Pergamon Appl. Radiat. lsot. Vol. 48, No. 2. pp. t53-157, 1997

Copyright © 1997 Elsevier Science Ltd Printed in Great Britain. All rights reserved

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Synthesis of [ C]Iodomethane by of [l C]Methane

Iodination

P E T E R L A R S E N *l, J O H A N U L I N 2, K E N T D A H L S T R O M 2 and M I K A E L JENSEN t

~The National University Hospital, Rigshospitalet, Cyclotron and PET Unit 3982, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark and :GEMS PET Systems AB, Husbyborg,

S-752 29 Uppsala, Sweden

(Received 6 November 1995; revised 17 July 1996)

[~C]iodomethane was synthesized by iodination of [~C]methane with iodine. The reaction was carried out in a system where [HC]methane, helium and iodine vapours were mixed and heated. The formed [~LC]iodomethane was continuously removed from the reaction mixture and the unchanged [~C]methane was recirculated into the reaction chamber by a pump. The decay-corrected radiochemical yield was 83% after a production time of 7 min (from trapped [HC]methane). The specific radioactivity was better than 550 GBq//~mol (15 Ci/mmol) at the end of the synthesis. Copyright ~ 1997 Elsevier Science Ltd

Introduction

[~LC]iodomethane is an important starting material in the production of '~C-labelled tracers used in investigations with Positron Emission Tomography (PET). It is usually prepared by reduction of ["C]carbon dioxide to ["C]methanol with lithium aluminium hydride followed by reaction with hydrogen iodide (for a review, see Crouzel et al.,

1987), diphosphorous tetraiodide (Oberdorfer et al.,

1985) or triphenylphosphine diiodide (Holschbach and Schueller, 1993). Since lithium aluminium hydride readily adsorbs carbon dioxide from the air, great care must be taken to achieve high specific radioactivity for the ["C]iodomethane. The use of this procedure requires careful cleaning and drying of equipment before each new synthesis. The cleaning process is time consuming and laborious to automate.

An alternative to the lithium aluminium hydride method is the gas phase halogenation of [t ~C]methane with chlorine, bromine or iodine (Prenant and Crouzel, 1991; Crouzel and Hinnen, 1993). If chlorine or bromine is used, the produced ["C]chloromethane or [~C]bromomethane can be used instead of [~ ~C]iodomethane in many methylation reactions. The yields of these alternative labelling agents are limited by reaction of the mono halogenated product to methyl-di-, -tri- or -tetra-halide with excess halo- genating agent, which will always be present when

*To whom all correspondence should be addressed.

working with tracer amounts of [HC]methane. The yield is further reduced, when a long reaction time or a high reaction temperature is applied to achieve a high degree of conversion, since traces of oxygen or water react with methane or halomethane to form [HC]carbon monoxide and [HC]carbon dioxide. This is the main problem if the halogen is iodine and the specific radioactivity is high. Hydrogen from the [~C]methane target for the catalytic conversion of ["C]carbon dioxide into [HC]methane can consume the halogen to form hydrogen halide. The hydrogen or the hydrogen halide can also reduce the methyl halide to methane. The kinetics for these reactions and side reactions between unlabelled methane and iodine have been described by Flowers and Benson (1963) and Golden et al. (1965).

Herein we describe how these problems can be solved by keeping the reaction temperature suffi- ciently low to avoid oxidation of methane or iodomethane, and by continuously removing mono iodomethane and hydrogen iodide from the reaction mixture.

Materials and Methods

General

Porapak N (80-100 mesh) was obtained from Waters Associates Inc. Shimalite nickel catalyst was obtained from Shimadzu and 4/~ molecular sieve (80-100 mesh) from Alltech. All other chemicals were obtained from Aldrich or Merck, and used without

153

154 Peter Larsen et al.

further purification. The pump used for recirculation was a KNF Neuberger type NMP 30 KNDC diaphragm pump. Electrically operated two-way valves were obtained from General Valve. Pneumat- ically operated three-way slider valves were obtained from Rheodyne. The quartz tube used in the ovens was 12 mm in o.d. with a wall thickens of 1 mm and a length of 50 cm. The length of the iodine evaporation zone was 8 cm and the length of the Ascarite section 11 cm. The Porapak N column was 8 mm diameter and 4 cm long.

Computer control was carried out by a PC connected to the iodomethane system with a two wire RS-485 serial communication line. Digital and analogue I/O was performed with ADAM I/O modules from Advantech Ltd. The software for the system was written in the high level graphical programming language LABWIEW from National Instruments.

