FIELD OF THE INVENTION

The present invention relates to a process for producing an organic compound comprising an ¹⁸ F atom. The present invention also relates to the use of activators in the [ ¹⁸ F]radiolabelling of organic compounds, kits comprising activators, compositions comprising radiolabelled compounds and [ ¹⁸ F]radiolabelled compounds.

BACKGROUND OF THE INVENTION

Positron Emission Tomography (PET) is a non-invasive quantitative imaging technology assessing biological and biochemical processes in living subjects. This imaging modality enhances understanding of disease states and drug activity during both preclinical and clinical drug development. The established value of PET for clinical applications combined with continuous technological advances has recently stimulated research activity within the academic sector, and has added strength and stability to institutions involved in imaging technologies. For a large number of studies, ¹⁸ F is the preferred positron-emitting

radioisotope due to its advantageous properties (a radioactive half-life of 109.771 minutes allowing for imaging durations of up to 10 hours, 97% positron emission, positron energy), the extensive use of 2-deoxy-2-[ ¹⁸ F]fluoroglucose ([ ¹⁸ F]FDG) in the clinic, and the importance of fluorine substitution in the context of drug discovery. The success of PET and the increasing interest in [ ¹⁸ F]radiochemistry recently led to creative methods to incorporate ¹⁸ F into molecules of increasing complexity. Despite these advances, clinically useful radiotracers lie within a narrow accessible space, with [ ¹⁸ F]fluoroalkanes and

[ ¹⁸ F]fluoroarenes at the forefront. Many potentially high value PET [ ¹⁸ F]labelled tracers and drugs lie outside this radiochemical space, and the ability to test tracers not amenable to traditional [ ¹⁸ F]labelling intervention would be a major boost for PET imaging. Medicinal chemists would immediately benefit from a more diverse range of ¹⁸ F-tags to perform in vivo studies that could inform the selection of leads for further optimization earlier in the drug discovery pipeline. Drug developers employ routinely di- and trifluoromethyl ether and thioether substitution to tune conformation on demand, or modulate physicochemical parameters such as lipophilicity. Examples of pharmaceutical drugs that have directly benefited from these substitutions are riluzole (an OCF ₃ containing 2-amino benzothiazole and the first drug approved for the treatment of amyotropic lateral sclerosis) and tiflorex (an SCF3 substituted 2-phenylethylamine which possesses anorectic activity). The prospect of preparing [ ¹⁸ F]labelled aryl-CF ₃ , -OCF3, -OCHF2, -SCF ₃ and -SCHF ₂ in high specific activity applying a common methodology is exciting for drug and radiotracer development.

Radiochemists have employed halogen exchange [ ¹⁸ F]fluorination for many years; alkyl halides and halogenated arenes activated by an electron withdrawing group (e.g. N0 ₂ ) respond to halex [ ¹⁸ F]fluorination. However, complications may arise from undesired displacement of the activating group itself. The method was applied to convert 2- and 4- chloropyridines to [ ¹⁸ F]fluorinated analogues but has met with limited success for RCF ₂ X precursors since the presence of two a-fluorines severely inhibits nucleophilic substitution. Harsh reaction conditions permit access to [ ¹⁸ F]aryl-CF ₃ , but the low radiochemical yields and specific activities implied that this chemistry has prohibitively narrow applicability. It is therefore greatly desirable to develop a new method for applying halogen exchange

[ ¹⁸ F]fluorination to R-CF ₂ X and R-CFHX precursors under mild reaction conditions which allows access to important [ ¹⁸ F]motifs currently not within reach. SUMMARY OF THE INVENTION

It has surprisingly been found that the use of an activator allows [ ¹⁸ F]fluorination through halogen exchange to reach a wide range of compounds comprising a trihalomethyl or dihalomethyl group, particularly -CF ₂ ¹⁸ F and -CFH ¹⁸ F. This approach of metal-based halogen exchange chemistry has never been considered as a generic activation manifold to promote halogen exchange [ ¹⁸ F]fluorination. The inventors have found that

[ ¹⁸ F]radiolabelled compounds comprising a -CF ₂ ¹⁸ F or related group can be produced under very mild conditions. This enables the production of [ ¹⁸ F]radiolabelled samples with high specific activities.

The invention therefore provides a process for producing an organic compound comprising an ¹⁸ F atom, which process comprises treating a precursor organic compound comprising a -CY ₂ X group with:

(i) [ ¹⁸ F] fluoride; and

(ϋ) an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum, wherein:

X is a leaving group; and each Y is independently selected from F, CI, Br and H.

The invention also provides the use of an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum, in a process for producing an organic compound comprising an F atom as defined herein.

The invention also provides a kit for [ ¹⁸ F]radiolabelling an organic compound, which kit comprises:

(i) an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum; and (ii) a precursor organic compound comprising a -CY ₂ X group, wherein X is a leaving group and each Y is independently selected from F, CI, Br and H.

The invention also provides a composition comprising a compound of formula:

R-CF ₂ ¹⁸ F;

R-CHF ¹⁸ F;

R-0-CF ₂ ¹⁸ F;

R-0-CHF ¹⁸ F;

R-N(R')-CF ₂ ¹⁸ F;

R-N(R')-CHF ¹⁸ F

R-S-CF ₂ ¹⁸ F; or

R-S-CHF ¹⁸ F;

or a pharmaceutically acceptable salt thereof;

and having a specific activity of greater than or equal to 50 GBq/μιηοΙ,

wherein:

R is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R' is H, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The invention also provides a compound which is [ ¹⁸ F]sorafenib, [ ¹⁸ F]aprepitant,

[ ¹⁸ F]tripanavar, [ ¹⁸ F]dutasteride, [ ¹⁸ F]dutasteride, [ ¹⁸ F]travoprost, [ ¹⁸ F]sitagliptin,

[ ¹⁸ F]cinacalcet, [ ¹⁸ F]notisinone, [ ¹⁸ F]trifluridine, [ ¹⁸ F]zardaverine, [ ¹⁸ F]riodipine, [ ¹⁸ F](-)- pantaprazole, [ ¹⁸ F]garenoxacin, [ ¹⁸ F]roflumilast, [ ¹⁸ F]celikalim, [ ¹⁸ F]riluzole, [ ¹⁸ F]tiflorex, [ ¹⁸ F]toltrazuril or [ ¹⁸ F]flomoxef sodium, or a pharmaceutically acceptable salt thereof, or a [ ¹⁸ F]radiolabelled Umemoto reagent.

DETAILED DESCRIPTION OF THE INVENTION

Definitions The term "organic group", as used herein, refers to a group derived by removing a hydrogen atom from an organic compound. An organic compound is typically a compound comprising a hydrogen atom bonded to a carbon atom, but may also include compounds comprising a covalent bond between carbon and another atom. The term organic compound is well known in the art. The term "C1-60 organic group" refers to an organic group comprising from 1 to 60 carbon atoms. Likewise, the term "Ci-40 organic group" refers to an organic group comprising from 1 to 40 carbon atoms. For instance, an example of a C10 organic group is a group derived by removing a hydrogen atom from an organic compound which contains 10 carbon atoms. Often, a C1-60 organic group is a substituted or unsubstituted aryl group or a substituted or unsubstituted hetroaryl group. The term "alkyl group", as used herein, refers to a straight or branched chain saturated hydrocarbon radical. Typically an alkyl group is C _1-20 alkyl, or C _1-10 alkyl, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl (including straight or branched chain isomers thereof), or Ci-6 alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl (including straight or branched chain isomers thereof), or C1-4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl. When an alkyl group is substituted it typically bears one or more substituents selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or

unsubstituted C _2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, formyl, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester. Examples of substituted alkyl groups include haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl and alkaryl groups. The term alkaryl, as used herein, pertains to a C _1-20 alkyl group in which at least one hydrogen atom has been replaced with an aryl group. Examples of such groups include, but are not limited to, benzyl (phenylmethyl, PI1CH2-), benzhydryl (Ph ₂ CH-), trityl (triphenylmethyl, Ph ₃ C-), and phenethyl (phenyl ethyl, Ph-CH ₂ CH ₂ -).

Typically a substituted alkyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

The term "perfluoroalkyl", as used herein, refers to a group which is a straight or branched chain saturated perfluonnated hydrocarbon radical. For example, a perfluoroalkyl group may be have from a to 12 carbon atoms. "Perfluonnated" in this context means completely fluorinated such that there are no carbon-bonded hydrogen atoms replaceable with fluorine. Examples of C _4-12 perfluoro alkyl groups are trifluoromethyl (Ci), pentafluoroethyl (C ₂ ), hetptafluoropropyl (C ₃ ), perfluorobutyl (C ₄ ) (for instance including perfluoro-«-butyl, perfluoro-sec-butyl and perfluoro-tert-butyl), perfluoropentyl (C ₅ ), perfluorohexyl (C ₆ ), perfluoroheptyl (C ₇ ), perfluorooctyl (C ₈ ), perfluorononyl (Cs>), perfluorodecyl (Cio), perfluoroundecyl (Cn) and perfluorododecyl (C ₁₂ ), including straight chained and branched isomers thereof.

