WO2007141529A1

WO2007141529A1 - Fluoridation method

Info

Publication number: WO2007141529A1
Application number: PCT/GB2007/002095
Authority: WO
Inventors: Michael Andrew Carroll; John Woodcraft
Original assignee: Ge Healthcare Limited; The University Of Newcastle Upon Tyne
Priority date: 2006-06-09
Filing date: 2007-06-07
Publication date: 2007-12-13

Abstract

The invention relates to a method for preparing a meta-fluoro pyridyl compound which comprises reaction of a compound of formula (I): with a fluoride ion source, suitably a [18F]fluoride source, wherein: the pyridyl ring is optionally substituted by 1 to 4 organic substituents.

Description

FLUORIDATION METHOD

The present invention relates to the field of fluoridation chemistry and in particular to radiofluoridation. Specifically, the invention relates to a novel method for the fluoridation of pyridyl derivatives.

The meta position of pyridine has been shown by the prior art to be unreactive to nucleophilic fluorination.

Karramkam et al; J. Labelled Compounds and Radiopharmaceuticals (2003), 46, 979-992 describes a study of radiofluorination reactions on pyridyl compounds by displacement of a leaving group (-Cl, -Br, -I, -NO₂, and -N⁺Me₃). Whilst ortho and para radiofluoridation was achieved in up to 72% yields, meta fluoridation was only achieved with a maximum 2% yield.

A review of 18F-labelled fluoropyridines by DoIIe; Current Pharmaceutical Design (2005), H, 3221-3235 states that "in the pyridine series, mefa-fluorination is normally not of interest for the preparation of a radiotracer by nucleophilic heteroaromatic substitution", giving only one example of a meta-[¹⁸F]fluoropyridine derivative known in which the structure bears an activating group.

Abrahim et al, J. Labelled Compounds and Radiopharmaceuticals (2006), 49, 345- 356 describes preparation of a meta-[¹⁸F]fluoropyridyl derivative but in only 6 to 10% non-decay-corrected yield.

Therefore, there exists a need for improved methods for the preparation of meta- fluoro pyridyl compounds, particularly in the field of [¹⁸F] radiochemistry.

According to the invention, there is provided a method for preparing a mefa-fluoro pyridyl compound which comprises reaction of a compound of formula (I):

with a fluoride ion source, wherein: the pyridyl ring is optionally substituted by 1 to 4 organic substituents; Y^" is an anion;

5 R¹-R⁵ are independently selected from hydrogen, nitro, cyano, halogen, CM₀ hydroxyalkyl, C_2-iocarboxyalkyl, C_M0 alkyl, C_2-io alkoxyalkyl, hydroxy, C-Moalkoxy, C₁-₁₀ aminoalkyl, C_M0 haloalkyl, C_6-M aryl, C_3-I₂ heteroaryl, C_3-2o alkylaryl, C_5-I₂ arylene, C₂-io alkenyl, C_2-io alkynyl, C-MO acyl, C_7-io aroyl, C_2-i₀ carboalkoxy, C_2-i₀ carbamoyl, C_2-I0 carbamyl, or C_M0 alkysulphinyl, or protected versions of any of io these groups; or alternatively forms a four- to six-membered ring together with the R group to which it is adjacent and the carbons to which they are attached which four- to six-membered ring is optionally substituted by two to four substituents independently selected from those listed for R¹-R⁵ , or a protected derivative thereof.

15

The optional organic substituents on the pyridyl ring are suitably selected from : - ^• .fluorό, chloro, bromo, iodo, cyano, nitro; _^R, -OR, -OC(O)R,>C(O)R, -SR, -NR₂,/

-C(O)NR₂, -N(R)COR wherein R at each occurrence is selected from C_halky!,

C_2-6alkenyl, C_2-6alkynyl, Ci_-6alkoxy-Ci_-6alkyl, Ci_-6haloalkyl, C_2-6haloalkenyl, 20 C_2-6haloalkynyl, Ci_-6 haloalkoxy-C_1-6alkyl, C_4-i₂aliphatic cyclic system, Cs-^aryl,

C_5-I₂ hetaryl; wherein said aryl and hetaryl substituents may be further substituted by the non- aryl and non-hetaryl substituents listed for the pyridyl ring; or two adjacent susbstituents together with the carbons to which they are attached 25 form a four to six membered ring which is optionally substituted by two to four substituents selected from those listed as substituents of the pyridyl ring; and a protected derivative of any thereof. Y is an anion, suitably selected from trifluoromethane sulphonate (triflate), methane sulphonate (mesylate), trifluoroacetate, toluene sulphonate (tosylate) and perfluoro C₂-Cioalkyl sulphonate (for example, nonaflate or hexaflate).

