WO2015004029A1 - Marquage au 18f de molécules aromatiques et hétéroaromatiques contenant des groupements d'acide carboxylique non protégés - Google Patents

Marquage au 18f de molécules aromatiques et hétéroaromatiques contenant des groupements d'acide carboxylique non protégés Download PDF

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WO2015004029A1
WO2015004029A1 PCT/EP2014/064353 EP2014064353W WO2015004029A1 WO 2015004029 A1 WO2015004029 A1 WO 2015004029A1 EP 2014064353 W EP2014064353 W EP 2014064353W WO 2015004029 A1 WO2015004029 A1 WO 2015004029A1
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group
aromatic
carboxylate
alkyl
precursor compound
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PCT/EP2014/064353
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Behrooz Hooshyar Yousefi
Markus BOLLINGER
Horst Kessler
Hans-Jürgen Wester
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Technische Universität München
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention provides methods for the nucleophilic aromatic and heteroaromatic radiofluorination of molecules with aliphatic or aromatic carboxylic acid groups.
  • Scheme 1 Exemplary structures for aromatic or heteroaromatic compounds for n.c.a. nucleophilic 18 F-fluorination (n > 0) wherein X may be a group CH or a heteroatom, and Y may be CH 2 , substituted CH or a heteroatom.
  • the invention provides, in a first aspect, a method for the radiofluorination of an aromatic or heteroaromatic compound containing a carboxylate group, comprising the steps of: a) providing a precursor compound comprising an aromatic or heteroaromatic ring, said aromatic or heteroaromatic ring bearing a leaving group for nucleophilic aromatic substitution reactions as a substituent L, such as nitro, bromo, chloro, fluoro, trialkylamino, etc., and at least one further substituent which is selected from a carboxylate group -COO " and a saturated or unsaturated aliphatic group or an aromatic group, which aliphatic or aromatic group carries at least one carboxylate group -COO " , wherein the carboxylate group -COO " is in the form of a carboxylate salt with a cation selected from (i) a cationic chelate composed of a metal cation and a chelating agent such as a cryptand or a crown ether
  • the invention provides, in a further aspect, a precursor compound comprising an aromatic or heteroaromatic ring, said aromatic or heteroaromatic ring bearing a leaving group for nucleophilic aromatic substitution reactions as a substituent L, such as nitro, bromo, chloro, fluoro, trialkylamino, etc., and at least one further substituent which is selected from a carboxylate group -COO " and a saturated or unsaturated aliphatic group or an aromatic group, which aliphatic or aromatic group carries at least one carboxylate group -COO " , wherein the carboxylate group -COO " is in the form of a carboxylate salt with a cation selected from (i) a cationic chelate composed of a metal cation and a chelating agent, such as a cryptand or a crown ether, and (ii) a quaternary ammonium cation.
  • a substituent L such as nitro, bromo, chloro, flu
  • the precursor compound provided by the invention is not a carboxylate salt of 5- methyl-isophthalic acid with a cationic chelate of Cs + and 18-crown-6, and not a carboxylate salt of 5-methoxy-isophthalic acid with a cationic chelate of Cs + and 18-crown-6.
  • the precursor compound provided by the invention is not a monocarboxylate salt of 5-methyl-isophthalic acid with a cationic chelate of Cs + and 18- crown-6 (i.e.
  • the term “radiofluorination” refers to n.c.a. 8 F-labeling of an aromatic or heteroaromatic compound by a reaction which leads to the formation of a covalent bond between the 18 F isotope and the compound to be labeled.
  • the corresponding term “radiofluorinated” thus refers to the state of a compound in which an 18 F isotope is covalently bound within the compound.
  • the method is a no-carrier-added synthesis, i.e. no unlabelled (i.e. non-radioactive or "cold") fluorine containing compound is added as a carrier.
