fnf. 1. Appl. Radiot. fsot. Vol. 34, No. 4. pp. 743-745. 1983 OO’O-708X 83 MO-~3-03503.00 0 Printed in Great Britain. All rights reserved Copyright Q 1983 Pergamon Press Ltd

Radiofluorination with Xenon Difluoride: A New High Yield Synthesis of

SUDESH SOOD, GUNTER FIRNAU and E. S. GARNETT

Department of Nuclear Medicine. AMcMaster University Medical Centre. Hamilton. Ontario. Canada LSN 325

(Recked 3 June 19S2)

The reaction between [“F]xenon ditluoride, 3,4.6-tri-0-acetyl-D-glucal and boron trifluoride in ether gives exclusively [‘sF]3.4,6-tri-O-acetyl-2-Ruoro-2-deoxy-D-~lucopyranosyl fluoride, which is hydrolvszd with 1 N HCI to [“FjZ-fluoro-2-deoxy-D-glucose. The overall chemical yield is 754;; the radioche&A yield is 20:$‘,. The procedure takes 45 min.

Introduction

[1*F]2-Fluoro-2-deoxy-~glucose, ([‘*Fl2-FDGX is used clinically to measure regional cerebral glucose metabolism by positron emission tomography.“+” The only published production method for [t*F]2- FDG gives a low chemical and a low radiochemical yield.‘3~‘*5’ It also produces variable quantities of an unidentified radiochemical impurity.@*‘)

The mild and versatile fluorinating agent xenon difluoride, (XeF,), can be labelled with fluorine-18’s’ and may be used for radiofluorinations.‘9’ A synthesis of 2-FDG from XeF, has been recently reported’ to1 in which the unsaturated carbohydrate derivative 3,4,6- tri-O-acetyl-n-glucal, TAG, has been reacted with XeF, in the presence of the mild catalyst boron tri- fluoride etherate in ether-benzene for 24 h to give two major products: 3,4,6-tri-O-acetyl-2-fluoro-2-deoxy- (a,&o-glucopyranosyl fluoride (73%) GLF, and 3,4,6- tri-O-acetyf-2-fluoro-2-deoxy-(B)-D-mannopyranosy) fluoride (5%). The former was hydrolysed to give 2- FDG. We, therefore, applied [‘*FJXeF2 for the syn- thesis of [‘*Fl2-FDG hoping to obtain high yields and high radiochemical purity.

Results and Discussion

Because of the short half life of t8F (110 min) syntheses with this isotope demand fast chemical reactions, and only those reactions that can be com- pleted in minutes are useful. In the present work we reinvestigated the reported synthesis described by KORYTNYK,“~’ and found that, instead of 24 h, it took only 5 min for XeF2 and TAG to react to completion. The reaction therefore promised to be useful for fluor-

* The fluorine in SO&IF and in these catalysts does not exchange with the t8F in [t8~XeF2.

ination with ‘*F. However, the solvent benzene reacts with XeFt”” and. in the presence of BF,. promotes the rearrangement of the double bond in TAG and the formation of carbohydrate dimers!“’

XeF, and TAG do not react without a catalyst and unfortunately the fluorine in XeF2 exchanges rapidly with that of the catalyst BF3.“’ When [lSflXeF, is used, this exchange lowers the specific activity and we, therefore, attempted to replace both benzene and BF3. In a search for a suitable solvent catalyst combi- nation we ran the reaction in either sulfur$ chloride fluoride, acetonitrile, methylene chloride or carbon tetrachloride using trifluoracetic acid or pentafluoro- thiophenol* as catalyst. With each solvent catalyst combination the starting material TAG was consumed in less than 10min. but up to 12 products were formed and the yield of 2-FDG was net-er greater than 496. When ethylacetate, tetrahydrohtran, tri- chlorofluoromethane or diethyl ether were used with the same catalysts, the reaction did not proceed.

Clearly none of these solvent-catalyst combinations was suitable. However, when we replaced benzene with diethyl ether but retained BFs as catalyst the reaction went reasonably quickly (ljmin) and produced only GLF.