Analytical HPLC was performed on a Gilson HPLC-system with a variable wavelength u.v. absorbance detector, and a radioactivity detector. The column was a Spherisorb $3 ODS2 column (150 × 4.6 ram) which was eluted with a 50/50 (v/v) mixture of acetonitrile and 0.01 M aqueous triethy- lammonium phosphate (pH = 6.5). Retention times (min) were: carbon dioxide, 1.6--2.8 (broad); CO, 3.6; methane, 4.1; CH3 I, 5.1; CH21~, 7.3; and CHI3, 10.4.

GC was performed on a Shimadzu GC-8A gas chromatograph using a Carboxen 1000 column from Supelco (15 ft x 1/8 in.), equipped with a radioac-

tivity detector in series with a methanizer and a FID detector. With an oven temperature of 150°C and a helium flow of 35 mL/min the retention times (min) were: CO, 2.1; CH4, 3.7; and CO,, 6.1. The radioactivity detector used in HPLC and GC was a NaI well counter.

["C]carbon dioxide and ['C]methane were pro- duced in target by the JaN(p, ~)lIC nuclear reaction of 17 MeV protons on N2 or N2 + 5%H2, respectively.

Description oJ'a system based on 'in target' production of ["C]methane

Figure 1 shows a scheme for the synthesis of [HC]iodomethane where [NC]methane is produced in the target.

After end of bombardment the target gas is released through V1, the phosphorus pentoxide trap, V2, the Porapak N trap, V3 and to waste through V4. The ammonia formed during the irradiation of the nitrogen-hydrogen mixture, is trapped on the phosphorus pentoxide and the ["C]methane is collected on the cooled (liquid nitrogen) Porapak N trap. Nitrogen and hydrogen are flushed out of the trap with helium with inlet at VI and waste at V4. Helium is then flushed through the whole system to remove traces of oxygen. The end of this step is referred to as the end of trapping of ["C]methane. After flushing with helium the pump is started and the Porapak N trap is removed from the liquid nitrogen and heated to room temperature with the Firerod cartridge heater. All valves are switched so

Oven 1 Oven 2

V3 V2..L--- '~IV5

outlet Phosphorous Waste pentoxide E.--Helium

~V1Target

Liquid nitrogen

Fig. 1. [HC]iodomethane production system based on a [HC]methane target. See text for detailed description of components and operation.

Synthesis of [HC]iodomethane 155

Oven 1 Oven 2

IV4 Waste

• V 3 ~

F i r e r o d

ckel

1 1C-CH31 Waste L outlet

Target Helium Helium + 25% Hydrogen

Fig. 2. ["C]iodomethane production system based on a [HC]carbon dioxide target. See text for detailed description of components and operation.

the ["C]methane-helium mixture is pumped at 500 mL/min from the trap to the quartz-tube. In oven 1 the gases are mixed with vapours from iodine crystals and heated to 60°C. In the reaction chamber in oven 2 (15 cm long) the temperature is increased to 725°C. After the ovens, the gases pass through a quartz tube (about 9 cm long) kept at room temperature, where most of the excess of iodine crystallizes, and then a tube (14 cm long) filled with Ascarite where hydrogen iodide and the rest of the iodine is trapped. The [~tC]iodomethane is trapped on the Porapak N trap at room temperature and the unchanged ["C]methane is recirculated. After recir- culation for 3-5 min at 500 mL/min the radioactivity in the Porapak N trap has reached a maximum. Valves 2, 3 and 4 are switched, the Porapak N trap is heated to 190°C and the [HC]iodomethane is released into a stream of helium through the ["C]iodomethane outlet into a suitable solvent or reaction mixture. The preparation of [HC]iodo- methane ready for use is 10.5 min from the end of radionuclide production.

Description of a system based on 'in target" production of ["C]carbon dioxide

Figure 2 shows a scheme for the synthesis of [HC]iodomethane where [NC]methane is produced outside the target by catalytic reduction of ["C]carbon dioxide.

Before the first production of the day, traces of oxygen from the air are flushed out of the system with helium. After the end of bombardment, the target gas is released via valve VI through a trap containing a 50:50 mixture of 4 ,~ molecular sieve and nickel. After trapping of ["C]carbon dioxide, traces of

nitrogen in the trap are flushed out with helium containing 25% hydrogen via valve V2. The gas flow is stopped and the trap with the nickel catalyst is heated to 360°C. ['~C]carbon dioxide is released from the molecular sieves and immediately reduced to [HC]methane on the nickel catalyst. The [HC]methane is transferred to the circulating part of the system by a stream of helium via valve V2. V5 and V6 are switched so the system is closed, and the pump is started. The procedure described above is then used to convert [~tC]methane into ["C]iodomethane. After the reaction the [~tC]iodomethane is released from the Porapak N trap as described before. The synthesis time is 10.5 rain.