  • precursor compound is used in the context of the invention to refer to a compound which is intended for radiofluorination and comprises a suitable leaving group L, such as nitro, bromo, chloro, trialkyl amino etc, together with a carboxylate group in the form of a salt with a cation selected from a cationic chelate composed of a metal cation and a chelating agent such as a cryptand (such as the potassium cryptate of kryptofix 222, [K/2.2.2] + ), or a crown ether (such as K + /18-crown-6), and a quaternary ammonium cation (e.g.
  • NR' 4l wherein the R' groups may be the same or different alkyl or aryl groups, such as tetrabutylammonium).
  • the 18 F isotope has a half life of about 1 10 min, a precursor compound or composition is generally prepared and optionally stored in a form ready for reaction with the 18 F fluoride anion.
  • the precursor compound to be subjected to n.c.a. radiofluorination comprises a combination of an aromatic or heteroaromatic ring with an unprotected carboxylate group in the form of a salt as defined above.
  • the aromatic or heteroaromatic precursor compound thus comprises a substituent L which represents a leaving group and a substituent R which bears or represents the carboxylic acid group in the form of a carboxylate salt as defined above.
  • substituent L and the second substituent R further substituents may be present, as stability and the number of available valencies permits. This includes the possibility that the aromatic or heteroaromatic ring comprises more than one substituent R.
  • the radiofluorinated compound as a target compound of the method in accordance with the invention which is obtainable by a radiofluorination reaction of the precursor compound, thus comprises a substituent R which bears or represents a carboxylic acid group, a substituent 18 F, and optionally further substituents, as stability and the number of available valencies permits. All these substituents are attached to the aromatic or heteroaromatic ring. As will be understood, the substituent 18 F in the radiofluorinated target compound replaces the leaving group L of the precursor compound.
  • the aromatic or heteroaromatic ring is preferably a monocyclic ring or an annellated bi- or trycyclic ring system having 5 to 14 ring members. More preferred is a monocyclic ring or a bicyclic ring.
  • the aromatic or heteroaromatic ring fulfills the requirements of aromaticity, i.e. it possesses a delocalized ⁇ -electron system.
  • Heteroatoms in the heteroaromatic ring are preferably selected from N, O or S, and it is particularly preferred that a heteroaromatic ring contains only nitrogen atoms as heteroatoms.
  • the number of heteroatoms in the heteroaromatic ring or ring system lies typically between 1 and 4, preferably between 1 and 2, and is most preferably 1.
  • the substituent R comprises one or more carboxylate groups. This encompasses the possibility of the substituent R being a) an unprotected carboxylate group directly attached to the aromatic or heteroaromatic ring or b) one or more unprotected carboxylate groups located in an aliphatic group R which may be saturated or unsaturated, or an aromatic group R as a side chain of the aromatic or heteroaromatic ring, including the aliphatic residues of aromatic amino acids derivatives.
  • the substituent R as a side chain of the aromatic or heteroaromatic ring may also comprise more than one, e.g. two carboxylic acid groups.
  • carboxylate group and “carboxylic acid group” do not encompass a protected carboxylic acid group, e.g. the case where it has been transformed into an ester.
  • carboxylate group(s) in the aromatic or heteroaromatic molecule used as a precursor compound in the method of the invention is (are) present in an unprotected form during the reaction with the 18 F " anion.
  • the alkyl or alkenyl group may be interspersed with one or more moieties independently selected from -NH-, -N(CH 3 )-, -0-, -S-, -S(O)-, -S(0) 2 -, -C(0)-0-, -O-C(O)-, -C(0)-NH-, -NH- C(O)-, or -C(O)- and a phenylene group. Furthermore, it may carry one or more substituents e.g.
  • each R 7 and each R 8 is independently selected from hydrogen or C1 -6 alkyl.
  • the carboxylate group may represent a terminal group in a linear substituent R, and may represent one of several groups in a branched group R. In any case, the carboxylate group may be present in the proximity of the aromatic or heteroaromatic ring or distanced, and separated from the aromatic or heteroaromatic ring to which L is attached.
