There is much interest in medicine in the investigation of the properties and actions of biologically active compounds in the body. In particular, the pharmacokinetics and bio-distribution of an active compound in the body is of interest during the development of new drugs and treatments. Investigations can be carried out using non-invasive means by administering labelled active compounds and monitoring their distribution, bioavailability etc in the body.

An example of a technique used for such investigations is Positron Emission Tomography (PET) which monitors the distribution of positron emitting isotopes such as 18F or compounds labelled with position emitting isotopes such as 18F in the body. There is therefore a need in the art for methods of manufacturing such labelled compounds.

The introduction of fluorine into aromatic systems is usually carried out in the art using electrophilic fluorine reagents ("F"). Examples of such electrophilic reagents include F2, XeF2, AcOF, CF3COOF, Selectfluor and N- fluorosulfonimides. Synthesis of these radiolabelled reagents is problematic however as the positron emitting isotope [18F] F2 used to produce these reagents can only be obtained with a relatively low specific activity.

Production of 18F with a high specific activity without added carrier can be carried out only for the fluoride ion [18F] F-.

Previous work using the fluoride ion [18F] F has concentrated on the fluoridation of electron deficient arene groups, including conventional aromatic nucleophilic substitution using a [18F] F anion to displace a suitable leaving group from an electron deficient benzene ring as indicated in scheme 1.

Scheme 1 wherein R is 2-or 4-electron withdrawing group and L is a suitable leaving group such as fluoride, bromide, nitrite, tertiary amine or iodoarene.

The most commonly used process to produce fluoroarenes from nucleophilic F- uses the Balz-Schieman reaction as indicated in scheme 2.

Scheme 2 wherein F* is'gF or 19F and (i) corresponds to [18F] F- and (ii) heat.

The partially labelled [18F] tetrafluoroborate is initially prepared by the exchange of the BF4-fluorine (s) with [18F] F-. The partially labelled aryldiazonium [18F] tetrafluoroborate then gives the partially labelled [18F] fluoroarene on thermal decomposition. While the Balz-Schieman reaction allows the production of the fluoroarene, only one fluorine atom from the fluoroborate is transferred and thus the maximum radiochemical yield is 25%.

In practise, as little as 2% radiochemical yield is observed.

The unfavourable radiochemical yield observed in the Balz-Schiemann reaction can be addressed by using a non-carrier added (NCA) intermediate such as aryldiazonium tetrachloroborate but this results in unsatisfactory chemical yields.

A NCA [18F] fluoroarene synthesis uses the diaryliodium salt. As indicated in scheme 3 below, the diaryliodonium salt cleaves on reaction with a fluoride source to form a fluoroarene and an iodoarene.

Scheme 3 wherein X is F or I, or the counter-ion Z and Y is I or F or the counter-ion Z.

It is postulated that fluoridation of the diaryliodonium salt depends on a balance of two effects : the relative electronic effects of the substituents R and R'and the relative steric effects of R and R'on the T-shaped intermediate generated. Of these effects, it appears that the electronic effect is predominant.

Investigations with the diaryliodonium salt have found that fluoridation occurs preferentially on the electron deficient arene (i. e. X is fluoride when the substituent R in scheme 3 is electron withdrawing).

While there have been a number of disclosures of fluoridation at electron deficient arenes as discussed above, the fluoridation of compounds containing electron rich arenes is more problematic. A number of biologically active molecules contain electron rich arenes. However, difficulties in fluoridating electron rich arenes means that the production of such compounds labelled with

18F is understood in the art to be extremely problematic and in some cases, not possible. There is a need in the art for the synthesis of biologically active molecules labelled with 18F. Example of biologically active molecules containing electron rich arene moieties include 6-fluoro-m-tyramine and 6F- DOPA.

Taking 6F-DOPA as an example, previous attempts to produce fluoridated DOPA using a fluoride ion involve an aromatic nucleophilic substitution reaction early in the synthesis. In order to complete the preparation of fluoridated DOPA it has been necessary to carry out a number of time consuming synthetic steps. The time effective radiochemical yield produced for fluorinated DOPA was therefore low because of the relatively short half-life of 18F (tlX2 110 min).

The methods of fluoridation in the art limit the variety of 18F-labelled compounds which can be produced due to the restriction of fluoridation to electron deficient arenes.

Introduction of the fluoride group onto an electron rich aryl ring presents a number of difficulties. The presence of substituents with electron donating properties result in an electron rich aryl group, which is not susceptible to attack by the nucleophilic fluoride group. While the prior art provides methods of fluoridating an electron-deficient aryl, there is no teaching regarding the fluoridation of an aryl group which is substituted with an electron donating group such as alkoxy. As discussed above, a number of biologically active compounds contain electron-rich fluoroarene moieties, which are not suitable for established fluoridation methods. There is therefore a need in the art for a method of fluoridating an electron rich aryl group.