Results and Discussion Figure 3 shows the radiochemical yield of

[HC]iodomethane from the system shown in Fig. 1 as a function of temperature in oven 2. The yield is decay-corrected to the end of the trapping of [~C]methane. The broad optimum between 700 and

• m ~ 1oo

- ~ s0 ~z~ 60

~ E 600 650 700 750 800

Temperature °C

Fig. 3. The decay-corrected radiochemical yield from the system in Fig. 1 as a function of temperature in oven 2.

156 Peter Larsen et al.

8 A

f - - - -~ - - : : ' ' t L - = - ~ : ~-B

I I I I I

0 l 2 3 4 5 I a I I I I

6 7 8 9 10 11

Time (rain)

Fig. 4. Output from a radiation detector (GM Tube ZP/300) placed close to the Porapak N trap in the system shown in Fig. 2.

750°C indicates that the process is relatively robust towards minor temperature variations.

The non decay-corrected yield from the system shown in Fig. 2 is lower (46 6%, n = 11) than the yield from system 1 (65 5%, n = 10). The main reason for this is that the conversion of [HC]carbon dioxide into [NC]methane is not quantitative and adds 3-4 min to the time from the end of trapping to the end of production. Furthermore, it is impossible to avoid hydrogen from the reduction step entering the circulating part of the system together with the ["C]methane. This hydrogen lowers the yield due to reaction with iodine.

However, trapping of ["C]methane on the Porapak N is slower (5 min) and less efficient than trapping of ["C]carbon dioxide on the molecular sieve (1.5 min). Therefore the absolute amount of ["C]iodomethane produced by the two systems are very similar after the same irradiation time and beam current.

We have performed more than one hundred ["C]iodomethane productions. For both systems the typical yield after a 10 min, 30 pA (5 pAh) irradiation is 15-18 GBq (400-500 mCi) of ["C]iodo- methane with a radiochemical purity that exceeds 98% and a specific radioactivity that exceeds 550 GBq//~mol (15 Ci//~mol).

Figure 4 shows the output from a radiation detector placed close to the Porapak N trap in the system shown in Fig. 2 as a function of time. From the start of the experiment until time A the target gas is released and the radioactivity accumulates in the molecular sieve trap. Between A and B, the target gas in the trap is replaced with hydrogen-helium mixture and the trap is heated in order to convert [~'C]carbon dioxide into [HC]methane. This does not change the distance between the radioactivity and the detector and therefore the signal is constant except for decay and noise. Between B and C, the radioactivity is transferred into the circulating part of the system.

The tube between the pump and the oven is close to the detector. Therefore there is a large peak between B and C. At point C the pump starts and the ["C]methane is circulated while the [HC]iodomethane begins to accumulate on the Porapak N trap until the maximum is reached at time D. Immediately after C the signal from the detector begins to oscillate. This shows that the [HC]methane is pumped around as a bolus which is broadened out after 7-8 passages. From the frequency of the oscillation the time for a single passage can be estimated to be approx. 5 s. Between times D and E the product is released and at time E, 10.5 min after end of bombardment, the production is finished.

[HC]iodomethane with a high specific radioactivity is unstable in solution. Decomposition can take place by reaction with traces of impurities in the solvent or by radiolysis. This problem can be overcome by trapping the [HC]iodomethane in a 1% solution of unlabelled iodomethane in N,N-dimethylformamide (DMF). In this solution the product is stable at room temperature and the radiochemical purity can be determined by HPLC. The main impurity is ["C]methane. Minor impurities are [HC]carbon monoxide and ["C]carbon dioxide. High amounts of the two last impurities indicate that oxygen has leaked into the system or that the reaction temperature is too high. [HC]diiodomethane is only detectable if the reaction temperature is too high, or the flow rate during circulation is too low. The Porapak N column used for trapping ["C]iodomethane during the circulation step can be used as a preparative gas chromatograph during release of the product. The waste valve (V4 in Fig. 1, V7 in Fig. 2) can then be used to collect the pure [~'C]iodomethane fraction. In this way a product with a radiochemical purity of > 99.5% can be obtained. The chromatographic resolution of the column is not very high and therefore the yield is reduced by 5-10%

Synthesis of [t~C]iodomethane 157

by this procedure depending of the required purity of the ["C]iodomethane. Small amounts of HC-labelled methane, carbon monoxide and carbon dioxide do not generally interfere with the reactions of [HC]iodomethane. Consequently, it is usually suffi- cient to flush out most of the impurities by a stream of helium for a few seconds, before the product is collected. The rest of the gaseous impurities is not trapped very efficiently in the DMF or precursor solution. In this way the obtained radiochemical purity is better than 98%.