  • the substituent L represents a leaving group.
  • such a leaving group is a group which can be replaced by an 18 F " fluoride anion in a nucleophiiic aromatic substitution reaction.
  • Exemplary leaving groups which are suitable for this purpose, can be selected from a nitro group, chloro, bromo, iodo, and -N(R 9 ) 3 + , with R 9 being selected, independently for each occurrence, from C1 -6 alkyl.
  • a fluorine (i.e. 19 F) substituent can also act as a leaving group. However, this is not preferred due to the fact that the equilibrium between the 18 F and the 19 F substituents may not allow an optimum specific activity in the product to be obtained.
  • Preferred leaving groups are selected from a nitro group, chlorine, bromine and -N(CH 3 ) 3 + . Particularly preferred are the nitro group or the group -N(CH 3 ) 3 + .
  • the precursor compound may comprise one substituent L or more than one, such as two, substituents L as activator. However, it is generally preferred if one substituent L is attached to the aromatic or heteroaromatic ring of the precursor compound independently of the position of the carboxylate group.
  • alkenyl represents a straight or branched chain unsaturated hydrocarbon residue comprising one or more than one (such as two or three) carbon-to-carbon double bond(s) which does not comprise any carbon-to-carbon triple bonds.
  • aryl represents an aromatic hydrocarbon ring, in particular a 6 to 10 membered ring (unless a different number of ring members is indicated in a specific context), including bridged ring or fused ring systems containing at least one aromatic ring.
  • Preferred as aryl groups are monocyclic groups with 6 ring members or fused bicyclic groups with 9 or 10 ring members.
  • aryl is phenyl.
  • cycloalkyl represents a saturated hydrocarbon ring, preferably a 3-1 1 membered ring (unless a different number of ring members is indicated in a specific context), including bridged ring, spiro ring or fused ring systems.
  • Cycloalkyl may, for example, refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Preferred as cycloalkyl groups is a monocyclic group with 5 or 6 ring members.
  • thienyl thiophenyl
  • benzo[b]thienyl naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, pyrrolyl (including, without limitation, 2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (pyridinyl; including, without limitation, 2-pyridyl, 3-pyridyl, and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl (including, without limitation, 3H-indolyl), indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl
  • aromatic or heteroaromatic compound which can be used as a precursor compound in the context of the invention are the compounds of the following formulae (III) to
  • L is defined as above, including preferred embodiments;
  • X is CH or N; and R 2 to R 6 are independently selected from H and alkoxy, in particular H and methoxy; and the carboxylate group -COO " is in the form of a carboxylate salt as defined above.
  • the aromatic or heteroaromatic compounds used as precursor compounds in the context of the invention, and consequently also the radiofluorinated target compounds, can contain optically active centres, and may thus exist in the form of different stereoisomers (including enantiomers and diastereomers). All such isomers are contemplated for use in the context of the present invention, either in admixture or in pure or substantially pure form. In particular, mixtures (such as racemic forms) and the isolated optical isomers of the aromatic or heteroaromatic compounds may be used in the context of the invention.
  • the racemic forms can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the carboxyiic acid group(s) in the precursor compound for use in accordance with the invention are in the form of a carboxylate salt with a cation selected from (i) a cationic chelate composed of a metal cation and a chelating agent, such as a cryptand (e.g. as [K/2.2.2] + ), or a crown ether (e.g. K7l 8-crown-6), and (ii) a quaternary ammonium cation (e.g. + NR' 4 . wherein the R' groups may be the same or different alkyl or aryl groups, such as tetrabutylammonium).
  • the different cations may be used singly or in combination. Among them, the cryptate cations are preferred.
  • Cryptands are azapolyethers, wherein two nitrogen atoms as bridgeheads are linked by three bridges, each of which contains one or more ether bonds.