The first aspect of the present invention provides a process for the fluoridation of an electron rich aryl group A comprising the steps of contacting a compound of formula I with a source of fluoride, <BR> <BR> <BR> <BR> <BR> <BR> <BR> +<BR> <BR> <BR> <BR> <BR> <BR> <BR> A#I#B (I) wherein A is a 5 or 6-membered aryl or heteroaryl group optionally substituted with one or more of hydrogen, Cl l2 alkyl, C6 12 aryl, C5 12 heterocyclyl, OR, SR6, CO2R6, NR6R6, CO2NR6R6, NR6CO2R6, NR6COR6, OCOR6 or halogen; the C1-12 alkyl group optionally incorporating one or two insertions selected from the group consisting of-O-,-C (O)-,-N (R6)-,-S (O)- and-S (02)- wherein each R6 may be the same or different and is as defined below; wherein the C1-12 alkyl, C6-12 aryl or C5 l2 heterocyclyl group above is optionally substituted with one or more of Cl 6 alkyl, C6_12 aryl, OR7, CO2R7, NR7R7 or halogen, wherein R6 is hydrogen, C1-12 alkyl, C6-12 aryl, C5-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, Cl 6 haloalkyl, OR8, SR8, N02, CN, NR8R8, NR8COR8, NR8CONR8R8, NR8COR8, NR8CO2R8, CO2R8, COR8, CONR82, S (O) 2R8, S (O) R8, SO2NR8R8, NR8S(O)2R8, wherein the Cl l2 alkyl group optionally incorporates one or two insertions selected from the group consisting of-O-,-N (R8)-,-S (O)-and-S (O2)-, wherein each R8 may be the same or different and is as defined below; R7 is hydrogen, Cl_6 alkyl or C1-6 haloalkyl.

R8 is hydrogen, C1-6 alkyl, or Cl-6 haloalkyl ;

and wherein at least one of Rl, R2, R3, R4 and R5 is an electron-donating group ; and B is an optionally substituted aryl group wherein said optional substituents are those as described for the group A, wherein the ring B is more electronegative than the ring A.

Preferably A is an optionally substituted 5 or 6-membered aryl or heteroaryl group, wherein said aryl or heteroaryl group can be optionally fused to a partially saturated, unsaturated or fully saturated three to seven membered ring, preferably a 5 to 7-membered ring containing zero to three heteroatoms, preferably selected from NR6, S or O ; More preferably, A is an aryl of formula (II) or heteroaryl group of formula (IIIa) or (IIIb) (II) (IIIa) (IIIb) wherein any one or more of G, H, J, L, M or Q is a heteroatom such as NR6, S or O and the remaining of G, H, J, L, M or Q are carbon atoms; As discussed above, the aryl or heteroaryl group can be fused to a partially saturated, unsaturated or fully saturated three to seven membered ring, preferably a 5 to 7-membered ring, containing zero to three heteroatoms, preferably selected from NR6, S or O, wherein preferably A is an aryl group of formula (IIa) fused to a partially saturated, unsaturated or fully saturated three to seven membered ring containing one to three heteroatoms;

wherein R1, R2, R3, R4 or Rsare independently hydrogen, C1-12 alkyl, C6-12 aryl, Cs-12 heterocyclyl, OR6, SR6, CO2R6, NR6R6, CO2NR6R6, NR6CO2R6, NR6COR6, OCOR6 or halogen; the CI 12 aLkyl group optionally incorporates one or two insertions selected from the group consisting of-O-,-C (O)-,-N (R6)- <BR> <BR> <BR> , -S (0)- and-8 (02)- wherein each R6 may be the same or different and is as defined below; wherein the alkyl, aryl or heterocyclyl group is optionally substituted with one or more of C1-6 alkyl, C6-12 aryl, OR7, CO2R7, NR7R7 or halogen, and wherein at least one of Ru, R2, R3, R4 or R5 is an electron-donating group, preferably wherein one or more of Ru, R2, R3, R4 or R5 is NR62, NR6COR6, oR6, OCCR6, SR6 or 6-12 aryl ; wherein R6 is hydrogen, Cl i2 alkyl, C6-iz aryl, C5-12 heterocyclyl, optionally substituted by one or more of C1-6 alkyl, halogen, Cl 6 haloalkyl, OR8, SR8, NO2, CN, NR8R8, NR8COR8, NR8CONR8R8, NR8COR8, NR8CO2R8, C02R8, COR8, CONS'2, S (0) 2reg, S (O) R8, SO2NR8R8, NR8S(O)2R8, wherein the Cl l2 alkyl group optionally incorporates one or two insertions selected from the group consisting of-O-,-N (R8)-,-S (O)- and -S(O2)-, wherein each R8 may be the same or different and is as defined below; R7 is hydrogen, C1-6 alkyl or Cl 6 haloalkyl ; R8 is hydrogen, C1-6 alkyl, or Cl 6 haloalkyl ;