5 R¹ to R⁵ are most suitably each hydrogen. In one aspect, one of the groups R¹ to R⁵ (for example the group R³) is Ci-i₀alkoxy, such as methoxy, and the others are each hydrogen.

The resultant product of the method according to the invention is a meta-fluoro o pyridyl compound of formula :

wherein the pyridyl compound is optionally substituted as described for the compound of formula (I).

5 The method according to the invention i.e. reaction of a compound of formula (I) with fluoride, suitably [¹⁸F]fluoride may be effected using a fluoride source such as NaF, KF, CsF, tetraalkylammonium fluoride, or tetraalkylphosphonium fluoride, suitably an [¹⁸F]fluoride source such as Na¹⁸F, K¹⁸F, Cs¹⁸F, tetraalkylammonium [¹⁸F]fluoride, or tetraalkylphosphonium ¹⁸F fluoride. To increase the reactivity of θςj the fluoride, a.phase transfer catalyst such as an aminopolyether or crown ether, > for example, 4,7,13,16,21 ,24 hexaoxa-1 ,10-diazabicyclo[8,8,8] hexacosane (Kryptofix 2.2.2) may be added and the reaction performed in a suitable solvent. These conditions give reactive fluoride ions. Optionally, a free radical trap may be used to improve fluoridation yields, as described in WO 2005/061415 . The term 5 "free radical trap" is defined as any agent that interacts with free radicals and inactivates them. A suitable free radical trap for this purpose may be selected from 2,2,6,6-Tetramethylpiperidine-N-Oxide (TEMPO), 1 ,2-diphenylethylene (DPE), ascorbate, para-amino benzoic acid (PABA), α-tocopherol, hydroquinone, di-t-butyl phenol, β-carotene and gentisic acid. Preferred free radical traps for use 0 in the method of the invention are TEMPO and DPE, with TEMPO being most preferred. The treatment with fluoride, suitably [¹⁸F]fluoride may be effected in the presence of a suitable organic solvent such as acetonitrile, dimethylformamide, dimethylsulphoxide, dimethylacetamide, tetrahydrofuran, dioxan, 1 ,2 dimethoxyethane, sulpholane, N-methylpyrolidininone, or in an ionic liquid such as an imidazolium derivative (for example 1-ethyl-3-methylimidazolium hexafluorophosphate), a pyridinium derivative (for example, 1-butyl-4- methylpyridinium tetrafluoroborate), a phosphonium compound, or tetralkylammonium compound at a non-extreme temperature, for example, 15°C to 180°C, preferably at elevated temperature, such as 80⁰C to 150⁰C, for example around 120°C.

In one aspect of the invention, the solvent used is dry, meaning that the level of water present is 1000 ppm or less, more suitably 600 ppm or less, and preferably lOOppm or less.

In one aspect of the invention, the fluoride used in the method of the invention is [¹⁸F]fluoride. There is particular need for novel radiofluoridation methods, especially for radiofluoridation of non-activated pyridyl systems.

"Alkyl" used either alone or as part of another group is defined herein as any "^■■. straight, branched or cyclic, saturated hydrocarbon group; having unless otherwise specified, 1 to 6 carbon atoms.

"Aryl" used either alone or as part of another group is defined herein as any C_6-H molecular fragment or group which is derived from a monocyclic or polycyclic aromatic hydrocarbon, or a monocyclic or polycyclic heteroaromatic hydrocarbon.

The term "halogen" means a group selected from fluorine, chlorine, bromine, and iodine, including all isotopes thereof.

Suitable protection for R¹ to R⁵ and any organic substituents on the pyridyl ring may be achieved using standard methods of protecting group chemistry. After the fluoridation is complete, any protecting groups may be removed by simple procedures which are also standard in the art. Suitable protection and deprotection methodologies may be found, for example, in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc.