  • a well known and preferred cryptand for use in the context of the invention is cryptand [2.2.2] (i.e. 1 ,10-diaza- 4,7, 13, 16,21 ,24-hexaoxabicyclo[8.8.8]hexacosane).
  • the numbers 2.2.2 indicate the number of oxygen atoms in each of the bridges. It is commercially available under the name "Kryptofix®”.
  • Particularly preferred carboxylate salts are salts with K + cations complexed by cryptand [2.2.2], which are also referred to as [K + c 2.2.2] or [K/2.2.2] + , as counter-ions.
  • Preferred ammonium cations as counter-ions for the carboxylate salts in the precursor compound for use in the context of the invention are formed with one or more types of the ammonium cation of the following structure:
  • R a to R are independently selected from a linear or branched alkyl group or phenyl.
  • R a to R d are methyl or butyl and are preferably methyl.
  • a precursor compound containing a carboxylate group for use in accordance with the invention can be prepared, e.g., via the addition of a salt selected from a salt of a cationic chelate, such as a cryptate salt or a crown ether salt, and an ammonium salt to a compound comprising an aromatic or heteroaromatic ring, said aromatic or heteroaromatic ring bearing a leaving group for nucleophilic aromatic substitution reactions as a substituent L and at least one further substituent which is selected from a carboxyiic acid group and a saturated or unsaturated aliphatic or an aromatic group, which aliphatic or aromatic group carries at least one carboxylic acid group, (also referred to herein as "aromatic or heteroaromatic compound with a carboxylic acid group").
  • a salt selected from a salt of a cationic chelate such as a cryptate salt or a crown ether salt
  • an ammonium salt to a compound comprising an aromatic or heteroaromatic
  • the carboxylic acid may be in free form or in the form of an inner salt, e.g. if the aromatic or heteroaromatic compound comprises a basic group, such as an amino group).
  • the anion which is present in salt selected from a salt of a cationic chelate, such as a cryptate salt or a crown ether salt, and an ammonium salt which may be used in the preparation of a precursor compound is preferably selected such that it does not have strong nucleophilic properties.
  • Such ions are known to the skilled person, and can be selected, e.g., from oxalate ions, carbonate ions, hydrogen carbonate ions and trifluoromethanesulfonate (triflate) ions, or combinations thereof.
  • the aromatic or heteroaromatic compound with a carboxylic acid group and a salt selected from a salt of a cationic chelate and an ammonium salt may be combined in a solvent. If desired, e.g. in order to facilitate the storage of the precursor compound, the solvent can be subsequently removed. Alternatively, the precursor compound can be subjected to the reaction with the 18 F " anion without being isolated as a solid intermediate.
  • Suitable solvents are in particular dry polar, non-protic solvents, such as acetonitrile, or DMSO, or mixtures of such solvents.
  • the precursor compound for use in the context of the present invention may be in the form of a solid compound, or in the form of a precursor composition including, e.g. a dry solvent, in particular a polar, non-protic solvents, such as acetonitrile or DMSO.
  • a dry solvent in particular a polar, non-protic solvents, such as acetonitrile or DMSO.
  • the aromatic or heteroaromatic compound with a carboxylic acid group, and the salt selected from a salt of a cationic chelate and an ammonium salt are typically combined in amounts such that the formal charge of the cations in the salt selected from a salt of a cationic chelate and an ammonium salt balances at least the number of carboxylic acid groups provided by the aromatic or heteroaromatic compound with a carboxylic acid group.
  • an excess of the salt selected from a salt of a cationic chelate and an ammonium salt is used, e.g. 1 to 10, preferably 5 to 10, and most preferably 4 to 8 equivalents of salt.
  • the molar ratio of carboxylic acid groups in the aromatic or heteroaromatic compound with a carboxylic acid group to the salt selected from a salt of a cationic chelate and an ammonium salt ranges from 1 to 10, preferably from 5 to 10, and more preferably from 4 to 8.
