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Title:
PREPARATIONS OF 11C METHYL IODIDE AND OF THE RADIOLIGAND 11C GB67
Document Type and Number:
WIPO Patent Application WO/2006/100481
Kind Code:
A2
Abstract:
A process for the preparation of 11C methyl iodide comprises coating the internal surface of a first reaction vessel with a solution of lithium aluminium hydride, wherein the first reaction vessel has an internal diameter not greater than about 1.5mm; introducing 11C carbon dioxide into the first reaction vessel such that it is reduced by the lithium aluminium hydride to give a reduction product; and reacting the reduction product with hydriodic acid.

Inventors:
TURTON, David (Hammersmith Imanet Limited, Cyclotron Building Hammersmith Hospital, Du Cane Roa, Hammersmith London W12 0NN, GB)
Application Number:
GB2006/001053
Publication Date:
September 28, 2006
Filing Date:
March 23, 2006
Export Citation:
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Assignee:
HAMMERSMITH IMANET LTD (Cyclotron Building, Hammersmith Hospital Du Cane Road, London W12 0NN, GB)
TURTON, David (Hammersmith Imanet Limited, Cyclotron Building Hammersmith Hospital, Du Cane Roa, Hammersmith London W12 0NN, GB)
International Classes:
C07B59/00; B01J19/24; C07C17/00; C07C17/16; C07C19/07; C07D405/12
Foreign References:
US5859070A1999-01-12
Other References:
PATENT ABSTRACTS OF JAPAN vol. 2000, no. 06, 22 September 2000 (2000-09-22) & JP 2000 086632 A (HAMAMATSU PHOTONICS KK), 28 March 2000 (2000-03-28)
C.CROUZEL ET AL.: "Recommandations for a practical production of [11C]methyl iodide" APPL.RADIAT.ISOT., vol. 38, no. 8, 1987, pages 601-603, XP009069800
R.J.DAVENPORT ET AL.: "Radiosynthesis of [11C]GB67- a potential radioligand for the study of alpha-1-adrenoreceptors with PET" J.LABEL.COMP.RADIOPHARM., vol. 37, 1995, pages 387-388, XP009069847
M.P. LAW ET AL.: "Evaluation of [11C]GB67, a novel radioligand for imaging myocardial alpha-1-adrenoreceptors with positron emission tomography" EUROPEAN JOURNAL OF NUCLEAR MEDICINE, vol. 27, no. 1, 2000, page 7-17, XP002391541
Attorney, Agent or Firm:
FRANKS, Barry et al. (GE Healthcare Limited, Amersham Place Little Chalfont, Buckinghamshire HP7 9NA, GB)
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Claims:

Claims

1. A process for the production of 11 C methyl iodide, the process comprising:

a) coating the internal surface of a first reaction vessel with a solution of lithium aluminium hydride, wherein the first reaction vessel has an internal diameter not greater than about 1.5mm;

b) introducing 11 C carbon dioxide into the first reaction vessel such that it is reduced by the lithium aluminium hydride to give a reduction product;

c) providing a second reaction vessel in fluid communication with the first reaction vessel, said second reaction vessel being heated; and,

d) passing hydriodic acid through the first reaction vessel, which contains the rreedduuccttiioonn J product, into the second reaction vessel where 11 C methyl iodide is produced.

2. A process as claimed in claim 1 wherein the first reaction vessel is a tube with an internal diameter of about 1 micrometre to 1.5mm.

3. A process as claimed in claim 2 wherein the first reaction vessel is a tube with an internal diameter of about 40 to 200μm.

4. A process as claimed in any one of claims 1 to 3, wherein the first reaction vessel is open at both ends.

5. A process as claimed in any one of claims 1 to 4, wherein the first reaction vessel is from about 5cm to 50cm long.

6. A process as claimed in claim 5, wherein the first reaction vessel is from about 5cm to 20cm long.

7. A process as claimed in any one of claims 1 to 6, wherein the LiAIH 4 solution is introduced into the first reaction vessel by injection.