The term "alkenyl", as used herein, refers to a linear or branched chain hydrocarbon radical comprising one or more double bonds. An alkenyl group may be a C _2-2 o alkenyl group, a C _2- io alkenyl group or a C _2- 6 alkenyl group. Examples of C _2-2 o alkenyl groups include those related to C _2-2 o alkyl groups by the insertion of one or more double bonds. Alkenyl groups typically comprise one or two double bonds. The alkenyl groups referred to herein may be substituted or unsubstituted, as defined for alkyl groups above.

The term "alkynyl", as used herein, refers to a linear or branched chain hydrocarbon radical comprising one or more triple bonds. An alkynyl group may be a C _2-2 o alkynyl group, a C _2-10 alkynyl group a C _2- 6 alkynyl group. Examples of C _2-2 o alkynyl groups include those related to C _2-2 o alkyl groups by the insertion of one or more triple bonds. Alkynyl groups typically comprise one or two triple bonds. The alkynyl groups referred to herein may be substituted or unsubstituted, as defined for alkyl groups above. The term "cycloalkyl group", as used herein, refers to an substituted or unsubstituted alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound. A cycloalkyl group may have from 3 to 25 carbon atoms (unless otherwise specified), including from 3 to 25 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkyenyl and cycloalkynyl. Examples of groups of C _3-25 cycloalkyl groups include C _3-2 o cycloalkyl, C _3-15 cycloalkyl, C _3-10 cycloalkyl, and C _{3 -} 7 cycloalkyl. When a C _3-25 cycloalkyl group is substituted it typically bears one or more substituents selected from substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl.

Typically a substituted cycloalkyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

Examples of C3-25 cycloalkyl groups include, but are not limited to, those derived from saturated monocyclic hydrocarbon compounds, which C3-25 cycloalkyl groups are substituted or unsubstituted as defined above: cyclopropane (C ₃ ), cyclobutane (C ₄ ), cyclopentane (C5), cyclohexane (C ₆ ), cycloheptane (C ₇ ), methylcyclopropane (C ₄ ), dimethylcyclopropane (C5), methylcyclobutane (C5), dimethylcyclobutane (C ₆ ), methylcyclopentane (C ₆ ),

dimethylcyclopentane (C ₇ ), methylcyclohexane (C ₇ ), dimethylcyclohexane (C ₈ ), menthane (Cio); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C ₃ ), cyclobutene (C ₄ ), cyclopentene (C5), cyclohexene (C ₆ ), methylcyclopropene (C ₄ ), dimethylcyclopropene (C5), methylcyclobutene (C5), dimethylcyclobutene (C ₆ ), methylcyclopentene (C ₆ ),

dimethylcyclopentene (C ₇ ), methylcyclohexene (C ₇ ), dimethylcyclohexene (C ₈ ); saturated polycyclic hydrocarbon compounds: thujane (Cio), carane (Cio), pinane (Cio), bornane (Cio), norcarane (C ₇ ), no inane (C ₇ ), norbornane (C ₇ ), adamantane (Cio), decalin

(decahydronaphthalene) (Cio); unsaturated polycyclic hydrocarbon compounds: camphene (Cio), limonene (Cio), pinene (Cio); polycyclic hydrocarbon compounds having an aromatic ring: indene (C9), indane (e.g., 2,3-dihydro-lH-indene) (C9), tetraline

(1,2,3,4-tetrahydronaphthalene) (Cio), acenaphthene (C12), fluorene (C ₁₃ ), phenalene (C ₁₃ ), acephenanthrene (C15), aceanthrene (C ₁₆ ), cholanthrene (C20). The term "heterocyclyl group", as used herein, refers to an substituted or unsubstituted monovalent moiety obtained by removing a hydrogen atom from a ring atom of a

heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Heterocyclic compounds include aromatic heterocyclic compounds and non-aromatic heterocyclic compounds. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. When a C3- 20 heterocyclyl group is substituted it typically bears one or more substituents selected from Ci-6 alkyl which is unsubstituted, aryl (as defined herein), cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, aiylamino, diaiylamino, aiylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl. Typically a substituted C _3-20 heterocyclyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

Examples of groups of heterocyclyl groups include C _3-20 heterocyclyl, C5-20 heterocyclyl, C3-15 heterocyclyl, C5-15 heterocyclyl, C3 -12 heterocyclyl, C5-12 heterocyclyl, C3 -10 heterocyclyl, C5-10 heterocyclyl, C3-7 heterocyclyl, C5-7 heterocyclyl, and C5-6 heterocyclyl.

Examples of (non-aromatic) monocyclic C _3-20 heterocyclyl groups include, but are not limited to, those derived from:

Ni: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g.,

3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine (C ₆ ), dihydropyridine (C ₆ ), tetrahydropyridine (C ₆ ), azepine (C7);

Oi: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C ₆ ), dihydropyran (C ₆ ), pyran (C ₆ ), oxepin (C7);

Si: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane

(tetrahydrothiopyran) (C ₆ ), thiepane (C7);

O2: dioxolane (C5), dioxane (C ₆ ), and dioxepane (C7);

O3 : trioxane (C ₆ );

N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline

(dihydropyrazole) (C5), piperazine (C ₆ );

N1O1 : tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5),

dihydroisoxazole (C5), morpholine (C ₆ ), tetrahydrooxazine (C ₆ ), dihydrooxazine (C ₆ ), oxazine (C ₆ );

N1S1 : thiazoline (C5), thiazolidine (C5), thiomorpholine (C ₆ );

N2O1 : oxadiazine (C ₆ );

O1S1 : oxathiole (C5) and oxathiane (thioxane) (C ₆ ); and,

N1O1S1 : oxathiazine (C ₆ ).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C5), such as

arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C ₆ ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Examples of C _3-20 heterocyclyl groups which are also aryl groups are described below as heteroaryl groups. The term "aryl group", as used herein, refers to a substituted or unsubstituted, monocyclic or poly cyclic (for instance bicyclic) aromatic group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. Examples include phenyl, naphthyl, indenyl, indanyl, anthracenyl and pyrenyl groups. An aryl group is substituted or unsubstituted. When an aryl group is substituted it typically bears one or more substituents selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, - SH), C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester. Typically it carries 0, 1, 2 or 3 substituents. A substituted aryl group may be substituted in two positions with a single Ci-6 alkylene group, or with a bidentate group represented by the formula -X-Ci-6 alkylene, or -X-Ci-6 alkylene-X-, wherein X is selected from O, S and R, and wherein R is H, aryl or C 1-6 alkyl. Thus a substituted aryl group may be an aryl group fused with a cycloalkyl group or with a heterocyclyl group. The term

"aralkyl" as used herein, pertains to an aryl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been substituted with a Ci-6 alkyl group. Examples of such groups include, but are not limited to, tolyl (from toluene), xylyl (from xylene), mesityl (from mesitylene), and cumenyl (or cumyl, from cumene), and duryl (from durene). The term "heteroaryl group", as used herein, refers to a substituted or unsubstituted, monocyclic or polycyclic (for instance bicyclic) aromatic group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion wherein the ring atoms of the group include one or more heteroatoms. Thus, a heteroaryl group is a substituted or unsubstituted monocyclic or polycyclic (for instance bicyclic) heteroaromatic group which typically contains from 6 to 14 atoms, for instance 6 to 10 atoms, in the ring portion including one or more heteroatoms. It is generally a 5- or 6-membered ring, containing at least one heteroatom selected from O, S, N, P, Se and Si. It may contain, for example, 1, 2 or 3 heteroatoms. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, quinolyl and isoquinolyl. A heteroaryl group may be substituted or unsubstituted, for instance, as specified above for aryl. Typically it carries 0, 1, 2 or 3 substituents.

The term "alkylene group" as used herein, refers to an substituted or unsubstituted bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below.

Typically it is C _1-10 alkylene, for instance Ci-6 alkylene. Typically it is Ci-4 alkylene, for example methylene, ethylene, i-propylene, n-propylene, t-butylene, s-butylene or n-butylene. It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof. An alkylene group may be substituted or unsubstituted, for instance, as specified above for alkyl. Typically a substituted alkylene group carries 1, 2 or 3

substituents, for instance 1 or 2.

In this context, the prefixes (e.g., Ci-4, C _1-7 , C _1-20 , C _2-7 , C _3-7 , etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "Ci-4alkylene," as used herein, pertains to an alkylene group having from 1 to 4 carbon atoms. Examples of groups of alkylene groups include Ci-4 alkylene ("lower alkylene"), C _1-7 alkylene, C _1-10 alkylene and C _1-20 alkylene.