  • the anions of the salt(s) can act as basic compounds to deprotonate the carboxylic acid groups, whereas the chelated cations and/or ammonium cations act as counterions for the carboxylate groups which are formed.
  • the combination of the aromatic or heteroaromatic compound with a carboxylic acid group with a salt selected from a salt of a cationic chelate and an ammonium salt contains a salt formed from carboxylate anions of the aromatic or heteroaromatic compound with a carboxylic acid group and cationic chelates and/or ammonium cations, optionally in combination with an excess of the salt selected from a salt of a cationic chelate and an ammonium salt in an equilibrium.
  • the aromatic or heteroaromatic compound with a carboxylic acid group can be conveniently combined with a salt selected from a salt of a cationic chelate and an ammonium salt at room temperature.
  • the 18 F " fluoride anion can be prepared by methods known in the art using a nuclear reaction of 18 0 atoms (generally by irradiation of highly enriched [ 8 0]H 2 0 with protons ( 18 0(p,n) 8 F)) induced by cyclotron irradiation.
  • the 18 F " fluoride is provided after irradiation and post-processing (anion exchange extraction and purification of 18 F-fuoride from the target water) as a salt with a cation of a phase transfer catalyst.
  • the cation is selected from the same cations disclosed above as suitable cations for the cryptate salt or the quaternary ammonium salts.
  • Particularly preferred cations for the 18 F " fluoride are selected from complexes of K + and cryptand [2.2.2], and tetramethylammonium hydroxide, carbonate or hydrogencarbonate. It will be understood that any reference to the addition of the 18 F " fluoride to another reactant, to the combination of the 18 F " fluoride with another reactant, etc., implies the presence of such a counterion.
  • the 18 F " fluoride anion used in the method of the invention is no carrier added (“n.c.a.") 18 F " fluoride, i.e. the fluoride is essentially free of intentionally added cold ( 19 F) fluoride, resulting in specific activities of >37 GBq/ ⁇ , preferably >1 1 1 GBq/pmol, most preferably >370 GBq/pmol.
  • the precursor compound and the 18 F " fluoride typically react in homogeneous solution.
  • a non protic, polar solvent such as DMSO, DMF or acetonitrile is used.
  • solvents or solvent mixtures with a high boiling point e.g. a boiling point above 150 °C.
  • the reaction is preferably carried out at temperatures between 80 and 180 °C, in particular from 100 to 150 °C.
  • the reaction time generally ranges from 1 min to 60 min, preferably from 3 min to 30 min, and in particular from 5 min to 20 min.
  • the 8 F " fluoride is typically used in amounts 10 MBq to 400 GBq, preferably 370MBq to 100 GBq of 18 F fluoride to be introduced into the aromatic or heteroaromatic compound with carboxylic acid.
  • phase transfer catalyst Conventional phase transfer catalysts can be used for this purpose, including typically used cryptates, quaternary alkyl ammonium compounds, etc. Examples are ([K + c 2.2.2]) 2 C0 3 , [K + C 2.2.2]0H, [K + C 2.2.2]HC0 3 , or ([K + C 2.2.2]) 2 C 2 0 4 , wherein [K + C 2.2.2] designates a potassium cation complexed by cryptand [2.2.2].
  • the phase transfer catalyst can be used e.g. in amounts of 5-50 mg in a volume of the reaction of 500 to 1500 ⁇ , preferably 10-30 mg, and most preferably 5-30 mg.
  • the radiofluorination method in accordance with the invention is advantageously a no- carrier-added method, i.e. no unlabelled (i.e. non-radioactive or "cold") fluorine containing compound is intentionally added as a carrier for the labeling of the precursor compound. Also, it is not necessary to add any compounds apart from the precursor composition and the 18 F " anion together with a suitable cation as described above to the reaction mixture in a solvent as described above in order to promote the reaction, such as a transition metal complex.