5 8. A process as claimed in any one of claims 1 to 7, wherein the LiAIH 4 solution comprises a 0.05 to 1 M solution of LiAIH 4 in tetrahydrofuran.

9. A process as claimed in any one of the preceding claims, further comprising the step of flushing out the first reaction vessel with an inert gas before coating the o internal surface with the LiAIH 4 solution.

10. A process as claimed in any one of the preceding claims further comprising the step of flushing the first reaction vessel with an inert gas between steps (a) and (b).

11. A process as claimed in any one of the preceding claims wherein the 11 CO 2 is introduced into the first reaction vessel by in a stream of an inert gas.

12. A process as claimed in any one of the preceding claims wherein the hydriodic 0 acid is present as an aqueous solution containing from 40 to 60% hydrogen iodide.

13. A process as claimed in any one of the preceding claims wherein the hydrogen iodide is introduced into the first reaction vessel in a stream of an inert gas. 5

14. A process as claimed in any of the preceding claims, wherein the second reaction vessel is heated to a temperature of about 150 to 200 0 C.

15. A process as claimed in any of the preceding claims, wherein the second o reaction vessel is in a generally vertical orientation such that its inlet end is lower than its outlet end, and that only the inlet end of said second reaction vessel is heated.

16. A process as claimed in any one of claims 1 to 15, further comprising the additional step of reacting the 11 C methyl iodide with a non-radiolabelled precursor of a 11 C-labelled PET tracer compound to produce a 11 C-labelled PET tracer compound.

17. A process as claimed in claim 16, wherein the precursor compound is an amine, amide, hydroxide, sulfide, sulfonamide or any other compound which can be methylated by reaction with methyl iodide.

18. A process as claimed in claim 16 or claim 17, wherein the precursor compound is N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl]-2- furancarboxamide.

19. A process for the preparation of N-[6[(4-amino-6,7-dimethoxy-2- qquuiinnaazzoolliinnyyll))mmeetthhyyllaammiinno]hexyl]-2-furancarboxy-[ 11 C]-methylamide, the process comprising the steps of:

a) coating the internal surface of a first reaction vessel with a solution of lithium aluminium hydride, wherein the first reaction vessel has an internal diameter not greater than about 1.5mm;

b) introducing 11 C carbon dioxide into the first reaction vessel such that it is reduced by the lithium aluminium hydride to give a reduction product; 5 c) producing a second reaction vessel in fluid communication with the first reaction vessel, said second reaction vessel being heated;

d) passing hydroiodic acid through the first reaction vessel, which contains the o rreedduuccttiioonn pprroodduuct, into the second reaction vessel where 11 C methyl iodide is produced; and,

e) reacting the 11 C methyl iodide with N-[6[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino]hexyl]-2-furancarboxamide under basic conditions to yield N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl]-2- furancarboxy-[ 11 C]-methylamide.

20. A process as claimed in claim 19, further including the features of any one of claims 2 to 16.

21. A process as claimed in claim 19 or claim 20, wherein step (e) of the process is carried out in a third reaction vessel is a tube having an internal diameter not greater than about 1.5mm

22. A process as claimed in any one of claims 19 to 21 , wherein the first reaction vessel is from about 5cm to 50cm long.

23. A process as claimed in any one of claims 19 to 22, wherein ,in step (e) the internal surface of the third reaction vessel is coated with a solution of N-[6[(4- amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl]-2-furancarboxamide and a solution of 11 C methyl iodide is passed though the vessel.