In a further aspect of the invention, the compound of formula (I) used in the methods of the invention is solid support-bound as in a compound of formula (II):

Y^"

SOLID _(||)

wherein the pyridyl ring is optionally substituted as defined for the compound of formula (I); and, the phenyl ring is unsubstituted or has 1 to 4 optional substituents as defined for R¹ to R⁵ and Y are as defined above for the compound of formula (I).

In the compound of formula (II), the "solid support" may be any suitable solid- phase support which is insoluble in any solvents to be used in the process but to which the linker can be covalently bound. Examples of suitable solid support¹ include polymers such as polystyrene (which may be block grafted, for example with polyethylene glycol), polyacrylamide, or polypropylene or glass or silicon coated with such a polymer. The solid support may be in the form of small discrete particles such as beads or pins, or as a coating on the inner surface of a cartridge or on a microfabricated vessel.

In the compound of formula (II) the "linker" may be any suitable organic group which serves to space the reactive site sufficiently from the solid support structure so as to maximise reactivity. Suitably, the linker comprises zero to four aryl groups and/or Ci-2o alkyl, C2-20 alkoxyalkyl or Ci_-2o haloalkyl, and optionally one or more additional substituents such as oxygen, halogen, amide or sulphonamide. The linker may also suitably be a polyethylene glycol (PEG) linker. Examples of such linkers and solid supports are well known to those skilled in the art of solid-phase chemistry, for example as described in Florencio Zaragoza Dorwald Organic Synthesis on Solid Phase; Supports, Linker, Reactions", Wiley-VCH (2000).

In a further aspect of the invention, the compound of formula (I) comprises a quinoline ring:

Y^"

wherein the quinoline is optionally substituted by 1 to 6 organic substituents as defined for the compound of formula (I) above.

This aspect of the invention may also be performed using a solid support-bound reagent as in a compound of formula (Ma):

SOLID

wherein the quinoline is optionally substituted by one to six organic substituents as defined for the compound of formula (I); and, the phenyl ring has 1 to 4 optional substituents as defined for R¹ to R⁵ above and Y is an anion.

Whether the method of the invention is carried out in solution or on a solid phase, the fluorine-labelled compound of the invention is preferably an [¹⁸F]-labelled compound and the fluoride ion source is preferably a source of ¹⁸F . Most preferably, the [¹⁸F]-labelled pyridyl compound prepared is an [¹⁸F]-labelled radiotracer, i.e. an [¹⁸F]-labelled compound that is suitable for the detection by PET imaging of particular biological targets within a subject.

The [¹⁸F]-labelled pyridyl compound is suitably selected from the compounds listed in the first column of Table I. The respective precursors of formula (I) of these [¹⁸F]-labelled tracers are given in the second column of Table I, in which R¹ to R⁵ are as defined for the compound of formula (I) above, Y^" is an anion, and any reactive substituents may be optionally protected during the fluoridation reaction by methods described above. Table I

Following the methods of the invention, the resultant mefa-fluoropyridine or meta- fluoroquinoline may be the subject of further routine steps, for example:

(i) purification;

(ii) removal of any protecting groups;

(iii) removal of organic solvent;

(iv) formulation, for example as an aqueous solution.

Purification step (i) may be performed for example to remove unwanted byproducts or excess reagents such as fluoride. Suitable techniques are well known in the art and include ion-exchange chromatography (for example using BIO-RAD AG 1-X8 or Waters QMA) and use of solid-phase absorbents (such as alumina). Excess fluoride may be removed using such solid phases at room temperature in aprotic solvents.

Removal of any protecting groups in step (ii) may be effected by standard methods known in the art, and as described in Protecting Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (see above).

Removal of organic solvent in step (iii) may be effected by standard methods known in the art such as by evaporation at elevated temperature in vacuo or by passing a stream of inert gas such as nitrogen or argon over the solution.

Formulation step (iv), may be effected by standard methods known in the art. Typically [¹⁸F]fluorinated products may be formulated as an aqueous solution by dissolving the product in sterile isotonic saline which may contain up to 10% of a suitable organic solvent such as ethanol. or a suitable buffered solution such as phosphate buffer. Other additives may be added such as ascorbic acid to reduce radiolysis.

