Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se

Definitions

• the present invention relates to the field of [ 18 F]radiofluorination chemistry for the preparation of Positron Emission Tomography (PET) radioligands and [ 18 F]radiofluorinating reagents.
• PET Positron Emission Tomography
• the invention further provides kits for preparation of the same.
• Commonly used methods for introducing 18 F are either direct displacement of a leaving group by nucleophilic [ 18 F]Fluoride, or using electrophilic reagents such as [ 18 F]F 2 , [ 18 F]acetylhypofluorite (Lerman et al, Appl. Radiat. Isot. 49 (1984), 806-813) or N-[ 18 F]fluoropyridinium salt (Oberdorfer et al, Appl. Radiat. Isot. 39 (1988), 806-813), or by a two step process involving preparation of an 18 F radiofluorinated labelling reagent which is in turn reacted with a ligand precursor by a second reaction such as an alkylation.
• electrophilic reagents such as [ 18 F]F 2 , [ 18 F]acetylhypofluorite (Lerman et al, Appl. Radiat. Isot. 49 (1984), 806-813) or N-[
• PET This latter approach generally involves incorporating via a nucleophilic centre O, N, or S, which in turn can lead to metabolic instability of the resulting PET radioligand.
• O, N, or S the nucleophilic centre
• the value of PET is the ability to use a radioligand which closely mimics the structure of the therapeutic pharmacaphore and it is therefore not always desirable to incorporate O, N, or S into the PET radioligand.
• Y is a biological targetting moiety, which comprises: reaction of a compound of formula (II):
• Y is as defined for the compound of formula (I)
• B is boron
• Z is selected from hydroxy, Ci- 6 alkoxy, Ci- 6 alkyl, C 5 -i 2 aryloxy and C 5 -i 2 aryl and each Z is optionally substituted by 1 to 4 substituents selected from hydroxy, Ci -6 alkyl, Ci- 6 alkoxy, and halo, or both groups Z together with the B to which they are attached form an organoboron cyclic moiety;
• Ci- 8 alkyl group is as defined for the compound of formula (I);
• Y is a biological targeting moiety , suitably a non-peptide small drug-like molecule or a protected derivative thereof, typically a substituted or unsubstituted, aromatic or aliphatic 5 to 8 membered 5 monocyclic ring, or a 10 to18 membered fused or unfused bicyclic ring system comprised of carbon, hydrogen, and optionally one to six heteroatoms selected from oxygen, nitrogen, and sulphur.
• the Ci- 8 alkyl group in the compounds of formulae (I) and (III) is a straight or l O branched chain alkyl group or a cyclic alkyl group, suitably selected from methyl, ethyl, iso-propyl, n-propyl, n-butyl, cyclohexyl, and cyclooctyl .
• organoboron cyclic moiety means a C 4 . 12 mono or bicyclic aliphatic hydrocarbyl group further containing boron, such as 15 9-borabicyclo[3.3.1 ]nonyl or a C 5 - 12 mono or bicyclic aryl group further containing boron, such as
• aryl rings may optionally be substituted by 1 to 4 substituents 20 selected from hydroxy, Ci -6 alkyl, C 1 ⁇ aIkOXy, and halo.
• Z is suitably selected from hydroxy, methoxy, ethoxy, methyl, and ethyl or the group -B(Z) 2 is 9-borabicyclo[3.3.1 ]nonyl,
• aryl rings may optionally be substituted by 1 to 4 substituents selected from hydroxy, Ci- 6 alkyl, Ci- 6 alkoxy, and halo.
• X in the compound of formula (III) is more suitably bromo or iodo, most suitably bromo.
• the compound of formula (III) is selected from 18 F- CH 2 Br, 18 F-CH 2 CH 2 Br and 18 F-CH 2 CH 2 CH 2 Br.
• Suitable solvents include N,N-dimethylformamide, dimethylsulphoxide, dichloromethane, chloroform, acetonitrile, toluene, tetrahydrofuran, iso- propanol, tert-amyl alcohol , diethyl ether, and tetrahydrofuran.
• the transition metal catalyst is suitably a palladium or nickel catalyst.
• Preferred nickel catalysts include nickel amino alcohol derivatives such as Ni I 2 / frans-2- aminocyclohexanol or NiCI 2 .GIyme/Prolinol, nickel metal (in the form of a finely divided powder, or nickel reaction vessel).
• Suitable Pd catalysts include Pd(PPhIs) 2 CI 2 , Pd(PPh 3 ) 4 ,
• the method is suitably performed at a non-extreme temperature, suitably at ambient temperature or elevated temperature up to the boiling point of the solvent, for example up to 100 °C.
• the method is performed using microwave heating.
• the reaction comprises a base, suitably an inorganic base such as potassium carbonate, caesium carbonate, sodium hydroxide, caesium hydroxide, tripotassium phosphate, or a Lewis Base such as KOt-Butyl.
• a base suitably an inorganic base such as potassium carbonate, caesium carbonate, sodium hydroxide, caesium hydroxide, tripotassium phosphate, or a Lewis Base such as KOt-Butyl.