and if the aryl or heteroaryl group A is fused to a 3 to 7-membered ring, each substitutable atom in the fused ring can be optionally substituted with a substituent as defined for the groups Rl to R5 In a more preferred feature of the first aspect, one of R1 or Rs is not hydrogen, preferably one or more of R1 or R5 is a sterically hindering group, preferably having a volume equal to or greater than that of a methyl radical, more preferably one or more of R1 or R5 is Cl l2 aLkyl or C3 12 aryl optionally substituted with one or more of Cl io alkyl, C6-12 aryl, Cs-iz heterocyclyl, OR6, SR6, CO2R6, NR6R6, CO2NR6R6, NR6CO2R6 or halogen.

Preferably B is an aryl group having the formula (IV), wherein R9, R'O, R", R12 or R13 are as defined for Ru, R2, R3, R4 or R5 and wherein ring B is more electronegative than ring A.

More preferably one or both of R9 or R'3 are not a sterically hindering group, preferably one or both of R9 or R13 have a volume less than that of a methyl radical wherein one or both of R9 or R13 is preferably hydrogen.

The present invention provides a process for the fluoridation of the electron rich arene group A (i. e. the"target ring") said process being previously unknown in the art. The inventors have found that for an diaryliodium salt where the non-target ring (B) is more electronegative (i. e. contains a greater density of electrons) than the target ring (A), fluoridation occurs at the target A

ring, even if the target A ring is electron rich. The application of this invention can be used to produce fluoridated electron rich arenes, whose synthesis was previously not available by conventional methods.

For the purposes of this invention fluoridation can involve the introduction of 8f or 19F. The source of fluoride can provide fluoride as labelled (for example [18F] F- or unlabelled fluoride. Examples of reagents that provide unlabelled fluoride include caesium fluoride. Labelled fluoride can be introduced using potassium Kryptofix [18F-].

It will be appreciated that functionalities such as OH, CO2H or NH2, present as a substituent on the target ring A, may require protection during the process outlined above. Suitable protecting groups for the purposes of this invention should not be labile in the acidic reaction conditions and include methyl, benzoyl and phthalimide groups.

For the purpose of this invention the target A-ring is electron rich i. e. has an electron density higher than that of benzene.

For the purposes of this invention, the term electron-donating group includes any group that can donate electrons to an aryl or heteroaryl group. Preferred electron-donating groups contain one or more lone pairs of electrons that are available to the aryl ring by resonance effects. Examples of such electron- donating groups include NR62, NR6COR6, OR, OCOR6, SR6, or C6-12 aryl, wherein R6 is as previously defined.

For the purposes of this invention,"alkyl"means a straight chain or branched alkyl radical of 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms and most

preferably 1 to 4 carbon atoms including but not limited to methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl etc.

"Aryl"means an aromatic 3-10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to phenyl, napthyl, anthracenyl or phenanthracenyl.

Heteroaryl"means an aromatic 3-10 membered aryl containing one or more heteroatoms selected from N, O or S and containing one ring or being fused to one or more saturated or unsaturated rings and.

"Heterocyclyl"means a 3-10 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl groups including e. g. cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, and trithiane ;.

Halogen means F, Cl, Br or I.

In a preferred feature of the first aspect, the compound of formula I further comprises a counter ion Z. Z-is preferably less nucleophilic than the fluoride nucleophile. Examples of such counter ions include trifluoroacetate, trifluoromethane sulfonate or an arenesulfonate. Alternatively, the counter ion can be a non-nucleophilic counter ion such as tetraphenylborate.

The present invention provides a method of fluoridation of electron rich arenes. It will be appreciated by a person skilled in the art that the degree of fluoridation required will depend on the required use of the final compound and/or the sensitivity of any detection apparatus used to detect the compound.

It is not necessary to obtain fluoridation with [l8F] F at 100% radiochemical yield for a compound to be useful in a technique such as PET. Instead fluoridation can be obtained at a level of 0.1-99%. It will be appreciated that for the purposes of this invention, fluoridation preferably occurs at a level of 40-90% radiochemical yield, more preferably 50-100%. However levels of fluoridation of 1-40% radiochemical yield, or 5 to 25% radiochemical yield are acceptable for the purposes of this invention. When the electron densities on the target (A) and the non-target (B) ring are similar, it is possible that fluoridation will occur on both the A and the B rings to varying extents. Such an outcome is consistent with the present invention. Fluoridation at the non- target B ring is not excluded from the present invention provided that fluoridation also occurs at the target A ring. Preferably, the extent of fluoridation at the target A ring is greater than that at the non-target B ring.

Similarly, if fluoridation occurs at the target A ring when said ring has a higher electron density than the B ring, this outcome is further encompassed by the present invention.