24. Apparatus for the production of 11 C methyl iodide, the apparatus comprising:

a first reaction vessel (10) having an internal diameter not greater than about 1.5mm;

a second reaction vessel (34) connected to the first reaction vessel (10), via a valve (28) which has a first and a second position such that when the valve (28) is in the first position, the first (10) and second (34) reaction vessels are not in fluid communication and when the valve (28) is in the second position the first (10) and second (34) reaction vessels are in fluid communication such that a mixture of hydriodic acid and a reduction product from the first reaction vessel (10) can pass from the first reaction vessel (10) into the second reaction vessel (34); and

means for heating the second reaction vessel (34).

25. Apparatus as claimed in claim 24, wherein when the valve is in the first position, the first reaction vessel is connected to a waste line.

26. Apparatus as claimed in claim 24 or claim 25, further comprising one or more of:

o means (15) for flushing out the first reaction vessel with nitrogen;

means (26) for introducing a solution of LiAIH 4 into the first reaction vessel such that the solution of LiAIH 4 forms a coating on the internal surface of the first reaction vessel; 5 means for introducing 11 CO 2 (16) into the first reaction vessel;

means (20, 24) for introducing hydriodic acid into the first reaction vessel; and

o means(40) for removing excess hydrogen iodide and water from the product.

27. Apparatus as claimed in claim 26, wherein the means for flushing out the first reaction vessel with nitrogen comprises a connection to a nitrogen source (15).

5 28. Apparatus as claimed in claim 26 or claim 27, wherein the means for introducing a solution of LiAIH 4 into the first reaction vessel comprises an injection system (26).

29. Apparatus as claimed in any one of claims 26 to 28, wherein the means for 0 introducing 11 CO 2 into the first reaction vessel comprises a cryogenic trap (16) containing the 11 CO 2 a nitrogen source (15), means for mixing the 11 CO 2 from the trap with the nitrogen source and a first inlet tube (17) which carries the mixture of

nitrogen and 11 CO 2 to the first reaction vessel.

30. Apparatus as claimed in claim 29, wherein the nitrogen used to carry the 11 CO 2 and the nitrogen used for flushing out the first reaction vessel are taken from the same nitrogen source (15).

31. Apparatus as claimed in any one of claims 26 to 30, wherein the means for introducing hydriodic acid into the first reaction vessel comprises a hydriodic acid loop (20) through which flows a stream of nitrogen and means (24) for introducing o hydriodic acid into the nitrogen stream.

32. Apparatus as claimed in any one of claims 24 to 31 , wherein the second reaction vessel comprises a tube having an internal diameter of about 0.2-20mm.

5 33. Apparatus as claimed in any one of claims 24 to 32, wherein the second reaction vessel (34) is constructed from a heat conducting material.

34. Apparatus as claimed in any one of claims 24 to 33, wherein the means for heating the second reaction vessel (34) comprises a block heater (36) surrounding o the reaction vessel (34).

35. Apparatus as claimed in any one of claims 24 to 34, wherein the second reaction vessel (34) is in a generally vertical orientation.

5 36. Apparatus as claimed in claim 35, wherein only the lower end of the second reaction vessel (34) is heated.

Description:

PREPARATION OF 11 C METHYL IODIDE

The present invention relates to a process for the preparation of 11 C methyl iodide and to apparatus for carrying out this process. In particular, the invention relates to a process comprising the reduction of 11 CO 2 followed by the reaction of the product with hydriodic acid. The process yields a product with a much higher specific activity than conventional processes.

Tracer compounds used in positron emission tomography (PET) are labelled with a variety of positron emitting isotopes, for example 11 C. However, one problem with the use of 11 C as a label is that it has a half-life of only 20.4 minutes. This means that, in order to obtain a tracer compound with a sufficiently high specific activity to be useful in PET, it is necessary to synthesise the compound as rapidly as possible.

11 C-labelled PET tracer compounds are often synthesised by reacting a precursor (for example an amine) with 11 C methyl iodide and the present invention relates to a process for producing 11 C methyl iodide. In order to produce a tracer having high specific activity, it is important that the intermediate 11 C methyl iodide itself has high specific activity and, consequently, that it is produced using a reaction process which is as rapid as possible.