  • the aromatic or heteroaromatic compound with a carboxylic acid group and the salt selected from a salt of a cationic chelate and an ammonium salt are first combined in a solution, and subsequently the solvent is removed to prepare a solid precursor compound.
  • the precursor compound with the 18 F " anion the precursor compound can be dissolved again, and can be reacted in a further step in the solution with the 18 F " anion in the presence of a phase transfer catalyst.
  • the elution of 18 F-fluoride from the cartridge is carried out by using a water/acetonitrile mixture (with a minimum of 5% water) containing carbonate, hydrogencarbonate, hydroxide or other commonly and less commonly used anions to exchange with 18 F-fluoride on the solid phase matrix of the extraction cartridge and thus used to mobilize and elute 18 F-fluoride from the cartridge.
  • a phase transfer catalyst PTCs e.g. kryptofix 2.2.2, or tetraalkylammonium salts (carbonates, hydrogencarbonates, hydroxides etc.) followed by azeotropic drying of the mixture.
  • 18 F-fluoride is converted into salts, such as [K + C 2.2.2] 18 F in presence of ([K + C 2.2.2]) 2 C0 3 , [K + C2.2.2]HC0 3 , [K + c2.2.2]OH, [K + /c2.2.2]OTf or ([K + C 2.2.2]) 2 C 2 0 4 , that are soluble in polar organic solvents, such as MeCN, DMF, fBuOH or DMSO, to mention only a few.
  • polar organic solvents such as MeCN, DMF, fBuOH or DMSO
  • [K + 2.2.2]0H is prepared by addition of a minimum of 2, e.g. 2.4 equivalents of kryptofix 2.2.2 to one equivalent of KOH in water/MeCN (50 vol%/ 50 vol%). The solvent is evaporated under reduced pressure and freeze dried.
  • [K + c2.2.2]HC0 3 is prepared by addition of a minimum of 1 , e.g. 1.2 equivalents of kryptofix 2.2.2 to one equivalent of KHC0 3 in water/MeCN (50 vol%/ 50 vol%). The solvent is evaporated under reduced pressure and freeze dried.
  • NMe 4 OTf is prepared by addition of a minimum of 1 , e.g. 1.2 equivalents of N e 4 HC0 3 to one equivalent of KOTf in water/MeCN (50 vol%/ 50 vol%). The solvent is evaporated under reduced pressure and freeze dried.
  • ammonium salts are prepared according to the above described procedures.
  • General procedure for the formation of a precursor composition :
  • the aromatic or heteroaromatic compound with a carboxylic acid group is added as free acid or, in the case of the use of amino acids, as inner salts to a minimum of 1 equivalent, typically 4-8 equivalents of the cryptates or ammonium salts e.g. ([K + 2.2.2]) 2 C 2 0 4 , ([K + c 2.2.2]) 2 C0 3 or combinations thereof as described above in solvent, typically in acetonitrile.
  • solvent is evaporated and the remaining substance carefully dried.
  • the precursors prepared according to this method are stored under inert gas until they are used for 18 F-fluorination.
  • Example 1 N.c.a. nucleophilic 18 F-fluorination of the precursor composition Tirofiban analogue 4 (scheme 2 and scheme 3)
  • N.c.a. 18 F-fluorination of analogs of the precursor composition tirofiban by nucleophilic 18 F- fluorination of the unprotected precursor compounds 4 and 7 (scheme 2) was carried out by nucleophilic substitution of the nitro group by [K + C 2.2.2] 18 F " of the precursor composition of 4 prepared following above mentioned procedure for the formation of a precursor composition with [K + C 2.2.2]C0 3 or [K + C 2.2.2]C0 3 and ([K + C 2.2.2]) 2 C 2 0 4 in CH 3 CN, iBuOH/CH 3 CN and DMSO at a temperature 100-150 °C for 10-60 min.