Examples of linear saturated C _1-7 alkylene groups include, but are not limited to, -(0¾)η- where n is an integer from 1 to 7, for example, -CH ₂ - (methylene), -CH2CH2- (ethylene), -CH2CH2CH2- (propylene), and -CH2CH2CH2CH2- (butylene). Examples of branched saturated C _1-7 alkylene groups include, but are not limited

to, -CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ ) CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ CH ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₂ CH ₃ )CH ₂ -,

and -CH2CH(CH2CH ₃ )CH2-. Examples of linear partially unsaturated C1-7 alkylene groups include, but is not limited to, -CH=CH- (vinylene), -CH=CH-CH ₂ -, -CH ₂ -

CH=CH ₂ -, -CH=CH-CH ₂ -CH ₂ -, -CH=CH-CH ₂ -CH ₂ -CH ₂ -, -CH=CH-CH=CH- , -CH=CH-CH=CH-CH ₂ -, -CH=CH-CH=CH-CH ₂ -CH ₂ -, -CH=CH-CH ₂ -CH=CH-, and -CH=CH-CH2-CH2-CH=CH-. Examples of branched partially unsaturated C _1-7 alkylene groups include, but is not limited to, -C(CH ₃ )=CH-, -C(CH ₃ )=CH-CH ₂ -,

and -CH=CH-CH(CH ₃ )-. Partially unsaturated alkylene groups comprising one or more double bonds may be referred to as alkenylene groups. Partially unsaturated alkylene groups comprising one or more triple bonds may be referred to as alkynylene groups (for instance - C≡C-, CH ₂ -C≡C-, and -CH ₂ -C≡C-CH ₂ -). Examples of alicyclic saturated C _1-7 alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-l,3-ylene), and cyclohexylene (e.g., cyclohex-l,4-ylene). Examples of alicyclic partially unsaturated C _1-7 alkylene groups include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-l,3-ylene),

cyclohexenylene (e.g., 2-cyclohexen-l,4-ylene; 3-cyclohexen-l,2-ylene; 2,5-cyclohexadien- 1,4-ylene).

C _1-20 alkylene and C _1-20 alkyl groups as defined herein are either uninterrupted or interrupted by one or more heteroatoms or heterogroups, such as S, O or N(R") wherein R" is H, Ci-6 alkyl or aryl (typically phenyl), or by one or more arylene (typically phenylene) groups, or by one or more -C(O)- or -C(0)N(R")- groups. The phrase "optionally interrupted" as used herein thus refers to a C _1-20 alkyl group or an alkylene group, as defined above, which is uninterrupted or which is interrupted between adjacent carbon atoms by a heteroatom such as oxygen or sulfur, by a heterogroup such as N(R") wherein R" is H, aryl or Ci-C ₆ alkyl, or by an arylene group, or by a -C(O)- or -C(0)N(R")- group, again wherein R" is H, aryl or Ci-C ₆ alkyl.

For instance, a C _1-20 alkyl group such as n-butyl may be interrupted by the heterogroup N(R") as follows: -CH ₂ N(R")CH ₂ CH ₂ CH _3, -CH ₂ CH ₂ N(R")CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₂ N(R")CH ₃ . Similarly, an alkylene group such as n-butylene may be interrupted by the heterogroup N(R") as follows: -CH ₂ N(R")CH ₂ CH ₂ CH ₂ - _, -CH ₂ CH ₂ N(R")CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ N(R")CH ₂ -. Typically an interrupted group, for instance an interrupted C _1-20 alkylene or C _1-20 alkyl group, is interrupted by 1, 2 or 3 heteroatoms or heterogroups or by 1, 2 or 3 arylene (typically phenylene) groups. More typically, an interrupted group, for instance an interrupted C _1-20 alkylene or C _1-20 alkyl group, is interrupted by 1 or 2 heteroatoms or heterogroups or by 1 or 2 arylene (typically phenylene) groups. For instance, a C _1-20 alkyl group such as n-butyl may be interrupted by 2 heterogroups N(R") as follows: -CH ₂ N(R")CH ₂ N(R")CH ₂ CH ₃ .

An arylene group is an substituted or unsubstituted bidentate moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms of an aromatic compound, which moiety has from 5 to 14 ring atoms (unless otherwise specified).

Typically, each ring has from 5 to 7 or from 5 to 6 ring atoms. An arylene group may be substituted or unsubstituted, for instance, as specified above for aryl.

In this context, the prefixes (e.g., C5-20, C ₆ -2o, C5-14, C5-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C5-6 arylene," as used herein, pertains to an arylene group having 5 or 6 ring atoms. Examples of groups of arylene groups include C5-20 arylene, C ₆ -2o arylene, C5-14 arylene, C ₆ -i4 arylene, C ₆ -io arylene, C5-12 arylene, C5-10 arylene, C5-7 arylene, C5-6 arylene, C5 arylene, and C ₆ arylene. The ring atoms may be all carbon atoms, as in "carboarylene groups" (e.g., C6-20

carboarylene, C ₆ -i4 carboarylene or C ₆ -io carboarylene).

Examples of C ₆ -2o arylene groups which do not have ring heteroatoms (i.e., C ₆ -2o carboarylene groups) include, but are not limited to, those derived from the compounds discussed above in regard to aryl groups, e.g. phenylene, and also include those derived from aryl groups which are bonded together, e.g. phenyl ene-phenylene (diphenylene) and phenylene-phenylene- phenylene (triphenylene).

Alternatively, the ring atoms may include one or more heteroatoms, as in " heteroaryl ene groups" (e.g., Cs-io heteroarylene).

Examples of C5-10 heteroarylene groups include, but are not limited to, those derived from the compounds discussed above in regard to heteroaryl groups.

As used herein the term "oxo" represents a group of formula: =0

As used herein the term "acyl" represents a group of formula: -C(=0)R, wherein R is an acyl substituent, for example, a substituted or unsubstituted C _1-20 alkyl group, substituted or unsubstituted C _2-20 alkenyl group, substituted or unsubstituted C _2-20 alkynyl group, a substituted or unsubstituted C _3-20 heterocyclyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, for instance a substituted or unsubstituted Ci-6 alkyl group. Examples of acyl groups include, but are not limited to, -C(=0)CH3 (acetyl), -C(=0)CH ₂ CH ₃ (propionyl), -C(=0)C(CH ₃ ) ₃ (t-butyryl), and -C(=0)Ph (benzoyl, phenone). As used herein the term "acyloxy" (or reverse ester) represents a group of

formula: -OC(=0)R, wherein R is an acyloxy substituent, for example, a substituted or unsubstituted C _1-20 alkyl group, substituted or unsubstituted C _2-20 alkenyl group, substituted or unsubstituted C ₂ -2o alkynyl group, a substituted or unsubstituted C3 -20 heterocyclyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, for instance a substituted or unsubstituted Ci-6 alkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=0)CH ₃

(acetoxy), -OC(=0)CH ₂ CH ₃ , -OC(=0)C(CH ₃ ) ₃ , -OC(=0)Ph, and -OC(=0)CH ₂ Ph.

As used herein the term "ester" (or carboxylate, carboxylic acid ester or oxycarbonyl) represents a group of formula: -C(=0)OR, wherein R is an ester substituent, for example, a substituted or unsubstituted C _1-20 alkyl group, substituted or unsubstituted C _2-20 alkenyl group, substituted or unsubstituted C _2-20 alkynyl group, a substituted or unsubstituted C _3- 2o heterocyclyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, for instance a substituted or unsubstituted Ci-6 alkyl group. Examples of ester groups include, but are not limited

to, -C(=0)OCH ₃ , -C(=0)OCH ₂ CH ₃ , -C(=0)OC(CH ₃ ) ₃ , and -C(=0)OPh.

As used herein the term "amino" represents a group of formula - H2. The term "C1-C10 alkylamino" represents a group of formula - HR ^' wherein R ^' is a C _1-10 alkyl group, preferably a Ci-6 alkyl group, as defined previously. The term "di(C _1-10 )alkylamino" represents a group of formula - R ^' R ^{' '} wherein R ^' and R ^{' '} are the same or different and represent C _1-10 alkyl groups, preferably Ci-6 alkyl groups, as defined previously. The term "arylamino" represents a group of formula -NHR ^' wherein R ^' is an aryl group, preferably a phenyl group, as defined previously. The term "diarylamino" represents a group of formula -NR ^' R ^{' '} wherein R ^' and R ^{' '} are the same or different and represent aryl groups, preferably phenyl groups, as defined previously. The term "arylalkylamino" represents a group of formula -NR ^' R ^" wherein R ^' is a C _1-10 alkyl group, preferably a Ci-6 alkyl group, and R ^" is an aryl group, preferably a phenyl group.

A halo group is chlorine, fluorine, bromine or iodine (a chloro group, a fluoro group, a bromo group or an iodo group). It is typically chlorine, fluorine or bromine. As used herein the term "amido" represents a group of formula: -C(=0)NR R , wherein R and R are independently amino substituents, as defined for di(C _1-10 )alkylamino groups. Examples of amido groups include, but are not limited

to, -C(=0) H ₂ , -C(=0) HCH ₃ , -C(=0)N(CH ₃ ) ₂ , -C(=0) HCH ₂ CH ₃ ,

and -C(=0)N(CH ₂ CH ₃ ) ₂ , as well as amido groups in which R and R , together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl.

