemental analysis:

theoretical value: c70.07% H8.65% N4.81%

Measurement values: c70.11% H8.63% N4.82%

e) Synthesis of 2- {4- [ (R) -2- (methylprop-2-ynylamino) propyl ] phenoxy } ethanol (5e)

Compound 5e was synthesized by general method N (on a 4-fold scale) from compound 5d in 88% yield (1.76mmol, 436 mg).

MS-ESI：248(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.84% H8.56% N5.66%

Measurement values: c72.81% H8.55% N5.67%

f) Methanesulfonic acid 2- {4- [ (R) -2- (methylprop-2-ynylamino) propyl ] phenoxy } ethyl ester (5f)

Compound 5f was synthesized by general procedure I, from compound 5e, in 93% yield (0.47mmol, 153 mg).

MS-ESI：326(M⁺+1，100)。

Elemental analysis:

theoretical value: c59.05% H7.12% N4.30%

Measurement values: c59.07% H7.11% N4.30%

g) Synthesis of { (R) -2- [4- (2-fluoroethoxy) phenyl ] -1-methylethyl } methylpropan-2-ynylamine (5g)

Compound 5g was synthesized by general method A from compound 5f in 61% yield (0.153mmol, 38 mg).

MS-ESI：250(M⁺+1，100)。

Elemental analysis:

theoretical value: c72.26% H8.09% N5.62%

Measurement values: c72.22% H8.07% N5.60%

h) Synthesis of [ F-18] { (R) -2- [4- (2-fluoroethoxy) phenyl ] -1-methylethyl } methylpropan-2-ynylamine (5h)

Compound 5h (210 MBq isolated from 1.41 GBq) was synthesized from compound 5f by general method B.

Example 6

a) Synthesis of ((R) -1-methyl-2-phenylethyl) prop-2-ynylamine (6a)

840mg (4mmol) ((R) -1-methyl-2-phenylethyl) prop-2-ynylammonium chloride (Sigma) are dissolved in 10ml dichloromethane and 1M aqueous sodium carbonate solution. The organic phase was separated. The aqueous phase is extracted 3 times with 10ml of dichloromethane. The combined organic phases were washed with brine and then dried over magnesium sulfate. The crude product 6a was used without further purification.

b) (2-fluoroethyl) - ((R) -1-methyl-2-phenylethyl) prop-2-ynylamine (6b)

Compound 6b was synthesized by general method H from compound 6a in 60% yield (1.2mmol, 262 mg).

MS-ESI：220(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.68% H8.27% N6.39%

Measurement values: c76.66% H8.26% N6.38%

c) [ F-18] (2-fluoroethyl) - ((R) -1-methyl-2-phenylethyl) prop-2-ynylamine (6c)

Compound 6c was synthesized by general method G from compound 6a and [ F-18] -2-fluoroethyl bromide (Bioorg.Med.chem.; 13; 20; 2005; 5779-. The desired 178MBq product 6c (decay corrected) was obtained from 1.98GBqF-18 fluoride.

d) Synthesis of 2- { [ (2R) -1-phenylprop-2-yl ] (prop-2-yn-1-yl) amino } ethanol (6d)

A mixture of desmethylselegiline (Sigma, 150mg, 0.72mmol) and NaOH (60mg, 1.5mmol) in MeCN (5ml) was stirred at room temperature for 30 min. To the stirred mixture was added 1-bromoethanol (1.0mmol) and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is in CH₂Cl₂(20ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed. With MgSO₄The organic layer was dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow liquid. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 8: 2).

MS-ESI：218(M⁺+1，100)。

Elemental analysis:

theoretical value: c77.38% H8.81% N6.45% O7.36%

Measurement values: c77.35% H8.79% N6.43% O7.35%

e) Synthesis of N- (2-chloroethyl) -N- [ (2R) -1-phenylprop-2-yl ] prop-2-yn-1-amine (6e)

A mixture of 2(150mg, 0.69mmol) and triethylamine (1.5mmol) in THF (3ml) was stirred at room temperature for 30 min. Methanesulfonyl chloride (1.4mmol) was added dropwise to the stirred mixture at-7 ℃ and then the reaction mixture was stirred at room temperature for another 30 min. Adding saturated Na₂CO₃The solution (2mL) was stirred for an additional 30 min. The organic layer was partitioned between CH2Cl2(20ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed over MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 3: 1).