  • [ 18 F]10 was performed with 10.0 ⁇ 1 .6% radiochemical yields (not optimized condition).
  • the direct one-step 18 F-labeling of the the precursor composition of totally unprotected precursor 4 afforded [ 18 F]5 was used also for further evaluation of the integrin tracer in vivo and in vitro.
  • [K + C 2.2.2] indicates a K + cation complexed by cryptand [2.2.2].
  • Scheme 2 shows the synthesis of para-nitro substituted precursors 3, 4 and 7 and 19 F- reference compounds 5 and 6.
  • Compound 1 was synthesized according to literature procedures (e.g. Bollinger et al. , J. Med. Chem. 2012, 55, 871 -882; Duggan et al. , J. Med. Chem. 2000, 43, 3736-3745).
  • HCI (aq) dioxane, RT, 1 h; f) 1 .
  • 4-Nitrobenzenesulfonyl chloride DIEA, DCM, RT, 5 h; 2. TFA, DCM, RT, 1 h; g) 1 .
  • Scheme 3 illustrates the radiosynthesis of 18 F-labeled compounds [ 18 F]5 and [ 18 F]10: a) 10 ⁇ mol 4 or 7 as their precursor composition (with 6 ⁇ [K + C 2.2.2]C0 3 and 12 pmol [K + C 2.2.2]C 2 0 4 ) in 150 ⁇ DMSO (150 °C, 20min) in the presence of [K + C 2.2.2] 18 F " .
  • the radiofluorination of precursor composition of 4 was studied using different amounts of precursor at a reaction temperature of 150 °C. After 20 min reaction time the mixture was analyzed by HPLC (cf. Fig.1 ). 5 mg of precursor gave the highest radiochemical yield. Furthermore, the radiofluorination of 5 mg of 4 analysed after reaction times of 10-60 min by radio thin layer chromatography (TLC) revealed an optimal radiochemical yield after 20 min under these reaction conditions (cf. Fig. 2).
  • Example 2 N.c.a. nucleophilic 8 F-fluorination of 2-amino-3-(4,5-dimethoxy-2- nitrophenyl)propanoic acid 13.
  • [ 18 F]14 was prepared by precursor 13 (5mg) as its precursor composition, [K + C 2.2.2]salt after adding ([K + C 2.2.2]) 2 C0 3 (0,012 mmol) and ([K + C 2.2.2]) 2 C 2 0 4 (0,032 mmol) in CH 3 CN and evaporation of the solvent in DMSO (150°C, 20 min) with 7 % RCY (not optimized result).
  • Scheme 4 illustrates the direct n.c.a. 18 F-fluorination of 13 as its precursor composition yielded [ 18 F]-2-amino-3-(4,5-dimethoxy-2-fluorophenyl) propanoic acid, [ 18 F]14.
  • Example 3 N.c.a. nucleophilic F-fluorination of the precursor composition of amino acid analogue (2S)-2-amino-3-(6-chloropyridin-3-yl)propanoic acid 15
  • (2S)-2-amino-3-(6-chloropyridin-3-yl)propanoic acid 15 (3,2 mg, 0,0135 mmol) was converted to its precursor composition [K + C 2.2.2]salt by ([K + C 2.2.2]) 2 C0 3 (0,012 mmol) and ([K + C 2.2.2]) 2 C 2 0 4 (0,032 mmol) and fluorinated by n.c.a. [K + C 2.2.2] 18 F at 150°C in DMSO.
  • Compound [ 18 F]16 was obtained after a reaction time of 20 min with 6 % RCY (not optimized).
  • Scheme 5 illustrates the n.c.a. 18 F-fluorination of (2S)-2-amino-3-(6-chloropyridin-3- yl)propanoic acid (15) yielded [ 18 F]-2-amino-3-(4,5-dimethoxy-2-fluorophenyl) propanoic acid [ 18 F]16 .