5 The compounds of formula (I) may be prepared from the corresponding meta-iodo pyridine or quinoline as described in the following examples. Methods for attachment to a solid support to form a compound of formula (II) are well known in the art, for example as described in Florencio Zaragoza Dorwald Organic Synthesis on Solid Phase; Supports, Linker, Reactions", Wiley-VCH (2000). 0

Conveniently, the compounds of formula (I), (Ia), (II), or (Ma) could be provided as part of a kit to a radiopharmacy. The kit may contain a cassette which can be plugged into an automated radiosynthesiser. The cassette may contain, the precursor compound of formula (I), (Ia), (II), or (Ma), one or more purification 5 columns, and one or more reaction vessels. The reagents and solvents and other consumables required for the synthesis may also be included in the kit as may a compact disc carrying software which allows the radiosynthesiser to be operated.

Therefore, in a further aspect of the invention, there is provided a o radiopharmaceutical kit for the preparation of a mete-[¹⁸F]fluoro pyridyl compound which comprises : r '(i) a vessel containing a compound of formula (I), (Ia), (II), or (Ma) as defined:iri. above; and (ii)means for eluting the vessel with an [¹⁸F]fluoride source. 5

The invention will now be illustrated by way of the following non-limiting examples in which these abbreviations are used: ppm: parts per million h. : hour(s) 0 ml_: millilitre(s) g : gram(s) mp : melting point DCM : dichloromethane

MeOH: methanol

RCP : radiochemical purity, defined as the amount of desired radioactive product as a percentage of all radioactivity.

RCY : radiochemical yield, defined as the RCP multiplied by the decay-corrected percentage of radioactivity recovered from the reaction vessel.

THF : tetrahydrofuran

Examples

Example 1 : Synthesis of 3-f¹⁸F1fluoropyridine

Example 1 (i) 3-lodopyridine Dichlόride

This experiment was carried out in a well ventilated fume hood. Chlorine gas was generated by drop-wise addition of concentrated hydrochloric acid on to potassium permanganate. The gas evolved was bubbled through water to remove any HCI -^ ;gas, then through the reaction mixture then twice through 20% sodium hydroxides solution to destroy any un-reacted chlorine. A chlorine gas detector was used throughout the experiment and was set to alarm at 0.10 ppm. The exhaust and joints were monitored for trace amounts of chlorine using wet starch paper.

Chlorine gas was bubbled slowly through a stirred solution of 3-iodopyridine (0.79 g, 5 mmol) in chloroform (150 ml_) at 0 ⁰C for 0.5 h. The resulting suspension containing a bright yellow crystalline solid was warmed to room temperature for 1 h when it was re-cooled to 0⁰C and the precipitate collected by filtration and washed with hexane (50 ml_) and dried in vacuo to give the title compound as a yellow crystalline solid which was used without further purification. (1.11 g, 4.85 mmol, 97%); mp 128-129 ⁰C dec. (from CHCI₃). Example Kii) : 3-Diacetoxyiodopyridine

OAc ^OAc

3-lodopyridine dichloride (1.66 g, 5 mmol) was added to 1OM aqueous sodium 5 hydroxide (10 ml_) solution with stirring and the suspension was stirred for 0.5 h when the solid was collected by filtration and washed with water (5 ml_) and air dried for 0.5 h. The colourless solid was then added to acetic acid (5 ml_) and stirred at room temperature for 0.5 h when water (30 ml_) was added and the mixture was extracted with dichloromethane (2 * 50 ml_), dried (MgSO₄) and l o concentrated in vacuo to give a yellow oil. Crystallisation gave the title compound as a colourless crystalline solid (0.36 g, 1.1 mmol, 22%); mp 104-105 °C (from DCM-ether-petrol); (Found C, 33.35; H, 3.05; N, 4.34. C₉H₁₀INO₄ requires C, 33.46; H, 3.12; N, 4.34%.); ι/_max/cm^"1 (neat) 1669, 1426, 1365, 1289, 1021 ; δ_H (300 MHz; CDCI₃) 9.17 (1H, d, H2 J 2 Hz), 8.85 (1H, d, HQ J 4 Hz), 8.42 (1 H, dt,

15 H4 J 4, 2 Hz), 7.48 (1 H, d, H5 J 4 Hz), 2.03 (6H, s, COMe); δ_c (75 MHz; CDCI₃) 176.53 (CO), 153.78 (C2), 152.02 (C6), 142.02 (C4), 125.94 (C5), 121.02 (C3), 20.26 (COMe).