This is well known to those of skill in the art and a number of authors have attempted to address the problems of producing 11 C methyl iodide having high specific activity. For example Larsen et al (WO 96/15086) teach the production of 11 C methyl iodide by halogenation of 11 C methane in a gas phase process and DE- A-4420670 relates to the production of 11 C methyl iodide from 11 C carbon monoxide or carbon dioxide in a gas phase process.

An alternative process for the production of 11 C methyl iodide is taught in EP-A- 0462546. In this process, 11 CO 2 is bubbled through a solution of a reducing agent

-1 - dOJrøLMATION CO? Ϋ

such as lithium aluminium hydride (LiAIH 4 ). The reducing agent solution is evaporated by heating and then hydriodic acid is added to the residue. The authors recognised that it was important to produce a product of high specific activity and introduced a number of control devices into their apparatus.

The present invention relates to a process for the production of 11 C methyl iodide which yields a product having a higher specific activity than conventional processes and yet is simpler than processes described in the prior art. In particular, the quantity of LiAIH 4 in the process of the present invention is much lower than in conventional processes. LiAIH 4 often contains small amounts of methanol/methoxide which is a reduction product of atmospheric CO 2 which has come into contact with the LiAIH 4 . Therefore, reducing the amount of LiAIH 4 leads to a reduction in the amount of stable methanol/methoxide contaminating the 11 C methanol/methoxide intermediate. In addition, the reaction using the process of the present invention proceeds much more rapidly than conventional reactions and this leads to a product which has a higher specific activity.

In a first aspect of the present invention, there is provided a process for the production of 11 C methyl iodide, the process comprising:

a) coating the internal surface of a first reaction vessel with a solution of lithium aluminium hydride, wherein the first reaction vessel has an internal diameter not greater than about 1.5mm;

b) introducing 11 C carbon dioxide into the first reaction vessel such that it is reduced by the lithium aluminium hydride to give a reduction product;

c) providing a second reaction vessel in fluid communication with the first reaction vessel, said second reaction vessel being heated; and,

d) passing hydriodic acid through the first reaction vessel, which contains the reduction product, into the second reaction vessel where 11 C methyl iodide is

produced.

Heating the second reaction vessel ensures that the hydriodic acid evaporates and that the iodination reaction proceeds rapidly. Typically, the second reaction vessel is heated to a temperature of about 150 to 200 0 C, preferably 160 to 19O 0 C.

11 CO 2 is introduced into the first reaction vessel at a flow rate of about 8 ml/min. The gas flow rate for the addition of hydriodic acid and hence the gas flow to distil the methyl iodide is about 15 ml/min.

The inventors have discovered that the use of a reaction vessel having a small internal diameter for the first part of the process leads to a product which has a much higher specific activity than conventionally produced 11 C methyl iodide. One reason for this is that the quantity of LiAIH 4 is much lower than in conventional processes. As exlplained above, LiAIH 4 is often contains small amounts of methanol/methoxide and therefore reducing the amount of LiAIH 4 leads to a reduction in the amount of stable methanol/methoxide contaminating the 11 C methanol/methoxide intermediate. In addition, the reaction using the process of the present invention proceeds much more rapidly than conventional reactions and this leads to a product which has a higher specific activity.

Radiochemical processes which make use of narrow bore reaction vessels are known. For example, US 2002/0155063 relates to a process in which 11 C methyl iodide and a PET precursor compound are reacted together in an HPLC injection loop. However, no prior author appears to have recognised the benefits of carrying out the reduction of 11 CO 2 in such a vessel.

The first reaction vessel preferably takes the form of a tube with a narrow bore, for example an HPLC loop. The internal diameter of the reaction vessel is usually in the range of about 1 micrometre to 1.5mm, preferably 40 to 200μm. It is particularly convenient if the first reaction vessel is open at both ends so that the reagents can be flushed through.