  • Examples 4-8 [ 18 F]18, [ 18 F]20, [ 18 F]22, [ 18 F]24, and [ 18 F]26 was prepared following similar procedure as above by converting precursor 17, 19, 21 , 23, or 25 (5mg) as its [K + c 2.2.2]salt after adding ([K + C 2.2.2]) 2 C0 3 (0,012 mmol) and ([K + C 2.2.2]) 2 C 2 0 4 (0,032 mmol) and reacting with [K + C 2.2.2] 18 F in DMSO (150°C, 20 min) with 6-26 % RCY (not optimized result).
  • n.c.a. nucleophilic 18 F-fluorination of aromatic compounds with free carboxylic acids i.e. benzoic acid analogues (17, 19, 21), a phenyl acetic acid (23) and a pyridine carboxylic acid (25) are illustrated below.
  • Figure 1 shows the result of the radiochemical labeling yield of precursor 4 in example 1 as a function of its concentration: a) 150 ⁇ DMSO (150 °C, 20min) in the presence of [K + C 2.2.2] 18 F and 6 pmol ([ + C 2.2.2]) 2 C0 3 and 12 pmol ([K + C 2.2.2]) 2 C 2 0 4 .
  • Figure 2 shows the result of the radiochemical labeling yield of precursor 4 in example 1 as a function of the reaction time: a) 10 pmol (5 mg) 4 in 150 ⁇ DMSO (150 °C) in the presence of [K + C 2.2.2] 18 F and 6 ⁇ ([K + C 2.2.2]) 2 C0 3 and 12 Mmol ([K + C 2.2.2]) 2 C 2 0 4 .

Abstract

La présente invention concerne un procédé de marquage au 18F de composés aromatiques ou hétéroaromatiques contenant un groupement d'acide carboxylique non protégé afin de produire des molécules marquées qui peuvent être utilisées comme radiotraceurs. De plus, l'invention concerne des composés précurseurs contenant un groupement d'acide carboxylique non protégé qui peut être utilisé dans ce procédé.
PCT/EP2014/064353 2013-07-08 2014-07-04 Marquage au 18f de molécules aromatiques et hétéroaromatiques contenant des groupements d'acide carboxylique non protégés WO2015004029A1 (fr)

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US10815200B2 (en) 2015-09-30 2020-10-27 Deutsches Krebsforschungszentrum 18F—tagged inhibitors of prostate specific membrane antigen (PSMA) and their use as imaging agents for prostate cancer
DE102016122273A1 (de) 2016-11-18 2018-05-24 Abx Advanced Biochemical Compounds Gmbh Präkursoren für die Radiofluorierung
WO2018091043A1 (fr) 2016-11-18 2018-05-24 Abx Advanced Biochemical Compounds Gmbh Précurseurs de radiofluoration
DE102016122273B4 (de) 2016-11-18 2018-06-21 Abx Advanced Biochemical Compounds Gmbh Präkursoren für die Radiofluorierung
KR20190070945A (ko) * 2016-11-18 2019-06-21 에이비엑스 어드밴스드 바이오케이컬 컴파운즈 게엠베하 방사성 불화를 위한 전구체
US10759760B2 (en) 2016-11-18 2020-09-01 Abx Advanced Biochemical Compounds Gmbh Precursors for radiofluorination
KR102233598B1 (ko) * 2016-11-18 2021-03-30 에이비엑스 어드밴스드 바이오케이컬 컴파운즈 게엠베하 방사성 불화를 위한 전구체
US11053200B2 (en) 2016-11-18 2021-07-06 Abx Advanced Biochemical Compounds Gmbh Precursors for radiofluorination
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
DE102019112040A1 (de) * 2019-05-08 2020-11-12 Helmholtz-Zentrum Dresden - Rossendorf E.V. 3-(4-Amino-2-methoxyphenyl)-2-cyanoacrylsäure-Derivate und deren Verwendung als Präkursoren für die Herstellung radiochemischer Verbindungen

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