^■* - Example KiiiK: (4-MethoxyphenvPpvridin-3-vl-iodonium trifluoroacetate .^■ Λ

0

Trifluoroacetic acid (0.15 ml_, 2 mmol) was added dropwise to a stirred solution of 3-iodopyridine diacetate (0.23 g, 1 mmol) in dichloromethane at -40⁰C and stirred for 0.5 h when the solution was allowed to warm to room temperature for 1 h after which time it was re-cooled to -40 ⁰C and anisole (0.11 ml_, 1 mmol) added 5 dropwise and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo to give a light brown oil. Crystallisation gave the title compound as a colourless crystalline solid (0.22 g, 0.52 mmol, 52%); mp 150-151 °C (from DCM-ether) ; silica gel TLC R_f0.20 (9:2 DCM-MeOH); (Found C, 39.67; H, 2.53; N, 3.21. C₁₄H₁₁F₃INO₃ requires C₁39.55; H, 2.61 ; N₁ 3.29%.); w/cm^"-¹ (neat) 3050, 1642, 1570, 1251 , 1177. 1130; δ_H (300 MHz; c/e-acetone) 8.93 (1 H, d, H2 J 2 Hz), 8.74 (1 H, d, H6, J 4 Hz), 8.39 (1 H, dt, H4 J 5, 2 Hz), 7.91 (2H, d, H27H6' J 5 Hz), 7.38 (1 H, dd, H5 J 5, 3 Hz), 6.93 (2H, d, H3VH5' J 5 Hz), 3.84 (3H, s, OMe); δ_c (75 MHzjdβ-Acetone) 163.99 (C4⁽), 154.59 (C2), 152.76 (C6), 143.06 (C4), 138.63 (C27C6¹), 127.45 (C5), 118.68 (C37C5¹), 116.64 (CV), 107.60 (C3), 56.51 (OMe); m/z (ES) 312(M⁺, 100%), 185(20). [Found: M⁺], 311.9878.

Example Kiv) ₁ [-18Fluoridation Method

[¹⁸F] fluoride (typically 100-150 MBq) was transferred to the reaction vessel from a P6 vial by suction. A solution of Kryptofix^® 222 (2.5mg), 0.1 M aqueous potassium carbonate (50μL) in acetonitrile (0.5mL) was added to the P6 vial and the solution transferred to the vessel. The solution was then dried by heating at 100⁰C under a flow of nitrogen gas (0.3 L/Min) for 15 min, during which time acetonitrile aliquots (0.5mL) were added after 5 and 7 min. The vessel was then cooled to 30⁰C using compressed air when a solution of (4-Methoxyphenyl)pyridin-3-yl-iodonium , ,. trifluoroacetate (5 mg) and TEMPO (5rηg) in Λ/,Λ/-Dimethylformamide (OJ.mL) was -^ "^* added. The vessel was sealed and heated to 120 ⁰C for 30 min when the- vessel^{* •}- was cooled using compressed air and the mixture analysed.

Pyridyl lodonium Salt

Example 2. Synthesis of 3-f 18r Fifluoroquinoline. Example 2(i) : 3-lodoquinoline

n-Butyl lithium (20 ml_ of a 1.9M solution in hexanes, 38 mmol) was added 5 dropwise to a stirred solution of butylmagnesium chloride (0.93 ml_ of a 2M solution in hexanes, 19 mmol) in THF at -10 ⁰C and stirred for 1 h when the solution was cooled to -30 ⁰C and 3-bromoquinoline (6.8 ml_, 50 mmol) added dropwise. The deep red solution was stirred at -10 °C for 2.5 h when iodine (12.7 g, 50 mmol) was added and the reaction mixture allowed to warm to room i o temperature overnight. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 * 100 mL), dried (MgSO₄) and concentrated in vacuo to give a brown oil. Purification by flash chromatography (SiO₂; DCM) gave the title compound as an off white solid. (9.20 g, 36 mmol, 72%); mp 48-^49 °C (from ether-petrol); silica gel TLC R_f 0.36 (DCM); (Found C, 42.24; H, 2.29; N, 5.40.