MS-ESI：235(M^+Cl35，100)。

Elemental analysis:

theoretical value: c71.33% H7.70% N5.94%

Measurement values: c71.30% H7.68% N5.92%

f) Synthesis of N- (2-fluoroethyl) -N- [ (2R) -1-phenylprop-2-yl ] prop-2-yn-1-amine (6b)

To N- [ (2R) -1-phenylpropan-2-yl group]To a solution of prop-2-yne-1-ammonium chloride (Sigma100mg, 0.578mmol) in anhydrous DMF (2mL) was added sodium hydride (48.0mg, 2 mmol). The reaction mixture was stirred at room temperature for 30min, then 1-bromo-2-fluoroethane (0.85mg, 0.603mmol) was added. The reaction mixture was stirred overnight, diluted with water (10ml) and then CH₂Cl₂(3 × 15mL) extraction the organic phase was separated and washed with saturated NaHCO₃The solution (15ml) and brine (15ml) were washed over MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 80: 20) and then analyzed by NMR, HPLC and LC-MS.

MS-ESI：220(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.68% H8.27% N6.39%

Measurement values: c76.65% H8.25% N6.36%

g) Synthesis of N- [2-, (¹⁸F) Fluoroethyl group]-N- [ (2R) -1-phenylpropan-2-yl]Prop-2-yne-1-amine (6c)

The desired product 6C was obtained from 6e according to general procedure C.

Example 7

a) Synthesis of (1R, 2R) -2- [ methyl (prop-2-yn-1-yl) amino ] -1-phenylpropan-1-ol (7a)

(1R, 2R) Pseudoephedrine at room temperature150mg, 0.72mmol) and NaOH (60mg, 1.5mmol) in MeCN (5ml) for 30 min. Propargyl bromide (1.0mmol) was added to the stirred mixture and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is in CH₂Cl₂(20ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed. With MgSO₄The organic layer was dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow liquid. The crude product 7a was purified by silica gel column chromatography (hexane/diethyl ether 8: 2).

MS-ESI：204(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.81% H8.43% N6.89%

Measurement values: c76.78% H8.42% N6.88%

b) Synthesis of N- [ (1S, 2R) -1-fluoro-1-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine (7b)

DAST (1.0mmol) was added dropwise to a stirred solution of 7a (150mg, 0.74mmol) in dichloromethane (3mL) at-5 deg.C and the reaction mixture was stirred at the same temperature for an additional 20 min. Saturated sodium carbonate solution (2.0mL) was added to terminate the untreated DAST. Placing the organic layer in CH₂Cl²(15ml) and water (10 ml). The organic phase was separated, washed with brine (10ml) and MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product was purified by silica gel column chromatography (hexane/diethyl ether 4: 1).

MS-ESI：206(M⁺+1，100)。

Elemental analysis:

theoretical value: c76.07% H7.86% N6.82%

Measurement values: c76.02% H7.85% N6.81%

c) Synthesis of N- [ (1S, 2R) -1-chloro-1-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine (7c)

To a stirred solution of 7a (120mg, 0.54mmol) in THF (2ml) was added triethylamine (1.0 mmol). The mixture was stirred at room temperature for 30 min. Methanesulfonyl chloride (0.60mmol) was added dropwise to the stirred mixture at-7 ℃ and then the reaction mixture was stirred at room temperature for another 30 min. Adding saturated Na₂CO₃The solution (1mL) was stirred for an additional 30 min. Placing the organic layer in CH₂Cl₂(15ml) and water (10 ml). The organic phase is separated and washed with saturated NaHCO₃The solution (10ml) and brine (10ml) were washed over MgSO₄Dried and then filtered. The solvent was removed under reduced pressure to give the crude product as a pale yellow oil. The crude product 7c was purified by silica gel column chromatography (hexane/diethyl ether 3: 1).