As used herein the term "acylamido" represents a group of formula: - R ¹ C(=0)R ² , wherein R ¹ is an amide substituent, for example, hydrogen, a Ci _-2 oalkyl group, a C _3-2 o heterocyclyl group, an aryl group, preferably hydrogen or a C _1-20 alkyl group, and R ² is an acyl substituent, for example, a Ci _-2 o alkyl group, a C _{3 -2} o heterocyclyl group, or an aryl group, preferably hydrogen or a Ci _-2 o alkyl group. Examples of acylamide groups include, but are not limited

and Thus, a substituted Ci _-2 o alkyl group may comprise an acylamido substituent defined by the formula

or R ¹ and R ² may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:

succinimidyl maleimidyl phthalimidyl

A C _1-10 alkylthio group is a said C _1-10 alkyl group, preferably a Ci-6 alkyl group, attached to a thio group. An arylthio group is an aryl group, preferably a phenyl group, attached to a thio group. A C _1-20 alkoxy group is a said substituted or unsubstituted Ci _-2 o alkyl group attached to an oxygen atom. A Ci-6 alkoxy group is a said substituted or unsubstituted Ci-6 alkyl group attached to an oxygen atom. A C1-4 alkoxy group is a substituted or unsubstituted C1-4 alkyl group attached to an oxygen atom. Said Ci _-2 o, Ci-6 and C1-4 alkyl groups are optionally interrupted as defined herein. Examples of C1-4 alkoxy groups include, -OMe

(methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), - O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy). Further examples of Ci- ₂ o alkoxy groups are -O(Adamantyl), -0-CH ₂ -Adamantyl and -0-CH ₂ -CH ₂ -Adamantyl. An aryloxy group is a substituted or unsubstituted aryl group, as defined herein, attached to an oxygen atom. An example of an aryloxy group is -OPh (phenoxy).

Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid or carboxyl group (-COOH) also includes the anionic (carboxylate) form (-COO ^" ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-^HR^ ² ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0 ^" ), a salt or solvate thereof, as well as conventional protected forms.

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair- forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or

"isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho- chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto, enol, and enolate forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,

thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.

keto enol enolate

Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¾, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ 0 and ¹⁸ 0; and the like, unless otherwise specified. However, reference to an isotope of fluorine refers only to that isotope of fluorine. In particular, reference to ¹⁸ F includes only ¹⁸ F. Reference to fluorine without specifying the isotope may refer to ¹⁸ F or ¹⁹ F depending on context. Typically, reference to "F" (i.e. without defining the isotope) refers to the ¹⁹ F, i.e. stable fluorine. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting known methods, in a known manner. The term "substituted", as used herein, may be as defined above for particular groups, e.g. for alkyl. Thus, the term substituted typically refers to a group substituted with a group selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, formyl, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester. In other instances, the term "substituted" may refer to a group substituted with a group selected from substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, Ci-6 alkoxy, aryloxy, haloalkyl, sulfonic acid, thiol, C 1-6 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester. For example, the term "substituted" may refer to a group substituted with a group selected unsubstituted Ci-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, unsubstituted aryl, unsubstituted heteroaryl, cyano, amino, unsubstituted Ci-6 alkylamino, unsubstituted di(Ci-6)alkylamino, unsubstituted arylamino, unsubstituted diarylamino, unsubstituted arylalkylamino, unsubstituted amido, unsubstituted acylamido, hydroxy, oxo, halo, carboxy, unsubstituted ester, unsubstituted acyl, unsubstituted acyloxy, unsubstituted Ci-6 alkoxy, unsubstituted aryloxy, sulfonic acid, thiol, unsubstituted Ci-6 alkylthio, unsubstituted arylthio, sulfonyl, phosphoric acid, unsubstituted phosphate ester, unsubstituted phosphonic acid and unsubstituted phosphonate ester.

The term " ¹⁸ F" refers to an atom of the specific isotope of fluorine having 9 protons and 9 neutrons. The term " ¹⁸ F ^~ " refers to an anion of the atom of the specific isotope of fluorine having 9 protons and 9 neutrons.

The term "protecting group", as used herein, takes its normal meaning in the art. Thus, a protecting group is a group which is introduced into a compound so that a subsequent step is chemo selective and does not affect the protected group. Protecting groups may be categorised as those suitable for protecting specific functional groups. Thus a protecting group may, for instance, be an alcohol protecting group, an amine protecting group or a carboxylic acid protecting group.

Process of the invention

The invention provides a process for producing an organic compound comprising an ¹⁸ F atom, which process comprises treating a precursor organic compound comprising a -CY2X group with:

(i) [ ¹⁸ F]fluoride; and

(ii) an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum, wherein

X is a leaving group and

each Y is independently selected from F, CI, Br and H.

The [ ¹⁸ F]fluoride and the activator do not usually come from the same compound (e.g. from a single salt). Components (i) and (ii) are typically added separately. The organic compound comprising an ¹⁸ F atom is generally an organic compound wherein the X in the -CY ₂ X group of the precursor organic compound has been replaced with ¹⁸ F. The organic compound comprising an ¹⁸ F atom or the precursor organic compound may be any suitable organic compound such as those discussed below. The precursor organic compound is typically a small organic compound, for instance having a molar mass of less than or equal to 1000 gmol ^"1 , often less than or equal to 600 gmol ^"1 .

X may be any suitable leaving group. Leaving groups are well known to the skilled person and include those groups which are susceptible to being replaced by another group, typically by nucleophilic substitution. X is typically a group selected from perfluoroalkylsulfonate groups (for instance triflate and nonaflate), sulfonate groups (for instance tosylate or mesylate), halide groups (for instance fluoride, chloride, bromide or iodide), carboxylate groups (for instance acetate or trifluoroacetate), nitrate groups and phosphate groups (for instance phosphate or alkylphosphate). Typically, X is a halide group. Preferably, the X is a leaving group which is CI, Br or I. Thus, X is often CI or Br. Each Y is typically independently selected from F and H. In particular, the -CY ₂ X group is often -CF ₂ X or -CFHX. In this embodiment, X is a leaving group which is usually a halide. Preferably, however, X in this embodiment is CI, Br or I, for instance CI or Br.

The precursor organic compound is often a compound of formula: R-CFXY; R-O-CFXY; R-N(R')-CFXY; R-S-CFXY; R-Se-CFXY; R-Te-CFXY; or a salt thereof, wherein: X is a leaving group, typically CI, Br or I; Y is F, CI, Br or H; R is a substituted or unsubstituted Ci- 60 organic group, typically a substituted or unsubstituted Ci-40 organic group; and R' is H or a substituted or unsubstituted Ci-40 organic group, which may optionally be bonded together with R to form a ring. For instance, the precursor compound may be a compound of formula R-O-CFXY; R-N(R')-CFXY; R-S-CFXY; R-Se-CFXY; R-Te-CFXY; or a salt thereof, wherein: X is a leaving group, typically CI, Br or I; Y is F, CI, Br or H; R is a substituted or unsubstituted Ci-40 organic group; and R' is H or a substituted or unsubstituted Ci-40 organic group, which may optionally be bonded together with R to form a ring.

Typically, the precursor organic compound is a compound of formula: R-CFXY; R-O- CFXY; R-S-CFXY; or a salt thereof, wherein: X is CI, Br or I; Y is F or H; and R is a substituted or unsubstituted Ci-40 organic group. In some cases, the precursor compound may be a compound of formula R-O-CFXY or a salt thereof. In other cases, the precursor compound may be a compound of formula R-S-CFXY or a salt thereof.

Often, X is CI and Y is F or H; or X is Br and Y is F. The -CFXY group is typically -CF ₂ I, - CF ₂ Br, -CF2CI, -CFHI, -CFHBr or -CFHC1. It may for instance be -CF ₂ Br or -CFHC1. The process of the invention applies very generally to a wide range of compounds and R may therefore be a wide range of organic groups.

R may be any C1-60 organic group (which may be substituted or unsubstituted) and is typically a C1-60 organic group comprising one or more aryl or heteroaryl rings. R may be any Ci-40 organic group (which may be substituted or unsubstituted) and is typically a Ci-40 organic group comprising one or more aryl or heteroaryl rings. R may be a substituted or unsubstituted C3-40 organic group, a substituted or unsubstituted C5-35 organic group or a substituted or unsubstituted Cio-30 organic group. R typically comprises one to four aryl or heteroaryl groups. Substituted organic groups are themselves organic groups. Often, the Ci- 40 organic group is unsubstituted. R may alternatively be H in some cases. Often, R is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. The aryl group or heteroaryl group is typically substituted as defined above. R may for instance be an aryl or heteroaryl group which is substituted with one or more aryl or heteroaryl groups, each of which may themselves be substituted or unsubstituted. As mentioned above, the identity of R is not particularly limited. Often, R is substituted or unsubstituted biphenyl.