• Compounds of formula (II) may be prepared by methods well known to the person skilled in the art, for example as described in Miyaura et al, Chem Rev 1995, vol 95(7) ; Brown etal, Organometallics (1983), 2, 131 1 -1316; Yang etal, Medicinal Research Reviews, VoI 23(3), 346-368 (2003); Coord Chem Rev 2002, 224(1 -2), 171 -243; and Boronic Acids- Preparation and Applications in Organic Synthesis, (Wiley-VCH, 2006) by Dennis G. Hall.
• Compounds of formula (III) may be prepared from commercially available starting materials by methods which are well known in the art. For example, [ 18 F]Fluorohaloalkanes have previously been prepared by nucleophilic displacement, by [ 18 F]F " , of a leaving group from a suitable precursor compound.
• Typical precursor compounds which may be [ 18 F]fluorinated to provide a compound of formula (III) include those of formula (IV):
• X is chloro, bromo, iodo, a Ci- 6 alkylsulphonate, haloCi- 6 alkylsulphonate, or arylsulphonate (such as trifluoromethanesulphonate, methanesulphonate, tolylsulphonate)
• the Ci -8 alkyl group is as defined for the compound of formula (I)
• L is a leaving group , for example, selected from chloro, bromo, iodo, a Ci- 6 alkylsulphonate, haloCi- 6 alkylsulphonate, or arylsulphonate (such as trifluoromethanesulphonate, methanesulphonate, tolylsulphonate).
• [ 18 F]fluoride is conveniently prepared from 18 O-enriched water using the (p,n)- nuclear reaction, (Guillaume et al, Appl. Radiat. Isot. 42 (1991 ) 749-762) and generally isolated as the potassium salt which is dried and solubilised with a phase transfer agent such as a tetraalkylammonium salt or an aminopolyether (for example, Kryptofix 2.2.2).
• a phase transfer agent such as a tetraalkylammonium salt or an aminopolyether (for example, Kryptofix 2.2.2).
• protected derivatives of synthetic intermediates such as a compound of formula (II) comprise one or more protecting groups to prevent unwanted reaction of certain reactive groups.
• Suitable protecting groups may be found in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc. which describes methods for incorporating and removing such protecting groups.
• the compound of formula (II) could be provided as part of a kit to a radiopharmacy.
• the kit may comprise a cartridge which can be plugged into a suitably adapted automated synthesiser.
• the cartridge may contain, apart from the compound of formula (II), a column to remove unwanted fluoride ion, and an appropriate vessel connected so as to allow the reaction mixture to be evaporated and allow the product to be formulated as required.
• the reagents and solvents and other consumables required for the synthesis may also be included together with a compact disc carrying the software which allows the synthesiser to be operated in a way so as to meet the customers requirements for radioactive concentration, volumes, time of delivery etc.
• the invention further provides a radiopharmaceutical kit for the preparation of a compound of formula (I) as defined above for use in PET, which comprises: (i) a vessel containing a compound of formula (II) as defined above; and (ii) a vessel containing a compound of formula (IV) as defined above and means for contacting said compound of formula (IV) with a source of 18 F "
• Application of the Ni-catalysed Suzuki cross-coupling chemistry would facilitate the coupling of a variety of [ 18 F]fluoroalkyl groups using a common boronic acid precursor prior to nitro group reduction.
• Step 1 Synthesis of the boronic acid precursor [2-(4- boronic acid-2-nitro- phenylsulfanyl)-benzyl]-dimethyl-amine.
• 2-thio-N,N-dimethylbenzamide reaction with 1 -bromo-4-iodo-2- nitrobenzene in the presence of potassium carbonate base according to the method of Choi et al. (Journal Label. Compd. Radiopharm., 2001 , 44, S190-192) yields 2-(4-iodo-2-nitro-phenylsulfanyl)-N,N-dimethyl-benzamide.
• Step 2 Suzuki Coupling chemistry to prepare [ 18 FIAFE, (2-r[2-Amino-4-(2- [ 18 F1fluoroethyl)phenyl1thio1- ⁇ /, ⁇ /-dimethylbenzenemethanamine)

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Saccharide Compounds (AREA)

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• 2009
  • 2009-03-31 GB GBGB0905515.3A patent/GB0905515D0/en not_active Ceased
• 2010
  • 2010-03-15 WO PCT/US2010/027278 patent/WO2010117557A1/en not_active Ceased
  • 2010-03-15 EP EP10713279A patent/EP2414308A1/en not_active Withdrawn
  • 2010-03-15 JP JP2012503472A patent/JP2012522051A/ja active Pending
  • 2010-03-15 CN CN2010800157775A patent/CN102369172A/zh active Pending
  • 2010-03-15 US US13/256,483 patent/US20120004404A1/en not_active Abandoned

Patent Citations (3)

Non-Patent Citations (24)

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