MS-ESI：221(M⁺35Cl+1.70)。

Elemental analysis:

theoretical value: c70.42% H7.27% Cl15.99% N6.32%

Measurement values: c70.39% H7.25% Cl15.97% N6.30%

Example 8

a) Synthesis of (3aS, 8aR) -3, 3a, 8, 8 a-tetrahydroindeno [1, 2-d ] [1, 2, 3] oxathiazole 2, 2-dioxide (8a)

To a stirred solution of 5g (33mmol) of commercially available (1S, 2R) -1-amino-2, 3-dihydro-1H-inden-2-ol in 200ml of dichloromethane and 9, 3ml (67mmol) of triethylamine at-65 deg.C was added 3,25ml (40mmol) of sulfonyl chloride (SO)₂Cl₂) Solution in 80ml dichloromethane. The reaction mixture was stirred for 3h, slowly warmed to room temperature and stirred at this temperature for 18 h. The precipitate was filtered, and the filtrate was washed with water 3 times, then with brine, dried over magnesium sulfate, and then concentrated. The residue was diluted in a little dichloromethane and then recrystallized in hexane. The product was purified by column chromatography (EtOAc/hexane 0: 100 → 100: 0) to give 2.2g of the desired product 8 a.

MS-ESI：212(M⁺+1)

Elemental analysis:

theoretical value: c51.17% H4.29% N6.63%

Measurement values: c57.20% H4.30% N6.61%

b) Synthesis of (3aS, 8aR) -3- (prop-2-yn-1-yl) -3, 3a, 8, 8 a-tetrahydroindeno [1, 2-d ] [1, 2, 3] oxathiazole 2, 2-dioxide (8b)

To a stirred solution of 2.2g (10.4mmol)8a in 120ml dimethylformamide were added 1.35ml (22.8mmol) prop-2-yn-1-ol and 6g (22.8mmol) triphenylphosphine and 4.42ml (22.8mmol) dipropylene 2-ester (E) -diazene-1, 2-dicarboxylate. The reaction mixture was stirred for 2h, then concentrated. The residue was purified by two successive column chromatographies (EtOAc/hexane 1: 20 → 2: 1) to give 970mg (37%) of the desired product 8 b.

MS-ESI：250(M⁺+1)

Elemental analysis:

theoretical value: c57.82% H4.45% N5.62%

Measurement values: c57.85% H4.46% N5.61%

c) Synthesis of [ (1S, 2S) -2-fluoro-2, 3-dihydro-1H-inden-1-yl ] prop-2-yn-1-yl sulfamic acid (8c)

To a stirred solution of 100mg (0.4mmol)8b in 2ml dry THF was added 139mg (0.44mmol) tetrabutylammonium fluoride. The reaction mixture was stirred for 90min, then concentrated. The residue was purified by preparative HPLC. The desired product 8c was obtained in 10% yield and contained trace amounts of TBAF.

d) Synthesis of [ (1S, 2S) -2-fluoro-N- (prop-2-yn-1-yl) -2, 3-dihydro-1H-inden-1-amine (8d)

To a stirred solution of 100mg (0.4mmol)8b in 2ml dry THF at 0 deg.C was added 139mg (0.44mmol) tetrabutylammonium fluoride. The reaction mixture was stirred for 90min, then concentrated. 2ml of 3N sulfuric acid was added and the solution was then heated in a microwave oven for 10 min. The solution was poured into 20 ice-cold, vigorously stirred 0.35N sodium hydroxide solution. The aqueous phase is extracted with a dichloromethane-isopropanol mixture (10: 1), and the organic phase is dried over magnesium sulfate and then concentrated. The residue was purified by preparative HPLC to give compound 8d as a 14mg quantity batch (amountbatch).

e) Synthesis of [ (1S, 2S) -2-, (¹⁸F) fluoro-N- (prop-2-yn-1-yl) -2, 3-dihydro-1H-inden-1-amine (8e)

Following general procedure E, the desired product 8E was obtained.

The features of the invention disclosed in the description, the claims and/or the drawings may be essential to the realization of the invention in its various forms, both individually and in any combination thereof.