R' may be any Ci-40 organic group (which may be substituted or unsubstituted) and is typically a Ci-40 organic group comprising one or more aryl or heteroaryl rings. R' may be a substituted or unsubstituted C3-40 organic group, a substituted or unsubstituted C5-35 organic group or a substituted or unsubstituted Cio-30 organic group. R' typically comprises one to four aryl or heteroaryl groups. Substituted organic groups are themselves organic groups. Often, the Ci-40 organic group is unsubstituted. R' may for instance be H, substituted or unsubstituted Ci-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R' is typically H, substituted or unsubstituted Ci-6 alkyl or substituted or unsubstituted aryl. R' is often unsubstituted Ci-6 alkyl or unsubstituted aryl. For instance, R' may be H, methyl, ethyl or phenyl.

The organic compounds comprising an ¹⁸ F atom are often intended for use in medical imaging, for instance PET imagining. Thus, the organic compound comprising an ¹⁸ F atom is often suitable for administration to a human subject and optionally suitable for use in PET imaging. In some embodiments, the invention provides a compound comprising an ¹⁸ F atom for use in PET imaging, or a method of PET imaging comprising administering a compound comprising an ¹⁸ F atom as defined herein to a patient.

The precursor organic compound may, for instance, be a precursor to a pharmaceutical compound wherein an F atom in the pharmaceutical compound has been replaced with X as defined herein, or a protected version thereof. Thus, the pharmaceutical compound comprises an F atom (which can be replaced by X). Lists of pharmaceutical compounds are readily available to the skilled person, for instance in the form of pharmacopoeias.

Specific examples of pharmaceutical compounds comprising an F atom are given below. Typically, the pharmaceutical compound is a selective serotonin reuptake inhibitor, a kinase inhibitor (e.g. a tyrosine kinase inhibitor), a prostaglandin, a substance P antagonist, a nonpeptidic protease inhibitor, a nonsteroidal anti-inflammatory drug, dipeptidyl peptidase-4 (DPP-4) inhibitor, a nucleoside analogue, a PDE4 inhibitor, an antibiotic drug, an

antihistamine drug, a potassium channel activator, a proton pump inhibitor or an anorectic drug. A protected version of the precursor compound is the precursor compound wherein one or more groups within the precursor compound have been protected. As the skilled person is well aware, it is often necessary to protect groups within a starting material (i.e. the precursor organic compound) before performing a reaction. Often, alcohol, amine and carboxylic acids in the precursor compound are protected using well known protecting groups. Examples of alcohol protecting groups include substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted -C(0)-C _1-10 alkyl, substituted or unsubstituted -C _1-10 alkylene-O- C _1-10 alkyl optionally wherein the C _1-10 alkylene group and C _1-10 alkyl group may be bonded together to form a ring, and substituted or unsubstituted tri(C _1-10 alkyl) silyl. Examples of carboxylic acid protecting group include substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted -C(0)-C _1-10 alkyl, and substituted or unsubstituted tri(C _{1 -10} alkyl) silyl.

Examples of amine protecting group include substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted -C(0)-C _1-10 alkyl, substituted or unsubstituted -C(0)-0-C _1-10 alkyl, substituted or unsubstituted -S(0)2-aryl.

Often, a protecting group is selected from methyl, ethyl, tert-butyl, benzyl, carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz), tert-butyloxycarbonyl (Boc), 9- fluorenylmethyloxycarbonyl (FMOC), acetyl and benzoyl. If the precursor organic compound is used as a protected version, the process of the invention often further comprises deprotecting the produced compound comprising an ¹⁸ F atom.

Deprotection may be performed by any suitable method. Such methods are well known to the skilled person. Often, removing one or more protecting groups from (deprotecting) the compound comprising an ¹⁸ F atom comprises performing hydrolysis on the compound. For instance, the process may further comprise treating the compound comprising an ¹⁸ F atom with an aqueous acid, for instance aqueous HI, HBr or HC1.

The precursor organic compound often does not comprise a a carboxylic acid group or a hydroxyl group.

The process of the invention may be performed as a no-carrier added radiofluorination process. Thus, often substantially no ¹⁹ F ^" is added during the reaction. For instance, no more than 1 mmol of ¹⁹ F ^" is added during the reaction or no more than 1 μιηοΐ of ¹⁹ F ^" is added during the reaction. Of course, some ¹⁹ F ^" may already present during the reaction for instance from the precursor compound or by substitution of existing ¹⁹ F atoms and "added" in this context means added from an external source. [ ¹⁸ F]fluoride is commercially available or may be manufactured using a cyclotron or linear accelerator, for instance by bombardment of ¹⁸ 0 with high energy protons. The [ ¹⁸ F]fluoride is typically added in the form of a salt. The [ ¹⁸ F]fluoride salt is typically a salt of

[ ¹⁸ F]fluoride with an alkali metal cation or a quaternary ammonium cation, for instance Li ¹⁸ F, Na ¹⁸ F, K ¹⁸ F, Rb ¹⁸ F, [NMe ₄ ] ¹⁸ F, [NEt ₄ ] ¹⁸ F or [ Bu ₄ ] ¹⁸ F. Preferably, the salt also contains a complexing agent, for instance a crown ether or a cryptand. Typically, the fluoride is added as an alkali metal [ ¹⁸ F]fluoride salt complexed with a cryptand. Examples of cryptands include aminopolyether 2.2.2 (K ₂₂₂ ), which is

commercially available as Kryptofix-222. Advantageously, the addition of such a cryptand enables the fluoride ion ¹⁸ F ^" to be solubilized in a polar aprotic solvent, for instance acetonitrile or DMF. It also enables the formation of a 'naked fluoride ion' as a KF-K222 complex. In one embodiment, therefore, the source of ¹⁸ F ^" is a K ¹⁸ F-K ₂ 22 complex.

Alternatively, the source of ¹⁸ F ^" may be [ ¹⁸ F]TEAF (tetraethylammonium fluoride),

[ ¹⁸ F]TBAF (tetrabutylammonium fluoride), [ ¹⁸ F]CsF, or [ ¹⁸ F]HF.

As discussed above, the organic compound comprising an ¹⁸ F atom is often a pharmaceutical compound or a protected version thereof. The pharmaceutical compound may be as defined above, and the protecting groups may be as defined above. The pharmaceutical compound in its unradiolabelled state often comprises a group selected from -CF ₃ , -CHF2, -O-CF3, -O- CHF2, -S-CF3 and -S-CHF2.

Pharmaceutical compounds comprising these groups may be readily identified by the skilled person, for instance by consulting a pharmacopeia. Preferably, the pharmaceutical compound (i.e. the compound from which the precursor organic compound, or the organic compound comprising the ¹⁸ F atom, is derived) is celecoxib, riluzole, tiflorex, fenfluramine, fluoxetine, efavirenz, sorafenib, nilotinib, aprepitant, tripanavar, travoprost, dutasteride, sitagliptin, cinacalcet, nitisinone, trifluridine, zardaverine, riodipine, pantaprazole, garenoxacin, roflumilast, celikalim, flutiorex, toltrazuril, flomoxef sodium, or a pharmaceutically acceptable salt thereof.

The term "pharmaceutically acceptable salt" as used herein refers to a salt which is tolerated in a clinical setting. Examples of pharmaceutically acceptable salts includes salts derived by addition of an acid selected from acetic acid, adipic acid, benzenesulfonic acid, carbonic acid, citric acid, ethanesulfonic acid, formic acid, hydrobromic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, methanesulfonic acid, nitric acid, oxalic acid, phosphoric acid, salicylic acid, succinic acid, and sulfuric acid. References to "salt" in general include references to salts formed with any acid (for instance as defined herein) or with any anion (for instance as defined for the activator). When the compound comprising an ¹⁸ F atom is a pharmaceutical or non-toxic compound, the process of the invention may further comprise using the compound in a method of PET imaging.

The activator comprises silver, gold, copper or platinum. Thus, the activator may comprise elemental silver, gold, copper or platinum, i.e. silver, gold, copper or platinum metal, or it may comprise a compound which comprises silver, gold, copper or platinum. If the activator comprises an elemental metal, it may be in the form of pellets, a mesh or a powder.

Preferably, the activator comprises a silver compound, a gold compound, a copper compound or a platinum compound. More preferably the activator comprises a silver compound or a gold compound. Most preferably, the activator is, or comprises, a silver compound.