The length of the first reaction vessel will be chosen such that it is long enough for the 11 CO 2 to react fully with the LiAIH 4 but is sufficiently short for the reaction time to be minimised. A convenient length for the first reaction vessel is from about 5cm to 50cm long, more usually 5cm to 20cm and typically about 15cm.

The LiAIH 4 solution may be introduced into the first reaction vessel by any convenient means, for example by injection. Because of the narrow bore of the first reaction vessel, the LiAIH 4 solution forms a coating on the internal walls of the first reaction vessel.

Suitable solvents for LiAIH 4 are well known to those of skill in the art and an example of such a solvent is tetrahydrofuran (THF). The LiAIH 4 solution will generally have a concentration of about 0.05 to 1M, more usually 0.05M to 0.5M and typically about 0.1 M.

In order to minimise the amount of atmospheric CO 2 in the first reaction vessel, it is preferable to flush out the first reaction vessel with an inert gas such as nitrogen or argon before coating the internal surface with the LiAIH 4 solution.

After the LiAIH 4 solution has been introduced into the first reaction vessel, it is advantageous to blow an inert gas such as nitrogen through the first reaction vessel to remove excess reagent.

The 11 CO 2 used in step (b) may be produced by any conventional means, for example it may be produced on a cyclotron and then cryogenically trapped. It may be introduced into the first reaction vessel by any convenient method, for example in a stream of an inert gas such as nitrogen or argon.

The hydriodic acid is present as an aqueous solution containing from 40 to 60% hydrogen iodide, and preferably from 50 to 60% hydrogen iodide. Suitable hydriodic acid solutions are commercially available.

The hydrogen iodide may be introduced into the first reaction vessel in a stream of an inert gas, for example nitrogen or argon, but preferably nitrogen.

It is particularly preferred that the second reaction vessel is positioned in a generally vertical orientation and that only the lower portion is heated. This configuration allows for the iodination reaction to take place in the lower part of the reaction vessel and for unreacted hydriodic acid and reduction product to condense in the upper part of the reaction vessel and fall back to the lower part.

After the iodination reaction, the 11 C methyl iodide product may be passed over a drying agent to remove water vapour. It is particularly useful to use a drying agent such as solid sodium hydroxide since this will also remove any unreacted hydriodic acid from the 11 C methyl iodide product.

As mentioned above, 11 C methyl iodide is a useful precursor for the production of 11 C-labeiled PET tracer compounds and therefore the process of the invention may comprise an additional step of reacting the 11 C methyl iodide with a non- radiolabelled precursor of a 11 C-labelled PET tracer compound to produce a 11 C- labelled PET tracer compound.

The precursor compound may be an amine, amide, hydroxide, sulfide, sulfonamide or any other compound which can be methylated by reaction with methyl iodide.

One PET tracer compound which can be produced by the process of the present invention is N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl ]-2- furancarboxy-[ 11 C]-methylamide. This compound may be produced by reacting the precursor compound, N-[6[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino]hexyl]-2-furancarboxamide with 11 C methyl iodide in the presence of a strong base such as sodium hydride.

Therefore, in a further aspect of the invention, there is provided a process for the preparation of N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl ]-2- furancarboxy-[ 11 C]-methylamide, the process comprising the steps of:

5 a) coating the internal surface of a first reaction vessel with a solution of lithium aluminium hydride, wherein the first reaction vessel has an internal diameter not greater than about 1.5mm;

b) introducing 11 C carbon dioxide into the first reaction vessel such that it is o reduced by the lithium aluminium hydride to give a reduction product;

c) producing a second reaction vessel in fluid communication with the first reaction vessel, said second reaction vessel being heated;

5 d) passing hydroiodic acid through the first reaction vessel, which contains the rreedduuccttiioonn pprrooddiuct, into the second reaction vessel where 11 C methyl iodide is produced; and,

e) reacting the 11 C methyl iodide with N-[6[(4-amino-6,7-dimethoxy-2- o quinazolinyl)methylamino]hexyl]-2-furancarboxamide under basic conditions to yield N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]hexyl ]-2- furancarboxy~[ 11 C]-methylamide.