Claims

1. A compound of formula Ia

Wherein

W is-C (U)¹)(U²)-C≡CH，U¹And U²Independently selected from hydrogen and deuterium;

a is selected from unsubstituted phenyl or substituted by one, two or three independently and independently selected from nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkoxy and (C)₁-C₆) Phenyl substituted by a substituent of the sulfanyl radical, unsubstituted furyl or by a substituent selected from the group consisting of halogen, nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) Furyl substituted with a substituent of a sulfanyl group, (C)₁-C₄) Alkyl radical, G⁴-(C₃-C₄) Alkynyl, G⁴-(C₁-C₃) Alkoxy (G)⁴-(C₁-C₃) Alkyl) phenyl and (G)⁴-(C₁-C₃) Alkoxy) phenyl groups, in which the phenyl groups are linked,

G¹、G²、G³and G⁴Independently and individually at each occurrence selected from hydrogen, (C)₁-C₄) Alkyl, L and- (C)₁-C₆) An alkyl group-L having a structure represented by,

provided that G is¹-G⁴Exactly one of which is selected from L and- (C)₁-C₆) An alkyl group-L having a structure represented by,

l is F or a leaving group selected from the group consisting of chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy and (4-methoxyphenyl) sulfonyloxy,

wherein n is an integer of 0 to 6,

and wherein m is an integer of 0 to 4,

and any pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein U¹And U²Independently hydrogen.

3. The compound of claim 1, wherein U¹And U²Independently is deuterium.

4. The compound of claim 1 wherein with respect to G¹、G²、G³And G⁴Said (C)₁-C₄) Alkyl is methyl.

5. The compound of claim 1, wherein n is an integer from 1 to 3.

6. The compound of claim 5, wherein n is an integer from 1 to 2.

7. The compound of claim 1, wherein m is an integer from 0 to 2.

8. The compound of claim 7, wherein m is an integer from 0 to 1.

9. The compound of any one of claims 1-8, wherein a is selected from unsubstituted phenyl or is substituted with one, two or three independently and individually selected from nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, (C)₁-C₆) Sulfonyl and (C)₁-C₆) Phenyl substituted by a substituent of the sulfanyl radical, unsubstituted furyl or by a substituent selected from the group consisting of halogen, nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) Furyl substituted with a substituent of a sulfanyl group, (G)⁴-(C₁-C₃) Alkyl) phenyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl.

10. The compound of claim 9, wherein a is selected from hydroxyphenylMethoxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl.

11. The compound of claim 9, wherein the furyl is furan-2-yl or furan-3-yl.

12. The compound of claim 9, wherein a is selected from unsubstituted phenyl or is substituted with one, two or three independently and independently selected from nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, (C)₁-C₆) Sulfonyl and (C)₁-C₆) Phenyl substituted by a substituent of sulfanyl, (G)⁴-(C₁-C₃) Alkoxy) phenyl.

13. The compound of claim 9, wherein a is selected from the group consisting of hydroxyphenyl, methoxyphenyl, and methylphenyl.

14. The compound of any one of claims 1-3 and 5-8, wherein G¹、G²、G³And G⁴Independently and individually at each occurrence selected from hydrogen, (C)₁-C₄) Alkyl, L and- (C)₁-C₄) An alkyl group-L having a structure represented by,

provided that G is¹-G⁴Exactly one of which is selected from L and- (C)₁-C₄) alkyl-L.

15. The compound of claim 14, wherein G¹、G²、G³And G⁴Independently and individually at each occurrence selected from the group consisting of hydrogen, methyl, L and- (C)₁-C₄) An alkyl group-L having a structure represented by,

16. The method of14, wherein G¹、G²、G³And G⁴Independently and individually at each occurrence selected from the group consisting of hydrogen, methyl, L and- (C)₁-C₂) An alkyl group-L having a structure represented by,

provided that G is¹-G⁴Exactly one of which is selected from L and- (C)₁-C₂) alkyl-L.

17. The compound of claim 16, wherein G¹、G²、G³And G⁴Independently and individually at each occurrence, selected from the group consisting of hydrogen, methyl, L and-methyl-L,

provided that G is¹-G⁴Exactly one of which is selected from L and-methyl-L.

18. The compound of any one of claims 1-8, wherein L is a leaving group selected from the group consisting of chloro, bromo, iodo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethylsulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy, and (4-methoxyphenyl) sulfonyloxy.

19. The compound of claim 18, wherein L is selected from the group consisting of chloro, bromo, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, and (2,4, 6-triisopropylphenyl) sulfonyloxy.