If the activator comprises a silver, gold, copper or platinum compound, it may be a covalent compound, an organometallic compound or a salt. Typically, the compound is a salt. The compound is typically soluble in organic solvents. For instance, the compound may have a solubility of greater than or equal to 1 mmol/L in dichloromethane. The activator may therefore comprise a silver salt, a gold salt, a copper salt or a platinum salt. The metal may be in any oxidation state. The activator may for instance comprise a silver (I) salt, a silver (II) salt, a silver (III) salt, a gold (I) salt, a gold (III) salt, a copper (I) salt, a copper (II) salt, a platinum (II) salt or a platinum (IV) salt. Preferably, the activator comprises a silver (I) salt or a gold (I) salt. The activator salt typically comprises the metal as the cation and an anion. The anion is often the conjugate base of a strong acid. For instance, the anion may be selected from anions of formula (-OS(0) ₂ Z)-, (-S(0) ₂ Z)-, (-OC(O)Z) ^" , triflate (OS0 ₂ CF ₃ ) -, triflyl (S0 ₂ CF ₃ ) ^" triflimide (N(S0 ₂ CF ₃ ) ₂ ) ^" , oxide, fluoride, chloride, bromide, iodide, nitrate, perchl orate, carbonate, nonaflate (OS0 ₂ (CF ₂ ) ₃ CF ₃ ) ^" , fluorosulfonate (OS0 ₂ F) ^" , tosylate (OS0 ₂ -p- C ₆ H ₄ CH ₃ )-, mesylate (OS0 ₂ CH ₃ ) ^_ , pivalate (OOCC(CH ₃ ) ₃ ) ^_ , acetate, trifluoroacetate

(OOCCF ₃ ) ^" and tetrafluorob orate (BF4) ^" wherein Z is a group selected from halide, substituted or unsubstituted C _1-10 alkyl, substituted or unsubstituted C _2- io alkenyl, substituted or unsubstituted C _2- io alkynyl, perfluoroalkyl, substituted or unsubstituted C _3- io cycloalkyl groups, substituted or unsubstituted aryl groups and substituted or unsubstituted heterocyclyl groups. Typically, the activator comprises:

a silver salt selected from silver triflate (AgOS0 ₂ CF ₃ ), silver triflyl (AgS0 ₂ CF ₃ ), silver triflimide (AgN(S0 ₂ CF ₃ ) ₂ ), silver oxide (Ag ₂ 0), silver fluoride (AgF), silver chloride (AgCl), silver bromide (AgBr), silver iodide (Agl), silver nitrate (AgN0 ₃ ), silver perchlorate (AgC10 ₄ ), silver carbonate (Ag ₂ C0 ₃ ), silver nonaflate (AgOS0 ₂ (CF ₂ ) ₃ CF ₃ ), silver fluorosulfonate (AgOS0 ₂ F), silver tosylate (AgOSC -p-CeFLtCFb), silver mesylate

(AgOS0 ₂ CH ₃ ), silver pivalate (AgOOCC(CH ₃ ) ₃ ), silver acetate (AgOOCCH ₃ ), silver trifluoroacetate (AgOOCCF ₃ ), and silver tetrafluorob orate (AgBF4);

a gold salt selected from gold triflimide ((Ph ₃ P)Au(N(S0 ₂ CF ₃ ) ₂ ), triphenylphosphine gold triflimide ((Ph ₃ P)Au(N(S0 ₂ CF ₃ ) ₂ ), (2-di-tert-butylphosphinobiphenyl) gold triflimide (JohnPhosAu(N(S0 ₂ CF ₃ ) ₂ ) triphenylphoshine gold chloride ((Ph ₃ P)AuCl), triethylphosphine gold chloride ((Et ₃ P)AuCl), l,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene gold chloride ((IPr)AuCl), methyl (triphenylphospine) gold ((Ph ₃ P)AuMe); or

a copper salt selected from copper (I) triflate (CuOS0 ₂ CF ₃ ), copper (II) triflate (Cu(OS0 ₂ CF ₃ ) ₂ ), tetrakis(acetonitrile) copper(I) triflate (Cu(OS0 ₂ CF ₃ ).4MeCN), and tetrakis(pyridine) copper(II) trilfate (Cu(OS0 ₂ CF ₃ ) ₂ .4Pyr).

Preferably, the activator comprises a silver (I) salt selected from silver (I) triflate

(AgOS0 ₂ CF ₃ ), silver triflimide (AgN(S0 ₂ CF ₃ ) ₂ ), silver (I) trifluoroacetate (AgOOCCF ₃ ) and silver (I) tetrafluorob orate (AgBF4). Most preferably, the salt is silver (I) triflate

(AgOS0 ₂ CF ₃ ).

The activator typically consists of, or consists essentially of (e.g. greater than 95 wt%), said compound comprising silver, gold, copper or platinum or said elemental silver, gold, copper or platinum.

Typically, the amount of the activator is from 0.05 to 20 equivalents of the precursor organic compound. Often, similar amounts of activator and precursor organic compound are used during the process. For instance, the amount of the activator may be from 0.5 to 4 equivalents of the precursor organic compound. The molar ratio activator: precursor organic compound is preferably from 2: 1 to 1 :2. In some cases, the molar ratio is about 1 : 1.

The concentration of the precursor organic compound may be any suitable value, for instance from 0.01 M to 1 M. The concentration of the activator compound may be any suitable value, for instance from 0.01 M to 1 M. For instance, the concentration of the activator may be from 0.01 M to 0.6 M, preferably from 0.1 M to 0.4 M.

The use of the activator in the halogen exchange process of the invention allows

[ ¹⁸ F]fluorination to occur at surprisingly low temperatures avoiding side reactions and maintaining high specificity. Typically, the process is carried out at a temperature of from 20°C to 100°C. Often, the temperature is greater than 30°C or greater than 40°C. Preferably, the process is carried out at a temperature of from 40°C to 90°C, more preferably from 50°C to 80°C. The temperature may, for instance, be from 55°C to 65°C.

The process of the invention is typically carried out for from 10 minutes to 2 hours, for instance for about 30 minutes.

The process of the invention is usually carried out in the presence of a solvent. Thus, the process often comprises treating a composition comprising a precursor organic compound comprising a -CY ₂ X group and a solvent with:

(i) [ ¹⁸ F] fluoride; and

(ii) an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum, wherein:

X is a leaving group; and

each Y is independently selected from F, CI, Br and H. The process of the invention may be carried out in the presence of any suitable solvent.

Examples of solvents include water, alcohol solvents (such as methanol, ethanol, n-propanol, isopropanol and n-butanol), ether solvents (such as dimethylether, diethylether and tetrahydrofuran), ester solvents (such as ethyl acetate), carboxylic acid solvents (such as formic acid and ethanoic acid), ketone solvents (such as acetone), amide solvents (such as dimethylformamide and diethylformamide), amine solvents (such as triethylamine), nitrile solvents (such as acetonitrile), sulfoxide solvents (dimethylsulfoxide), hydrocarbon solvents (such as hexane, cyclohexane and benzene) and halogenated solvents (such as

dichloromethane (DCM), dichloroethylene (DCE), chloroform, and chlorobenzene).

Typically, the solvent is a non-coordinating solvent, e.g. a solvent which does not comprise an -OH group. Thus, in some embodiments, the solvent may be any of those listed above except for water, an alcohol solvent or a carboxylic acid solvent. Typically, during the process of the invention a halogenated solvent is present.

Examples of halogenated solvents include benzotri chloride, bromoform, bromomethane, carbon tetrachloride, chlorobenzene, chlorofluorocarbon, chloroform, chlorom ethane, 1, 1- dichloro-l-fluoroethane, 1, 1-dichloroethane, 1,2-dichloroethane, 1, 1-dichloroethene, 1,2- dichloroethene, dichloromethane, diiodomethane, haloalkane, halomethane,

hexachlorobutadiene, hexafluoro-2-propanol, parachlorobenzotrifluoride, perfluoro-1,3- dimethylcyclohexane, perfluorodecalin, perfluorohexane, perfluoromethylcyclohexane, perfluoromethyldecalin, perfluorooctane, perfluorotripentylamine, tetrabromomethane, 1, 1,1,2-tetrachloroethane, 1, 1,2,2-tetrachloroethane, tetrachloroethylene, 1,3,5- trichlorobenzene, 1, 1, 1-trichloroethane, 1, 1,2-trichloroethane, trichloroethylene and 1,2,3- trichloropropane. Preferably the solvent is a halogenated solvent which is dichloromethane (DCM) or dichloroethylene (DCE), which may be 1, 1-dichloroethene, 1,2-dichloroethene or a mixture thereof.

The concentration of the [ ¹⁸ F]fluoride is usually relatively low, as is typical during radiochemistry. For instance, the concentration of [ ¹⁸ F]fluoride is typically less than 1 mM, less than 1 μΜ, or less than 1 nM. For instance, the concentration of [ ¹⁸ F]fluoride may be from 1 pM to 1 mM, or lpM to 1 nM.

In a preferred embodiment of the invention, the activator comprises silver (I) triflate

(AgOSC CFs), dichloroethylene is present as a solvent, the reaction is carried out at a temperature of from 40°C to 80°C, and the amount of the silver (I) triflate is from 0.8 to 2 equivalents of the amount of precursor organic compound.

For instance, the process of the invention may comprise adding from 0.01 to 0.1 mmol of the precursor organic compound to a container comprising [ ¹⁸ F]KF/K ₂₂₂ and from 0.01 to 0.1 mmol AgOTf in from 100 to 1000 DCM or DCE. The mixture is allowed to stir at a temperature from 40°C to 80°C for 10 to 1000 minutes, optionally after which time the reaction is quenched by the addition of EtOH/H ₂ O.

In one embodiment of the invention, the process is conducted in an automated synthesizer. The automated synthesizer may be any suitable automated synthesizer, as are well known to the skilled person. Automated synthesizers may include one or more means for performing the process of the invention. For instance, an automated synthesizer may comprise one or more of (i) a means for mixing the reagents used in the process of the invention, (ii) a means for heating the mixed reagents of the invention and (iii) means for isolating the compound comprising an ¹⁸ F atom. Such automated synthesizers may be used for the production of PET ligands comprising an ¹⁸ F atom. Thus, the automated synthesizer may be suitable for use in a clinical setting, for instance in a imaging centre equipped with PET imaging and/or scanning apparatus.