The specific radioactivity of the [t~C]iodomethane can be determined by HPLC after trapping in acetonitrile at - 45°C. The u.v. extinction coefficient of the product is not very high, and decomposition and trapping of [HC]methane together with the [~C]iodomethane may make the analysis imprecise. A better method is to use the ["C]iodomethane to label a nucleophile with a good u.v. extinction coefficient, measure the specific radioactivity of the product and then calculate the specific radioactivity of the [~ ~C]iodomethane.

We have used the ["C]iodomethane for labelling three substances: NNC-756 (methylation as described by Halldin et al., 1993), methionine (Ishiwata et al., 1988), and a cyclohexylamine derivative (methylation of an amino group).* The decay-corrected radio- chemical yields as compared with those published for the [HC]iodomethane prepared by lithium aluminium hydride reduction were 42% for NNC-756 (Halldin et al. achieved 40%) and 63% for methionine (Ishiwata et al., 70%). The decay-corrected radio- chemical yield of the N-["C]methyl cyclohexylamine was 76% . The specific radioactivity of the N- [HC]methyl cyclohexylamine compound was deter- mined, on the basis of its u.v. absorbance for mass determination to be 299 GBq/#mol (8.1 Ci//~mol) at 22 min after the end of trapping of the [t~C]iodomethane. Thus the specific radioactivity of the [~C]iodomethane could be calculated to be 610 GBq//zmol (16.5 Ci/#mol). This indicates that the [~LC]iodomethane is not contaminated by reactive chemical impurities that could not be detected by HPLC or GC.

Both systems are well suited for automation, and require no washing and drying prior to each

*The exact structure of the compound is confidential and unpublished, but has no impact on the argument.

production. The system shown in Fig. 2 is especially simple to use since there is no liquid nitrogen trap. The iodine tube can be used for more than 15 productions, but the Ascarite trap at the end of the tube slowly gets clogged up during use. At the end of the lifetime of the tube the flow restriction of the trap grows rapidly and the yield drops to zero within one or two productions. In order to avoid production failures and unnecessary radiation dose to the operator, we normally change the iodine tube after 10 productions.

Only a small fraction of the starting radioactivity is left in the system after production. This combined with the low starting radioactivity required to obtain a good specific radioactivity, results in a low radiation level in the hot-cell after the product is removed. The short irradiations required decreases the activation of the cyclotron and target, and increases the productivity with respect to methylated radioligands for PET.

References

Crouzel C., L~ngstro B., Pike V. W. and Coenen H. H. (1987) Recommendations for a practical production of ["C]methyl iodide. Appl. Radiat. Isot. 38, 601-603.

Crouzel C. and Hinnen F. (1993) Synthesis of [~C]labelled lower chloromethanes: application in methylenation reaction. J. Label. Comp. Radiopharm. 35, 92-93 (abstract).

Flowers M. C. and Benson S. W. (1963) Kinetics of the gas-phase reaction of CHd with HI. J. Chem. Phys. 38, 882-889.

Golden D. M., Walsh R. and Benson S. W. (1965) The thermochemistry of the gas phase equilibrium I2 + CH4~-CH3I + HI and the heat of formation of the methyl radical. J. Am. Chem. Sot'. 87, 4053-4057.

Halldin C., Foged C., Farde L., Karlsson P., Hansen K., Gro F., Swahn C.-G., Hall H. and Sedvall (3. (1993) ["C]NNC 687 and [HC]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investi- gation in monkey. Nucl. Med. Biol. 20, 945 953.

Holschbach M. and Schueller M. (1993) A new and simple method for the preparation of n.c.a. [HC]methyl iodide. Appl. Radiat. lsot. 44, 779 780.

Ishiwata K., ldo T. and Vaalburg W. (1988) Increased amounts of D-enantiomer dependent on alkaline concen- tration in the synthesis of L-[methyl -~'C]methionine. Appl. Radiat. lsot. 39, 311-314.

Oberdorfer F., Hanish M., Helus F. and Borst W. M. (1985) A new procedure for the preparation of [~C]labelled methyl iodide. J. Appl. Radiat. Isot. 36, 435-438.

Prenant C. and Crouzel C. (1991) A new simple and attractive method of [~C]halogenomethanes production. J. Label. Compd. Radiopharm. 30, 125- 131.