20. The compound of claim 1 which is

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -3-phenylpropyl ester,

or

Methanesulfonic acid 2- (methylpropan-2-ynylamino) -1-phenylpropyl ester,

or

Methanesulfonic acid 3-furan-2 yl-2- (methylpropan-2-ynylamino) propyl ester,

or

Methanesulfonic acid 1-benzyl-2- (methylpropyl-2-alkynylamino) propyl ester,

or

Methanesulfonic acid 1- (methylprop-2-ynylamino) -2-phenylethyl ester,

or

Methanesulfonic acid 2- [ (2-furan-2-yl-1-methylethyl) prop-2-ynylamino ] ethyl ester,

or

Methanesulfonic acid 2- [ (1-methyl-2-phenylethyl) prop-2-ynylamino ] ethyl ester,

or

Methanesulfonic acid 2- {4- [2- (methylpropan-2-ynylamino) propyl ] phenoxy } ethyl ester,

or

(2S) -2- [ methyl (prop-2-yn-1-yl) amino ] -3-phenylpropyl methanesulfonate,

or

N- [ (2S) -1-chloro-3-phenylprop-2-yl ] -N-methylprop-2-yn-1-amine,

or

(2S) -3- (furan-2-yl) -2- [ methyl (prop-2-yn-yl) amino ] propyl methanesulfonate,

or

n- [ (2S) -1-chloro-3- (furan-2-yl) prop-2-yl ] -N-methylprop-2-yn-1-amine

Or

21. The compound of any one of claims 1-8, wherein L is not F.

22. The compound of any one of claims 1-8, wherein L is not¹⁸F and is not¹⁹F。

23. The compound of any one of claims 1-8, wherein L is¹⁸F or¹⁹F。

24. The compound of any one of claims 1-8, wherein L is¹⁸F, or, wherein the mesyloxy, chloro and tosyloxy groups in any of the compounds shown in claim 20 are substituted with¹⁸F is replaced.

25. The compound of any one of claims 1-8, wherein L is¹⁹F, or, wherein the mesyloxy, chloro and tosyloxy groups in any of the compounds shown in claim 20 are substituted with¹⁹F is replaced.

26. A process for the synthesis of a compound as defined in claim 24 or claim 25, wherein a compound of claim 18 or 21 is reacted with a compound wherein F ═ F¹⁸F or¹⁹F-fluorinating agent reaction of F.

27. The method of claim 26, wherein said F-fluorinating agent is a compound comprising F-anions.

28. The method of claim 27, wherein said F-fluorinating agent is selected from the group consisting of 4,7,13,16,21, 24-hexaoxa-1, 10-diazabicyclo [8.8.8 ™]Hexacosane KF, HF, KHF₂A compound of tetraalkylammonium salt of CsF, NaF, and F, and wherein F ═ F¹⁸F or¹⁹F。

29. The method of claim 28, wherein the tetraalkylammonium salt of F is [ alpha ], [ beta¹⁸F]Tetrabutylammonium fluoride.

30. A method of synthesizing a compound as defined in claim 24 or claim 25, comprising the steps of:

fluorination of compounds of formula V with F-fluorinating agents F

To give a compound of the formula IV

-substitution of said compound of formula IV with a compound of formula VI

Wherein F is¹⁸F or¹⁹F，

a is an integer of 0 to 4 and,

b is a leaving group, and B is a leaving group,

and wherein W²Is a radical W as defined in claim 1,

wherein A is²Selected from: r¹²-O-heteroaryl; unsubstituted aryl is optionally substituted by one, two or three substituents independently and independently selected from halogen, nitro, or a substituted aryl,(C₁-C₆) Carbonyl, cyano, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) Aryl substituted with a substituent of sulfanyl; a heteroaryl group; (C)₁-C₁₀) An alkyl group; (C)₂-C₄) An alkynyl group; and (C)₁-C₄) An alkoxy group;

wherein R is¹¹Is selected from (C)₁-C₆) Alkyl and R¹²，

Wherein R is¹²Is a hydrogen atom, and is,

wherein d is an integer from 0 to 4, and

wherein the F-fluorinating agent is as defined in any of claims 27 to 29,

and wherein F ═¹⁸F or¹⁹F，

With the proviso that the compound of formula VI contains exactly one R¹²。

31. The method of claim 30, wherein a is an integer from 0 to 2.

32. The method of claim 31, wherein a is an integer from 0 to 1.

33. The method of claim 30, wherein a²Is selected from R¹²-O-aryl, R¹²-O-heteroaryl, aryl, furyl, (C)₁-C₁₀) Alkyl, (C)₂-C₄) Alkynyl, (C)₁-C₄) Alkoxy group, ((C)₁-C₄) Alkoxy) aryl, ((C)₁-C₄) Alkyl) aryl.