An automated synthesizer may comprise one or more reagents used in the process of the invention. For example, the automated synthesizer may be pre-loaded with one or more reagents, for instance an activator as described herein or a precursor organic compound as described herein. Alternatively, the process of the invention may be conducted in an automated synthesizer, which process further comprises loading the automated synthesizer with one or more reagents. The reagents may be loaded into the automated synthesizer by inserting a pre-packaged amount of the reagent, for instance in the form of a capsule. For instance, the process of the invention may further comprise inserting a pre-packaged sample of an activator as defined herein or a precursor organic compound as defined herein into an automated synthesizer.

The process of the invention is useful for producing radiolabelled pharmaceutical compounds as described above. The invention also allows the production of precursors for useful reagents for performing -CF ₂ ¹⁸ F trifluoromethylation, and particularly Umemoto reagents (Zhang, Org. Biomol. Chem., 2014, 12, 6580-6589). Thus, in one embodiment the precursor organic compound is a compound of formula (1) or a salt thereof,

wherein:

Q is O, R', S, Se or Te, typically S, Se or Te;

X is CI, Br or I;

Y is F, CI, Br or H; each R ^A is independently a group selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, thiol, C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester, wherein two or more R ^A groups may be bonded together to form one or more rings;

R' is H, substituted or unsubstituted Ci-6 alkyl or substituted or unsubstituted aryl; and each n is independently selected from 0, 1, 2, 3 and 4.

[ ¹⁸ F]fluorinated compounds produced from compounds of formula (1) can easily be oxidised to produce trifluoromethylation agents such as Umemoto reagents. Thus, in one

embodiment, the process further comprises oxidising a compound of formula (1) or a salt thereof to produce a compound of formula (3) or a salt thereof:

wherein R ^A , n and Q are as defined for formula (1). Compounds of formula (3) herein are cationic and will be accompanied by an anion. The anion may be any suitable anion, for instance one of the anions in the silver (I) salts defined herein. Often the anion is

tetrafluorob orate or triflate.

Q is preferably S in formulae (1) and (3). Y is typically F or H in formulae (1) and (3). X and Y may be as further defined above.

Each n is typically 0, 1 or 2. Preferably each n is 0 or 1.

Typically, each R ^A is independently a group selected from unsubstituted C _1-10 alkyl, unsubstituted C2-10 alkenyl, unsubstituted C2-10 alkynyl, unsubstituted C3-10 cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, wherein two or more R ^A groups may be bonded together to form one or more rings.

Often, both n are 0 and the compound of formula (1) is unsubstituted.

The organic precursor compound may be a compound of formula (la) or a salt thereof

wherein Q is O, S, Se or Te (usually S, Se or Te), preferably S, and X is CI, Br or I.

The invention also provides the use of an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum, in a process for producing an organic compound comprising an F atom as defined herein. Thus, the invention provides the use of an activator as defined herein as an activator in [ ¹⁸ F]fluorination of a precursor organic compound by halogen exchange.

The activator may be as defined above. Preferably, the activator comprises a silver (I) salt selected from silver (I) triflate (AgOS0 ₂ CF ₃ ), silver triflimide (AgN(S0 ₂ CF ₃ ) ₂ ), silver (I) trifluoroacetate (AgOOCCF ₃ ) and silver (I) tetrafluorob orate (AgBF4). More preferably, the activator comprises silver (I) triflate (AgOS0 ₂ CF ₃ ).

The invention also provides a kit for [ ¹⁸ F]radiolabelling an organic compound, which kit comprises:

(i) an activator which comprises a compound comprising silver, gold, copper or platinum, or which comprises elemental silver, gold, copper or platinum; and

(ii) a precursor organic compound comprising a -CY ₂ X group, wherein X is a leaving group and each Y is independently selected from F, CI, Br and H.

The activator may be as further defined herein. The precursor organic compound may be as defined herein. The kit is typically in the form of packaging comprising components (i) and (ii), each of which may be present in one or more separate containers. Often, the kit further comprises instructions for carrying out a process as defined herein. The instructions may be written or may be in the form of an electronic data carrier.

The process of the invention allows facile radiolabelling of organic compounds such as those described above. This means that samples of radiolabelled compounds having high specific activity can be produced. The invention therefore provides a composition comprising a compound of formula:

R-CF ₂ ¹⁸ F;

R-CHF ¹⁸ F;

R-0-CF ₂ ¹⁸ F;

R-0-CHF ¹⁸ F;

R-N(R')-CF ₂ ¹⁸ F;

R-N(R')-CHF ¹⁸ F

R-S-CF ₂ ¹⁸ F;

R-S-CHF ¹⁸ F;

or a pharmaceutically acceptable salt thereof, and having a specific activity of greater than or equal to 50 GBq/μιηοΙ, wherein R is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and R' is H, substituted or unsubstituted Ci- ₆ alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R and R' may be as further defined herein.

The specific activity of the composition is preferably greater than or equal to 70 GBq/μτηοΙ. In some cases, the specific activity of the composition is greater than or equal to 80

GBq/μιηοΙ or greater than or equal to 100 GBq/μτηοΙ.

Often, the compound in the composition has any one of the following formulae or is a pharmaceutically acceptable salt of a compound of any one of the following formulae:

The process of the invention also allows access to [ ¹⁸ F]radiolabelled compounds which have not been produced before. The invention therefore provides a compound, which compound has any one of the following formulae or is a pharmaceutically acceptable salt of a compound of any one of the following formulae:

The invention also provides a compound of formula (2) or formula (3) or a salt of a compound of formula (2) or formula (3),

wherein:

Q is O, NR', S, Se or Te, preferably S, Se or Te;

each R ^A is independently a group selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di( C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, thiol, C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester, wherein two or more R ^A groups may be bonded together to form one or more rings;

R' is H, substituted or unsubstituted Ci-6 alkyl or substituted or unsubstituted aryl; and each n is independently selected from 0, 1, 2, 3 and 4.

As mentioned above, compounds of formula (3) are cationic and may have any suitable anion, for instance those defined for salt activators (e.g. tetrafluorob orate or triflate).

Q is preferably S. Each n is typically 0, 1 or 2. Preferably each n is 0 or 1. Typically, each R ^A is independently a group selected from unsubstituted C _1-10 alkyl, unsubstituted C2-10 alkenyl, unsubstituted C _2- 10 alkynyl, unsubstituted C3-10 cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, wherein two or more groups may be bonded together to form one or more rings.

Preferably, the compound of the invention is:

or a salt therof. For instance, the salt may comprise an anion as defined herein, for instance triflate or tetrafluorob orate.

Compounds of formula (3) may be referred to as Umemoto reagents and are useful as electrophilic sources of CF ₂ ¹⁸ F. These compounds can be reached by oxidising compounds of formula (2) to cause ring closure. The process may therefore further comprise producing and using compounds of formula (3).

Thus, the invention also provides a process for producing an organic compound comprising a -CF ₂ ¹⁸ F group, which process comprises:

(a) producing a compound of formula (2) or a salt thereof by a process as defined herein,

wherein:

Q is O, S, Se or Te, preferably S, Se or Te, more preferably S;

each R ^A is independently a group selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, thiol, C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester, wherein two or more R ^A groups may be bonded together to form one or more rings; and

each n is independently selected from 0, 1, 2, 3 and 4; and

(b) oxidising the compound of formula (2) or a salt thereof to produce a compound of formula (3) or a salt thereof:

wherein:

Q is O, S, Se or Te, preferably S, Se or Te, more preferably S;

each R ^A is independently a group selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted C _2-20 alkenyl, substituted or unsubstituted C _2-20 alkynyl, substituted or unsubstituted C _3-20 cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, thiol, C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester, wherein two or more groups may be bonded together to form one or more rings; and each n is independently selected from 0, 1, 2, 3 and 4. The process may optionally further comprise: (c) trifluoromethylating a reactant organic compound by treating it with the compound of formula (3) or salt thereof.

Typically in compounds (2) and (3), each n is typically 0, 1 or 2. Preferably each n is 0 or 1. Typically in compounds (2) and (3), each R ^A is independently a group selected from unsubstituted C _1-10 alkyl, unsubstituted C2-10 alkenyl, unsubstituted C2-10 alkynyl,

unsubstituted C3-10 cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, wherein two or more groups may be bonded together to form one or more rings. Preferably, the compound of formula

and the compound of formula (3) is

The reactant organic compound is typically a nucleophilic organic compound, i.e. a compound suitable for nucleophilic substitution of the cationic tricylic sulfur species. The reactant organic compound is oftent an organic compound comprising an alkyne group, an alkene group, a 1,3-diketone group, an aryl group, a boronic acid group or an amine group.