Preferred features of steps (a) to (d) are as detailed for the first aspect of the 5 invention.

It has been found that particularly successful results are obtained when step (e) of the process are carried out in a third reaction vessel which is similar to the first reaction vessel. Therefore, the third reaction vessel preferably has an internal o diameter not greater than about 1.5mm and preferably takes the form of a tube with a narrow bore, for example an HPLC loop. The internal diameter of the third reaction vessel is usually in the range of about 1 micrometre to 1.5mm, preferably

40 to 200μm. It is particularly convenient if the first reaction vessel is open at both ends so that the reagents can be flushed through.

The length of the third reaction vessel will be chosen such that it is long enough for the 11 C methyl iodide to react fully with the N-[6[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino]hexyl]-2-furancarboxamide but is sufficiently short for the reaction time to be minimised. A convenient length for the first reaction vessel is from about 5cm to 50cm long, more usually 5cm to 20cm and typically about 10cm.

In step (e) it is preferred that the internal surface of the third reaction vessel is coated with a solution of N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino]hexyl]-2-furancarboxamide and that a solution of 11 C methyl iodide is passed though the vessel.

The invention also relates to apparatus for carrying out the method. Therefore, in a further aspect there is provided apparatus for the production of 11 C methyl iodide, the apparatus comprising:

a first reaction vessel having an internal diameter not greater than about 1.5mm;

a second reaction vessel connected to the first reaction vessel, via a valve which has a first and a second position such that when the valve is in the first position, the first and second reaction vessels are not in fluid communication and when the valve is in the second position the first and second reaction vessels are in fluid communication such that a mixture of hydriodic acid and a reduction product from the first reaction vessel can pass from the first reaction vessel into the second reaction vessel; and

means for heating the second reaction vessel.

It is greatly preferred that when the valve is in the position, the first reaction vessel

is connected to a waste line. The waste is gas used to flush out the first reaction vessel and excess LiAIH 4 .

Optionally, the apparatus may also comprise one or more of:

means for flushing out the first reaction vessel with nitrogen;

means for introducing a solution of LiAIH 4 into the first reaction vessel such that the solution of LiAIH 4 forms a coating on the internal surface of the first reaction vessel;

means for introducing 11 CO 2 into the first reaction vessel;

means for passing hydriodic acid into the first reaction vessel; and

means for removing excess hydrogen iodide and water from the product.

The means for flushing out the first reaction vessel with nitrogen may comprise a connection to a nitrogen source.

The means for introducing a solution of LiAIH 4 into the first reaction vessel may comprise an injection system.

The means for introducing 11 CO 2 into the first reaction vessel may comprise a cryogenic trap containing the 11 CO 2 , a nitrogen source, means for mixing the 11 CO 2 from the trap with the nitrogen source and a first inlet tube which carries the mixture of nitrogen and 11 CO 2 to the first reaction vessel.

Optionally, the nitrogen used to carry the 11 CO 2 and the nitrogen used for flushing out the first reaction vessel may be taken from the same source.

The means for passing hydriodic acid through the first reaction vessel into the

second reaction vessel may comprise a hydriodic acid loop, a stream of nitrogen flowing through the hydriodic acid loop and means for introducing hydriodic acid into the nitrogen stream.

The nitrogen stream carrying the hydriodic acid may enter the first reaction vessel via an inlet valve. The hydriodic acid may be an aqueous solution of hydrogen iodide as described above for the first aspect of the invention.

The apparatus may also comprise a waste line connected to the valve between the first and second reaction vessels through which gas or by-products of the reaction can be vented.