34. The method of claim 30, wherein d is an integer from 0 to 2.

35. The method of claim 34, wherein d is an integer from 0 to 1.

36. The process of claim 30, wherein B is selected from the group consisting of halogen, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy, perfluorobutylsulfonyloxy, (4-bromophenyl) sulfonyloxy, (4-nitrophenyl) sulfonyloxy, (2-nitrophenyl) sulfonyloxy, (4-isopropylphenyl) sulfonyloxy, (2,4, 6-triisopropylphenyl) sulfonyloxy, (2,4, 6-trimethylphenyl) sulfonyloxy, (4-tert-butylphenyl) sulfonyloxy, and (4-methoxyphenyl) sulfonyloxy.

37. The method of claim 36, wherein the halogen is chlorine, bromine, iodine.

38. The method of claim 36, wherein B is selected from the group consisting of iodo, bromo, chloro, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, and perfluorobutylsulfonyloxy.

39. The method of claim 30, wherein a²Is ((C)₁-C₄) Alkoxy) aryl or ((C)₁-C₄) Alkyl) aryl.

40. The method of any one of claims 30-38, wherein a is²Selected from phenyl, furyl and (C)₁-C₄) Alkyl, (C)₃-C₄) Alkynyl, (C)₁-C₃) Alkoxy and is independently and individually selected from halogen, nitro, (C)₁-C₆) Carbonyl, cyano, hydroxy, trifluoromethyl, (C)₁-C₆) Sulfonyl group, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy and (C)₁-C₆) Phenyl substituted with a substituent of sulfanyl.

41. The method of claim 40, wherein A²Selected from phenyl, furyl, ((C)₁-C₃) Alkoxy) phenyl, hydroxyphenyl, dimethoxyphenyl, trifluoromethylphenyl and ((C)₁-C₄) Alkyl) phenyl.

42. The method of claim 41, wherein A²Selected from phenyl, furyl, hydroxyphenyl, methoxyphenyl and methylphenyl.

43. The method of any one of claims 30-38, wherein R⁹And R¹⁰Independently and individually at each occurrence selected from (C)₁-C₄) Alkyl and hydrogen.

44. The method of claim 43, wherein R⁹And R¹⁰Independently and individually at each occurrence, is selected from methyl and hydrogen.

45. The method of any one of claims 30-38, wherein R¹¹Is selected from (C)₁-C₄) Alkyl and R¹²。

46. The method of claim 45, wherein R¹¹Selected from methyl and R¹²。

47. A pharmaceutical composition comprising a compound of any one of claims 1-25 and a pharmaceutically acceptable carrier or diluent.

48. The composition of claim 47, wherein the compound is a compound of claim 24.

49. The composition of claim 47, wherein the compound is a compound of claim 25.

50. The composition of claim 47, wherein the compound is a compound of claim 21.

51. The composition of claim 47, wherein the compound is a compound of claim 22.

52. Use of a compound according to any one of claims 1 to 25, or a composition according to any one of claims 47 to 51, for the preparation of a medicament for the treatment and/or diagnosis and/or imaging of a central nervous system disease.

53. The use of claim 52, wherein the compound is a compound of claim 24.

54. The use of claim 52, wherein the compound is a compound of claim 25.

55. Kit comprising a closed vial containing a predetermined quantity of

a) A compound of claim 21 or

b) Compounds of formulae V and VI as defined in any one of claims 30 to 46.

56. Use of a compound of claim 24 or a composition of claim 48 in the manufacture of a medicament for detecting the presence of monoamine oxidase in a patient.

57. Use of a compound of claim 24 or a composition of claim 48 in the manufacture of a medicament for imaging a central nervous system disorder in a patient.

58. Use of a compound according to any one of claims 1 to 25 for the manufacture of a medicament for the treatment of a central nervous system disorder in a patient

59. The use of claim 58, wherein the compound is a compound of claim 24.

60. The use of claim 58, wherein the compound is a compound of claim 25.