Step (b) of forming compound of formula (3) typically comprises treating the compound of formula (2) with a compound such as triflic anhydride (trifluoromethanesulfonic anhydride, 0(S0 ₂ CF ₃ ) ₂ ). Step (c) of trifluoromethylating a reactant organic compound by treating it with the compound of formula (3), typically comprises mixing the reactant organic compound and the compound of formula (3) in a solvent and optionally heating the mixture.

The invention will now be described further by the following Examples. EXAMPLES

Production of precursor organic compounds

The following general procedures were used to produce the precursor organic compounds used in the radiolabelling procedures.

Ar-OCF2Br and Ar-OCHFCl - General procedure

To a solution of an appropriate carboxylic acid (1.0 mmol) in DCM (2 mL) was added DMF (7.7 0.1 eq.) and oxalyl chloride (129 μL., 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. To the crude acyl chloride was added BrCC1 ₃ (3 mL), 4-dimethylaminopyridine (30.7 mg, 0.25 mmol) and sodium-N-hydroxy-2-thiopyridone (149 mg, 1.0 mmol). The reaction mixture was refluxed at 120°C for 2 hours and then concentrated in vacuo. The crude product was purified by silica gel column chromatography. Ar-CHFCl - General procedure

To a solution of an appropriate carboxylic acid (1.0 mmol) in DCM (2 mL) was added DMF (7.7 μL., 0.1 eq.) and oxalyl chloride (129 μL., 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. To the crude acyl chloride was added degassed BrCC1 ₃ (3 mL), 4-dimethylaminopyridine (30.7 mg, 0.25 mmol) and sodium-N-hydroxy-2-thiopyridone (149 mg, 1.0 mmol). The reaction mixture was stirred under UV light irradiation for 12 hours. Tetrabutylammonium chloride (0.54g, 2.0 mmol) was added and stirring was continued for 2 hrs without irradiation. After concentrating in vacuo the crude product was purified by silica gel column chromatography.

Ar-CF2Br - General procedure 1

To a solution of an appropriate carboxylic acid (1.0 mmol) in DCM (2 mL) was added DMF (7.7 μL, 0.1 eq.) and oxalyl chloride (129 μL, 1.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. To the crude acyl chloride was added degassed BrCC1 ₃ (3 mL), 4-dimethylaminopyridine (30.7 mg, 0.25 mmol) and sodium-N-hydroxy-2-thiopyridone (149 mg, 1.0 mmol). The reaction mixture was stirred under irradiation from a sunlamp (300W) for 12 hours and concentrated in vacuo. The crude product was purified by silica gel column chromatography. Ar-CF2Br - General procedure 2

To a solution of an appropriate difluoromethylarene (10.0 mmol) in degassed CC1 ₄ (30 mL) was added N-bromosuccinimide (NBS, 3.02g, 17 mmol). The reaction mixture was stirred under irradiation from a sunlamp (300W) for 18 hours, after which it was filtered over

Celite®, washed with saturated NaS ₂ 03 solution (30 mL), H ₂ O (30 mL), then dried (Na ₂ S04) and concentrated in vacuo. The crude product was purified by silica gel column

chromatography.

Ar-SCF2Br - General procedure 1

A suspension of sodium hydride (60% on oil ; 0.30g, 7.5 mmol) in degassed NMP (5 mL) was cooled in an ice bath and the appropriate thiophenol (5 mmol) was added in one portion. The mixture was stirred for 10 min at 0°C followed by 30 min at room temperature. The reaction mixture was then cooled to -78°C in a dry-ice acetone cooling bath and

dibromodifluoromethane (0.55 mL, 6 mmol) was added in one portion. The reaction flask was sealed, the cooling bath removed and the reaction mixture was stirred overnight (18 hrs) at room temperature after which it was carefully quenched by addition of H ₂ O (30 mL). The crude mixture was extracted with MTBE (3 x 25 mL) and the organic layers were washed with H ₂ O (30 mL), brine (30 mL), dried over Na ₂ SC"4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography.

Ar-SCF2Br - General Procedure 2

A solution of sodium dithionite (85% pure; 1.54g, 7.5 mmol) and disodium

hydrogenphosphate (1.06g, 7.5 mmol) in H ₂ O (20 ml) was added in one portion to a mixture of the appropriate arenedisulfide in a mixture of DMF (75 mL) and H ₂ O (5 mL) under cooling from a water bath. Dibromodifluoromethane (1.37 mL, 15 mmol) was added in one portion after which the reaction mixture was stirred overnight (18 hrs) at room temperature. The mixture was poured into H ₂ O (200 mL) and extracted with MTBE (3 x 100 mL). The organic extracts were washed with H ₂ O (100 mL), brine (100 mL), dried over Na ₂ SC"4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography.

General radiochemical procedure

The following general radiochemical procedures were used to produce [18F]radiolabelled compounds. Procedures using activators other than AgOTf were performed by replacing the AgOTf with the other activator in an amount of 0.04 mmol (unless otherwise stated).

Ar-CF ₂ Br to Ar-CF ₂ - ¹⁸ F

To a V-vial containing [ ¹⁸ F]KF/K ₂₂₂ and AgOTf (0.04 mmol) is added substrate (0.04 mmol) in DCM (300 μL). This mixture is allowed to stir at rt for 20 minutes, after which time the reaction is quenched by the addition of EtOH/H ₂ O (9: 1, 500 μL).

Ar-SCF ₂ Br to Ar-SCF ₂ - ¹⁸ F

To a V-vial containing [ ¹⁸ F]KF/K ₂₂₂ and AgOTf (0.04 mmol) is added substrate (0.04 mmol) in DCM (300 μL). This mixture is allowed to stir at rt for 20 minutes, after which time the reaction is quenched by the addition of EtOH/H ₂ O (9: 1, 500 μL). Ar-OCF ₂ Br to Ar-OCF ₂ - ¹⁸ F

To a V-vial containing [ ¹⁸ F]KF/K222 and AgOTf (0.08 mmol) is added substrate (0.04 mmol) in DCE (300 This mixture is allowed to stir at 60 °C for 20 minutes, after which time the reaction is quenched the addition of ΕΐΟΗ/Η ₂ 0 (9: 1, 500 μL).

Ar-OCHFCl to Ar-OCHF- ¹⁸ F

To a V-vial containing [ ¹⁸ F]KF/K ₂ 22 and AgOTf (0.04 mmol) is added substrate (0.04 mmol) in DCM (300 μL). This mixture is allowed to stir at rt for 20 minutes, after which time the reaction is quenched by the addition of EtOH/FbO (9: 1, 500 μL).

For Ar-CF ₂ Br to Ar-CF ₂ - ¹⁸ F and Ar-SCF ₂ Br to Ar-SCF ₂ - ¹⁸ F, yields can be increased by the use of the following conditions: to a V-vial containing [ ¹⁸ F]KF/K222 and AgOTf (0.08 mmol) is added substrate (0.04 mmol) in DCE (300 μL). This mixture is allowed to stir at 60 °C for 20 minutes, after which time the reaction is quenched the addition of EtOH/FbO (9: 1, 500 μL).

Optimisation and substrate scope

Throughout the examples, percentages given for products represent radiochemical yield (RCY).

Aryl-CF2-Br to Aryl-CFr- ¹⁸ F

The process conditions for this conversion were optimised by performing the procedures below. A solvent screen was performed confirming that non-coordinating solvents such as dichloromethane (DCM) and dichloroethylene (DCE) are preferred.

(0.04 mrnol)

The reaction was performed with and without the silver triflate confirming the importance of the activator in the halogen exchange radiofluorination.

The effect of the presence of aryl halides was investigated.

The metal catalysts were screened showing that a wide range of activators can be used.

The effect of the stoichiometry was investigated.

The "thermal reaction" without the halogen exchange activating activator was performed as a comparison.

The reaction was then performed on a number of different substrates to determine the substrate scope of the reaction. Radiofluorination of electron rich and electron poor aryl compounds was found to be possible.

The activators were screened.

The activator, solvent and temperature were screened. The reaction was then performed on a number of different substrates to determine the substrate scope of the reaction. Radiofluonnation of electron rich and electron poor substrates was found to be possible.

A comparison was made between the method of the invention and a thermal method. The method of the invention produces substantially higher radiochemical yields (RCY).

Metai Catalysed Thermal Reaction

The reaction was then performed on a number of different substrates to determine the substrate scope of the reaction. Radiofluorination of electron rich and electron poor substrates was found to be possible.

A solvent screen was performed which demonstrated that non-coordinating solvents such as DCM and DCE are preferred.

A screen of metal activators was performed.

The thermal reaction was performed in a number of solvents for comparison.

Different stoichiometnes of the activator and substrate precursor compound were investigated.

The reaction was performed on a number of different substrates to determine the substrate scope of the reaction. Radiofluorination of electron rich and electron poor substrates was found to be possible.

Production of radiolabelled celecoxib

The COX-2 selective nonsteroidal anti-inflammatory drug (NSAID) celecoxib was successfully [ ¹⁸ F]radiolabelled using the process of the invention at 60°C. A protected precursor comprising a -CF ₂ Br group was prepared and this was converted by the process of the invention at two different temperatures.