The second reaction vessel may comprise a tube having an inlet end and an outlet end. The tube typically has an internal diameter of about0.2-20mm, more usually about 0.5 to 10mm and may be constructed from a heat conducting material, particularly a metal such as stainless steel.

The means for heating the second reaction vessel may comprise a block heater surrounding the reaction vessel. Typically, the heating means is capable of heating the second reaction vessel to a temperature of from about 150 to 200 0 C, preferably 160 to 19O 0 C.

It is greatly preferred that the second reaction vessel is in a generally vertical orientation such that the inlet end is lower than its outlet end and that only the lower (inlet) end of the second reaction vessel is heated. This arrangement allows the aqueous mixture of reduction product, hydriodic acid and water to evaporate in the lower portion of the tube and the gaseous reagents to react to form the 11 C methyl iodide. When the mixture reaches the upper unheated part of the reaction vessel the unreacted hydriodic acid and reduction product will recondense and fall to the bottom of the tube, while the more volatile 11 C methyl iodide passes to the outlet of the second reaction vessel.

The invention will now be described in greater detail, by way of example only with reference to the figures and examples.

Figure 1 is a schematic representation of apparatus for preparing 11 C methyl iodide.

The apparatus shown in Figure 1 comprises a reaction vessel (10), which is an HPLC grade stainless steel tube having an external diameter of 1/16 inches (1.58mm) and 10cm in length. First and second three port input valves (12) and (14) are connected to the input side of the reaction vessel (10). A first source of nitrogen (15) and source of 11 CO 2 (16) are both connected to the first input valve (12) via a cryogenic trap (50) and a line (17). The cryogenic trap (50) is known from the prior art and can be set either so that the trap is cooled, trapping 11 CO 2 and allowing nitrogen to pass through the line (17) or so that the trap is not cooled and a mixture of 11 CO 2 and nitrogen passes through the line (17). A second source of nitrogen (18) is also connected to the first input valve (12) via a nitrogen line (19) and a hydriodic acid loop (20), which is an HPLC loop formed from a material such as polytetrafluoroethylene (PTFE). The nitrogen line (19) has a needle valve (22), which controls the flow rate of the nitrogen. Between the nitrogen line (19) and the hydriodic acid loop (20) is a valve (24) through which hydriodic acid can be introduced into the hydriodic acid loop (20).

Connected to the second input valve (14) is an injection system (26) through which LiAIH 4 can be introduced into the reaction vessel (10) via the second input valve (14).

A three port output valve (28) is connected to the output side of the reaction vessel (10). One port of the output valve (28) is connected to a waste line (30) and another to a second reaction vessel (34) via a first output line (32). The second reaction vessel comprises a stainless steel tube having an external diameter of % inches (6.35mm).

The second reaction vessel is held in a vertical orientation and its lower end is surrounded by an aluminium block heater (36) which heats the temperature of the second reaction vessel (34) to a temperature of 185 0 C. The output end of the second reaction vessel (34) is connected to a sodium hydroxide trap (40) via a second output line (38). The sodium hydroxide trap (40) comprises a tube packed with solid sodium hydroxide which removes excess water and hydrogen iodide from the product and is connected to a third output line (42). The trap (40) may be made from any suitable material, for example glass.

In use, the cryogenic trap (50) is set in the uncooled configuration such that nitrogen passes from the nitrogen source (15) and through the line (17) to flush out the first reaction vessel (10) in order to remove atmospheric carbon dioxide from the first reaction vessel (10). The nitrogen passes through the first reaction vessel (10) and to the waste line (30) via the output valve (28). A 0.1 M solution of LiAIH 4 in tetrahydrofuran (THF) is injected into the first reaction vessel (10) via the injection system (26) and the second input valve (14). The first reaction vessel (10) is then flushed again with nitrogen as before in order to remove excess LiAIH 4 solution from the first reaction vessel (10).