15 C₉H₆IN requires C, 42.38; H, 2.37; N, 5.49%.); iWcrrT¹ (neat) 2083, 1654, 1489,

1275, 1070; δ_H (300 MHz; CDCI₃) 9.05 (1 H, s, H2), 8.55 (1 H, d, H4 J 2 Hz), 8.08

(1 H, d, H8 J 8 Hz), 7.78-7.51 (3H, m, H5-H7); δ_c (75 MHz; CDCI₃) 155.91 (C2),

146.89 (C9), 143.85 (C4), 130.31 (C7), 130.15 (C10), 130.00 (C8), 127.60 (C5),

.. 127.02 (C6), 90.04 (C3); m/z (El) 255(M+H⁺, 40%), 127(100), 101(95), 75(70). 0>~r[Found:

* ^"-

Example 2(ii) 3-lodoquinoline dichloride

Chlorine gas was bubbled through a solution of 3-iodoquinoline (9.2 g, 36 mmol) in chloroform (50 mL) at 0⁰C for 0.5 h. The resulting suspension containing a yellow o crystalline solid was warmed to room temperature for 1 h when it was re-cooled to 0 °C and the precipitate collected by filtration and washed with hexane (50 ml_) and dried in vacuo to give the title compound as a yellow crystalline solid (10.8 g, 33 mmol, 91 %); mp 114-115 °C dec. (from chloroform). Used without further purification

Example 2(iii) : 3-lodosylquinoline

3-lodoquinoline dichloride (1.63 g, 5 mmol) was stirred in 10M sodium hydroxide solution (10 ml_) for 0.5 h when the off white solid was collected by filtration and air o dried for 1 h to give the title compound as an off white solid (0.43 g, 1.6 mmol 32%). Used without further purification

Example 2(iv) : (4-Methoxyphenyl)quinolin-3-yl-iodonium trifluoroacetate

5

Trifluoroacetic acid (0.15 ml_, 2 mmol) was added dropwise to a stirred solution of 3-iodosylquinoline (271 mg, 1 mmol) in dichloromethane (3 ml_) at -40 ⁰C and :X: stirred for O.S hiw.hen the solutioawas.allowed to warm to room temperature fQfttk h after which time it was re-cooled to -40⁰C and anisole (0.11 ml_, 1 mmol) added o dropwise and the reaction mixture allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo to give a light brown oil. Crystallisation gave the title compound as a colourless crystalline solid (276 mg, 0.58 mmol, 58%); mp 161-162 ⁰C (from DCM-ether); silica gel TLC R_f 0.15 (9:2 DCM-MeOH); (Found C, 45.37; H, 2.67; N, 2.87. Ci₈H₁₃IF₃NO₃ requires C, 45.50; 5 H, 2.76; N, 2.95%.); w/crτT¹ (neat) 3420, 2821 , 2083, 1652, 1508, 1255, 1081 ; δ_H (300 MHz; CZ₆-DMSO) 9.47 (1 H, d, H2 J 3 Hz), 9.39 (1 H, d, H4 J 3 Hz), 8.25 (2H, d, H27H6' J 9 Hz), 8.11-8.06 (2H₁ m, H5/H8), 7.95 (1 H, t, H6 J 9 Hz), 7.79 (1 H, t, H7 J H7), 7.08 (2H, d, H37H5' J 9 Hz), 3.78 (3H, s, OMe); δ_c (75 MHz; Cf₆- DMSO) 162.55 (C4'), 152.25 (C2), 147.62 (C9), 143.59 (C4), 137.65 (C27C6¹), 132.84, 129.42, 129.06, 128.98, 128.80, 118.03 (C3VC5¹), 112.58 (C1¹), 105.99 (C3), 56.12 (OMe); m/z (ES) 363(M+H\ 10%), 362(M⁺, 50), 235(100), 220 (90), 128 (95). [Found: M⁺, 362.0037].

Example 2(v) F r18 FlFIuoridation Method

By methods analogous to Example 1 (iv)

Claims

1. A method for preparing a mefa-fluoro pyridyl compound which comprises reaction of a compound of formula (I):

Y^"

with a fluoride ion source, wherein: the pyridyl ring is optionally substituted by 1 to 4 organic substituents;

Y^" is an anion; 0

R¹ to R⁵ are independently selected from hydrogen, nitro, cyano, halogen, C-M_O hydroxyalkyl, C_2-iocarboxyalkyl, Ci-i_O alkyl, C_2-io alkoxyalkyl, hydroxy, Ci.i₀alkoxy, C-ι-₁₀ aminoalkyl, C-M_O haloalkyl, C_6-U aryl, 03.12 heteroaryl, C_3-2O alkylaryl, C_5-I₂ arylene, C_2-io alkenyl, C_2-io alkynyl, C1-10 acyl, C_7-I₀ aroyl, C_2-io carboalkoxy, C_2-I₀ 5 carbamoyl, C_2-io carbamyl, or C-_MO alkysulphinyl, or protected versions of any of these groups; or alternatively forms a four- to six-membered ring together with the

?$^■«^•■ R group to which it is adjacent and the carbons to which they are attached which four- to six-membered ring is optionally substituted by two to four substituents independently selected from those listed for R¹ to R⁵ , or a protected derivative o thereof.