It will be appreciated by a person skilled in the art that the electron density on the A-ring can be decreased by modification of the substituents thereon or by modification of the A-ring itself. The A-ring or its substituents may therefore be modified to decrease the electron density of the A-ring prior to the fluoridation reaction of the present invention. Such modification can be removed subsequent to the fluoridation reaction. Such modification of the substituents (including functional group protection, functional group interconversion) or directly on the A-ring (by the introduction of a group which will decrease the electron density on the A-ring) will be carried out in particular when the unmodified A-ring has a higher electron density than the B- ring. In this case such modification will preferably decrease the electron density on the A-ring to equal to or less than the electron density of the B-ring.

Modification of the A-ring or the substituents on the A-ring can be carried out by methods well known to those in the art.

Fluoridation at the electron rich A ring can be further enhanced by the presence of one or more sterically hindering groups at the ortho position to the iodine group on the target A ring. Without being bound by scientific theory it is proposed that the presence of one or more substituents at the ortho position of the A ring forces the diaryliodonium salt into a conformation which favours fluoridation via ipso substitution at the A ring. This steric effect can be used to improve the degree of fluoridation on electron rich target A rings. Indeed, the presence of such sterically hindering groups can be used to drive fluoridation onto the target A ring even if the A ring has a higher electron density than the non-target B ring.

In a particularly preferred feature of the first aspect, there is provided a process for the production of a compound of formula (VI)

by the fluorination of a compound of formula (V) wherein R is C1-6 alkyl, optionally substituted with one or more of CO2R21, NHR22, preferably R13 is methyl or ethyl.

R14 is hydrogen or Cl 6 alkyl, preferably methyl or C1-6 alkoxy, preferably methoxy; R15 is hydrogen hydroxy or OBz; R16 is hydrogen or OR21 ; R17 is hydrogen; Rlg is hydrogen or OR21 ; R19 is hydrogen or methyl; and Wo is hydrogen or OR21 wherein R21 is hydrogen or C1-6 alkyl, preferably methyl or ethyl and R22 is hydrogen or an amino protecting group such as acyl, phthalyl benzyl etc.

Fluoridation of the compound of formula (V) can be carried out using a source of fluoride, such as caesium fluoride.

The compound of formula (V) is prepared from compound (VII) as illustrated.

(VII) (V) wherein W is for example acetate or trifluoroacetate.

Alternatively, the compound of formula (V) can be produced from a compound of formula (VIII) ; (VIII) (V) wherein X is SnR3 or B (OR) 2.

Compounds (VII) and (VIII) can be prepared from commercially available starting materials using methods and techniques well known in the art.

The second aspect of the invention relates to a product as produced by the process of the first aspect of the invention.

All preferred features of the first aspect of the invention apply to the second aspect mutandis mutandi.

The invention will now be illustrated by reference to one or more of the following non-limiting examples.

EXAMPLES The functionalised diaryliodonium salts of the present invention can be synthesised according to Shah et al, J. Chem. Soc., Perkin Trans. 7, 1997, 2463.

Reaction of diaryliodonium salts with cold CsF: general method The diaryliodonium salt (0.04 mmol) in anhydrous acetonitrile (0.5 ml) was treated with CsF (0.02 mmol), in a pyrex flask, under N2. The flask was heated in an oil both to 85°C, with stirring for 40 min. The flask was allowed to cool to room temperature and the products in solution were identified (by comparison with standards) and their relative yields estimated by GC-MS.

Reaction of diaryliodonium salts with [18F] F K-APE 2.2. 2: general method The diaryliodonium salt (20 mg) along with acetonitrile (0.5 ml) was added to a glassy-carbon vessel containing dry [18F] F-K+-APE 2.2. 2 (ca. 110 MBq). The vessel was sealed, pressurised to 20 psi with nitrogen and heated to 85°C for a reaction time of 40 min. The vessel was allowed to cool to room temperature and the solution was analysed for radiochemical products by radio-HPLC. The radiochemical yields of [18F]-fluoroarenes (decay-corrected) were calculated

from the radio-chromatograph relative to the amount of unreacted starting [l8F] fluoride present after the reaction.

Reaction of diaryliodonium salts with Cs+ [18F] F- : general method The diaryliodonium salt (20 mg) along with acetonitrile (0.5 ml) was added to a glassy-carbon vessel containing dry Cs+ ["F] F- (ca. 110 MBq). The vessel was sealed, pressurised to 20 psi with nitrogen and heated to 85°C for 40 min. The vessel was allowed to cool to room temperature and the solution was analysed for radiochemical products by radio-HPLC. A B W Ratio Yield (%) Target Non-target AF : BF CFsSOgI80" Me CF3SO3 100 : 0 96a Me I I-zz Me- Me Me Me Me Me"'Me li Me Me Me

aradiochemical yield