The cryogenic trap (50) is then reconfigured so that it is in the cooled position: 11 CO 2 from the cyclotron is then trapped in the cryogenic trap.

The cryogenic trap (50) is then reconfigured so that it is in the uncooled position such that 11 CO 2 from is introduced into the first line (17) and thus passes into the first reaction vessel (10) via the first and second input valves (12) and (14). In the first reaction vessel, the 11 CO 2 is reduced to 11 C methoxide.

Next, hydriodic acid (a 57% aqueous solution of hydrogen iodide) is introduced into the hydriodic acid loop (20) via the valve (24). The hydriodic acid loop (20) has previously been flushed with nitrogen from the second nitrogen source (18). Nitrogen from the second nitrogen source (18) carries the hydriodic acid to the first and second input valves (12) and (14), and into the first reaction vessel (10) where

it flushes the 11 C methoxide product into the output valve (30), along the first product line (32) and into the second reaction vessel (34).

The second reaction vessel (34) is pre-heated to 185 0 C or maintained at 185 0 C from the start of the process by the aluminium block heater (36) and this ensures that the aqueous solution containing the hydrogen iodide and the 11 C methoxide evaporates and that the reaction between the two reagents proceeds rapidly.

When the reagents reach the upper, unheated part of the second reaction vessel

(34), unreacted hydrogen iodide and reduction product condense and fall back to the lower part of the tube, while the more volatile 11 C methyl iodide product leaves the second reaction vessel (34) via the second product line (38).

The 11 C methyl iodide product passes from the second output line (38) to a trap (40) which contains solid sodium hydroxide. This removes both unreacted hydrogen iodide and excess water from the product.

After passing through the trap (40), the 11 C methyl iodide produced in the apparatus passes via a third output line (42) to a reaction vessel (not shown) in which the 11 C methylation of a PET precursor compound takes place.

Example 1 - Preparation of N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino]hexyl]-2-furancarboxy-[ 11 C]-methylamide

This example demonstrates that preparation of N-[6[(4-amino-6,7-dimethoxy-2- quinazolinyl)methylamino]hexyl]-2-furancarboxy-[ 11 C]-methylamide from 11 C methyl iodide produced according to the method of the invention has a higher specific activity than the same product prepared using 11 C methyl iodide produced in conventional apparatus in which the LiAIH 4 and the 11 CO 2 are reacted in a conventional reaction vessel rather than in a small bore tube such as an HPLC loop.

11 C methyl iodide was prepared in the apparatus shown in Figure 1 according to

the method described above. Thus, 200μl_ of a 0.1 M solution of LiAIH 4 in THF was introduced into the first reaction vessel (the loop, 10), following which, the loop (10) was flushed through with nitrogen. 11 / CO 2 was then pased through the loop where it was trapped and converted to 11 / C methoxide.

Next, hydriodic acid was introduced into the loop via the hydriodic acid loop (20) (100μ!_ of a 57% aqueous solution of hydrogen iodide) such that the 11 C methoxide product was carried with the hydriodic acid into the second reaction vessel (34).

The hydrogen iodide reacts with the methoxide to give the product, 11 C methyl iodide, which is purified by passing through the sodium hydroxide trap (40).

The 11 C methyl iodide produced was fed directly into a second loop which had previously been flushed with nitrogen and of which the internal surface was coated with the precursor compound N-[6[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino]hexyl]-2-furancarboxamide (0.3-0.5mg in 100μL dimethyl formamide). The reaction was conducted in the presence of 0.7-1.3mg sodium hydride.

The yield of the product on three synthetic runs and the sepcific activity of the product at the end of the synthesis are shown in Table 1.

In comparison, the same product prepared using conventionally prepared 11 / C methyl iodide usually has a specific activity of about 50,000 to 100,000 MBq/μmol.

It can therefore be seen that the present invention provides 11 C methyl iodide with much greater specific activity which can, in turn, be converted to a product having higher specific activity.