2. A method according to claim 1 wherein the compound of formula (I) is:

wherein the quinoline is optionally substituted by one to six organic substituents ; R¹ to R⁵ are as defined in claim 1 and Y^" is an anion.

3. A method for preparing a mefø-fluoro pyridyl compound which comprises reaction of a compound of formula (II):

Y^"

SOLID

Y^" is an anion;

« - the pheny! ringjs unsubstituted or has 1 to ^optional sifbstituents independently selected from nitro, cyano, halogen, C_MO hydroxyalkyl, C_2-io carboxyalkyl, Ci-io alkyl, C_2-io alkoxyalkyl, hydroxy, C_MO alkoxy, C-_MO aminoalkyl, Ci-iohaloalkyl, C-β-u aryl, C_3-I₂ heteroaryl, C_3-2o alkylaryl, C_5-^ arylene, C_2-io alkenyl, C_2-io alkynyl, Ci-io acyl, C7-₁₀ aroyl, C_2-io carboalkoxy, C_2-io carbamoyl, C_2-10 carbamyl, or C-MO alkysulphinyl, or protected versions of any of these groups; or alternatively forms a four- to six-membered ring together with the substituent group to which it is adjacent and the carbons to which they are attached which four- to six-membered ring is optionally substituted by two to four substituents independently selected from those listed as optional substituents on the phenyl ring , or a protected derivative thereof.

4. A method according to claim 3 which comprises reaction of a compound of formula (Ha):

SOLID

5 wherein the quinoline is optionally substituted by one to six organic substituents; and, the phenyl ring has 1 to 4 optional substituents as defined in claim 3 and Y is an anion.

o 5. A method according to any of claims 1 to 4 in which organic substituents on the pyridyl or quinoline ring are selected from fluoro, chloro, bromo, iodo, cyano, nitro, -R, -OR, -OC(O)R, -C(O)R, -SR, -NR₂, -C(O)NR₂, -N(R)COR wherein R at each occurrence is selected from Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, Ci-₆alkoxy-Ci-₆alkyl, d-βhaloalkyl, C_2-6haloalkenyl, CWialoalkynyl, C-ι-₆ haloalkoxy-C-i-βalkyl, C_4- 5 i₂aliphatic cyclic system , C₅-i₂aryl, C_5-I2 hetaryl; wherein said aryl and hetaryl substituents may be further substituted by the non- aryl and non-hetaryl substituents listed for the pyridyl or quinoline ring; or two adjacent susbstituents together with the carbons to which they are attached

**** form a four to six membered ring which is -optionally substituted by/two to four 0 substituents selected from those listed as substituents of the pyridyl or quinoline ring; and a protected derivative of any thereof.

5 6. A method according to any one of claims 1 to 5 wherein the fluoride ion source is an [¹⁸F]fluoride source such as Na¹⁸F, K¹⁸F, Cs¹⁸F, tetraalkylammonium [¹⁸F]fluoride, or tetraalkylphosphonium ¹⁸F fluoride.

7. A method according to any one of claims 1 to 5 wherein the phenyl ring in the 0 compound of formula (I), (Ia), (II) or (Ma) is unsubstituted.

8. A method according to any one of claims 1 to 7 , further comprising one or more of the following steps:

(i) purification of the resultant fluorinated product; (ii) removal of any protecting groups; (iii) removal of organic solvent; (iv) formulation, for example as an aqueous solution.

9. A radiopharmaceutical kit for the preparation of a metø-[¹⁸F]fluoro pyridyl compound which comprises :

(i) a vessel containing a compound of formula (I), (Ia), (II), or (Ma) as defined in any one of claims 1 to 7; and

(ii)means for eluting the vessel with an [¹⁸F]fluoride source.