The effects of the concentration and relative amount of reactants on. the yield of 2-FDG are sum- marized in Table 1. In all runs the amount of BF, was kept low (l/5 of the batch size) and constant. The rate of the reaction was found to vary with the concentra- tion of the reactants. Below 6Opmol/mL of TAG the reaction is slow and produced low yields during the reaction time of 15 min (run 1.2). Above 6O/fmol/mL of TAG or XeF,, yields of more than 60% were obtained consistently (run 3,4, 5). The yields were not influenced by excess of either XeF2 or TAG (runs 6,7,&g).

743

Su&sh Sood et al.

T.ABLE 1. The effect of amount and concentration of reactants on the yield of 2-FDG

2-FDG Concentration pm01

XeF, TAG BFs Ether pmol/mL produced Yield Run pm01 firno pm01 mL XeF, TAG in 15 min “/L

I 125 125 25 4.2 29.7 ‘9.7 6 4.8 2 125 125 25 3.0 41.2 41.2 21 16.9 , ; 125 125 125 1’5 25 25 2.0 2.0 62.5 62.5 62.5 62.5 86 83 69.1 66.3

; 125 186 125 125 25 25 2.0 2.0 93.0 62.5 62.5 62.5 109 105 86.8 84.0 7 125 186 25 2.0 62.5 93.0 95 76.1 8 I25 250 25 2.0 62.5 125.0 111 89.0 9 292 29s 59 4.1 62.1 63.4 212 71.3

On the basis of these results we have designed a new synthesis for [“F-j2-FDG in which reaction between [181;1XeFz, TAG and BF, is followed by acid hydrolysis of the reaction mixture. The reaction sequence is completed in one vessel. The chemical yield is 70’;; and the radiochemical yield is 20%. The difference between the chemical and radiochemical yields is due to dilution of 18F by isotopic exchange of 18F between XeFz and BF, . When the exchange is taken into account the radiochemical yield is calcu- lated to 770/, which tallies with the chemical yield.

The specific activity of [18FJ2-FDG produced by the new synthesis is directly proportional to that of the initial [“FjXeF2 but inversely to the amount of BF3. Lowering the amount of BFB or replacing BF, will increase the specific activity of [‘8F]2-FDG.

[‘8F]XeF2 is now available in 1.85 GBq (50 mCi) quantities from which about 370MBq (10mCi) of [‘8F]2-FDG can be produced. This amount is suf- ficient for one or two brain studies in humans with the present day high efficiency tomographs.“3.*4’

Experimental

Incestigations into the effect of the amount and concen- tration ofreactants on the yield of 2-FDG

In a series of experiments TAG (Aldrich) and XeF2 in anhydrous diethylether were stirred at room tem- perature and boron trifluoride etherate (Aldrich, 25I.tmol) was added slowly. The details of these ex- periments are listed in Table 1. The progress of each reaction was monitored by both GLC (6ft x 1/4in. OV-17 column, lQO’C, He 20 mL/min. FID) and TLC (glass plates precoated with silica gel 60, Merck; de- veloped with ether-petroleum ether 7:3, visual&d with 50/d sulphuric acid in methanol). TAG was con- sumed after 15 min reaction time. Most of the diethyl- ether was then evaporated in a stream of nitrogen. The remaining pale yellow concentrated solution was chromatographed on a silica gel column (1 x 13 cm, kieselgel 60-H, 7736 Merck). 3,4,6-Tri-O-acetyl-2- fluoro-2-deoxy-D-glucopyranosyi fluoride was eluted from the column with 60mL of ethylacetate-petro-

leum ether 1:3. A further elution with the higher polarity solvent ethylacetate-petroleum ether 1:2 was used to bring off any 3,4,6-tri-0-acetyl-2-fluoro-2- deoxy-o-mannopyranosyl fluoride. None was found.

3,4,6-Tri-O-acetyl-2-ffuoro-2-deoxy-r)-glucopyrano- syl fluoride was identified by its NMR spectra. The ‘H-NMR spectrum (Brucker WP-80 FT. 80 MHZ) was identical to that of authentic GLF.(15’ The 19F- NMR spectrum (Brucker WH-90, FT, 84.66 MHz; in carbon tetrachloride, with CFCIJ as reference) showed signals at 150.9 ppm for the fluoride on Cl (J[F(l) - H(l)] 51 Hz; J[F(l) - H(2)] 22.8 Hz and 203.8 ppm for the fluorine on C2 (J[F(Z) - H(2)] 45.5 Hz, J[F(Z) - H(3)] 11.4I-I~.

The eluate containing GLF was evaporated. The residue obtained was treated with l-2mL HCl at 130’C for 30min and the resulting yellow solution was transferred to a column (15 x 0.7 cm) packed successively with 5 cm of ion retarding resin (AG 1 l- A8, 50-100 mesh, BioRadA 5cm of neutral alumina (Brockmann 1, 80-200 mesh) and 5cm of the ion retarding resin, and equilibrated with water.‘“’ 2-FDG was eluted with 6 mL of water. It was compared chromatographically with authentic 2-FDG (Calbio- them-Behring Corp.). TLC (Silica gel 60, acetonitrile- water 95:5 or chloroform-methanol-water 3O:Q: 1, spots visualised with 5% sulfuric acid in methanol) showed single spots with R, 0.42 and 0.13 respect- ively. The R, values were identical to those of auth- entic 2-FDG. HPLC (Water’s carbohydrate columns, 0.4 x 30 cm, mobile phase acetonitrile-water 95:5, 1 mL/min, RI detector) also showed a single com- pound at the elution time of authentic 2-FDG. The yield was measured by HPLC with a calibrated RI detector. The ‘H-NMR spectrum (in D,O; TMS as reference) was identical to that of authentic 2-FDG. The 19F-NMR spectrum (in D,O; with CFCla as reference) showed one signal at 199.1 ppm with mul- tiple fine structure J [F(2) - H(2)] 50.3 Hz, J [F(2) - H(3)] 11.4 Hz.

Preparation oj”[“FJXeF2

Fluorine-18 was produced by the deuteron reaction on neon in a gas target.‘16’ The content of the gas

145

target was transferred into a high pressure nickel

vessel that was previously charged with xenon gas. The vessel was heated to 39O’C for 30min. After the vessel was cooled to -4O’C. neon. xenon and un- reacted fluorine were released. Then, [‘*FjXeF, was transferred from the nickel vessel into a glass vial by vacuum sublimation.

[‘*F-JXeF2 (13.0mCi,* 292 pmol) and TAG (298 pmol) were dissolved in 4mL of ether. To this sol- ution BF, etherate (59 pmol) in 1 mL ether was added dropwise. After the reaction mixture had been stirred at room temperature for 15 min the ether was evapor- ated. An aliquot of the residue was analysed by thin layer radiochromatography (Silica gel, 20 cm glass plates, mobile phase ether-petroleum ether 7 : 3 ; radio- chromatogram scanner, Packard, model 7201). ‘sF was equally divided between the origin, presumed to be [‘sF]BF3 complex, and [t8F-JGLF.

The bulk of the residue, 443.3 MBq (11.98 mCi), was treated with 2.0 mL 1 N HCl at 130°C for 30 min. This reaction mixture was then passed through a column packed with ion retarding resin and alumina as described above. The column was eluted with water. The eluate (6 mL) contained 99.9 MBq (2.7 mCi) of ‘SF.

An aliquot of the [18Fj2-FDG solution was chro- matographed on HPLC. The eluate from the HPLC was monitored for both ‘*F (NaI(Tl) detector) and 2-FDG (calibrated RI detector). The chemical yield was 71.3%. The radiochemical purity was 95.3%.

* All measurements of t*F were done with a calibrated ionization chamber (Capintec) and corrected for radio-

Acknowledgemenrs-We thank Dr G. Schrobilgen for sup- plying the xenon difluoride and both the Medical Research Council of Canada and the Ontario Mental Health Foun- dation for financial support.

1.

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