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Fluorine-18-labeled fluorine gas for synthesis of tracer molecules
Nuclear Medicine & Biology, Vol. 24, pp. 677-683, Copyright 0 1997 Elsevier Science Inc.
ISSN 0969-8051/97/$17.00 + 0.00 PII SO969-8051(97)00078-4
1997
ELSEVIER
Fluorine+ 1&Labeled Fluorine Gas for Synthesis of Tracer Molecules JBrgen Berg-mm andOlaf Solin TURKU
PET CENTRE,
ACCELERATOR
LABORATORY,
LABORATORY,
i.BO
AKADEMI
UNIVERSITY
UNIVERSITY,
OF TURKU,
TURKU,
TURKU,
AND
MEDlCITYjPET
RESEARCH
FINLAND
ABSTRACT. The aim of this work was to develop a method to produce “F-labeled fluorine gas ([ ‘sF]F2) with high specific radioactivity (SA, radioactivity/mass-ratio). ‘sF-Labeled methyl fluoride ([ “F]CH3F) was synthesized from [18F]Fand mixed with carrier F, in an inert neon matrix. The constituents were atomized in an electric disc“it arge, after which a rearrangement and l*F for ‘9 exchange took place. [‘sF]F2 with a specific radioactivity of up to 55 GBq/p mo 1 is available for the labeling synthesis of tracers for positron NUCL MED BIOL 24;7:677-683, 1997. 0 1997 Elsevier Science Inc. emission tomography (PET). KEY WORDS. Fluorine-18. ceuticals,
ElectroDhilic
fluorine.
Fluorodestannylation,
Specific
radioactivity,
Radiopharma-
PET
INTRODUCTION Electrophilic fluorination of organic molecules with F, or its derivatives is efficient, controllable, and fast (16, 23, 28). F, is a very potent chemical agent; indeed, it is the most reactive pure element. The fluorine atom is about the same size as the hydrogen atom. This makes it possible for fluorine to mimic hydrogen with respect to steric requirements in molecules as well as at binding sites on receptors and enzymes. Fluorine substitution can also have a profound effect on the lipofilicity and biological activity of small molecules (21). The PET technique makes it possible to follow, in the living man, the binding of radiolabeled ligands to receptor sites, thus making it possible to quantitate the number of binding sites in both healthy and diseased states. Displacement of the labeled ligands makes it possible to measure the affinity to the binding site. Tracer studies with potent and/or toxic neuroreceptor ligands require high specific radioactivity for the tracer, as the amount of mass that can be injected into a human subject is limited by the toxicity of the substance and its affinity for the receptor site. For an injected dose of typically 185 MBq, the amount will be 10 nmol when the SA is 18.5 GBq/kmol. Electrophilic radiofluorine is particularly suitable for the synthesis of fluoroaryl compounds ([ “F]Ar-F) by cleavage of aryl-metal bonds of typically Ar-MR (M=Sn, Hg, Si, R=(CH,),) compounds either with [18F]Fz or [“F]CH,COOF (12, 17-19). The factor limiting the more widespread use of the method has been the low specific radioactivity of the labeled fluorine gas available through radionuclide production from gas phase target materials (10, 11, 20), typically neon or ‘sOz mixed with carrier Fz. Gas targetry for the production of [I’F]Fz has recently been extensively reported (6-9). Straatman et al. (27) describe a method where n.c.a. [18F]HF, in an exchange reaction with F,, is converted to [‘“F]F, by a microwave discharge. A facile way of producing 18F is to irradiate, with a particle Address rep@ requests to: Olof Solin, Turku PET Center, Accelerator Laboratory, Abo Akademi University, Porthansgatan 3, FIN-20500 Turku, Finland; E-mail: [email protected] Received 19 February 1997. Accepted 3 May 1997.
accelerator beam, highly “O-enriched water. Through the *‘O(p,n)“F nuclear reaction, up to several curies of radioactivity can be produced (13, 22). The radiolabeled fluoride ([‘sF]F-,,) recovered after charged particle irradiation can be used for the production of numerous labeled neurotracers (16). However, the synthetic chemistry with this anion is usually neither simple nor fast, especially if more complex molecules are needed. The aim of the present work has been to develop a method suitable for the routine use of [“F]F, for synthesis of radiotracers for PET. The SA of the product should be such that studies with receptor ligands are possible. Figure 1 shows some specific radioactivities for 18F. Initially, a semitheoretical model for gas phase exchange of fluorine between unlabelled fluorine gas and a radiolabelled inert gas was studied. Calculations showed that if rigorous purity of the reactants could be maintained and a suitable method of excitation found, the method was workable (1, 25). Radiolabelled methyl fluoride was considered to be a suitable vehicle for supplying the “F-atom to the reaction. Four different methods of excitation were considered: (a) excitation with the cyclotron particle beam, (b) excitation with hard UV-light, (c) excitation via an electric discharge through the gas, and (d) excitation with laser light (excimer lasers). Methods b and c were considered to be practical, and were therefore tested. As materials for the handling system, both quartz and Teflon were used.
MATERIALS Cjeneral
AND METHODS
An overview of the computer-controlled production system is shown in Figure 2. Starting from [“F]F-, [“F]CH,F is synthesized to get the radioactive fluorine into gas phase. The synthesis of [18F]CH,F has the advantage of being fast, and the radiochemical yield is high (3). To get rid of solvents and other impurities, the [18F]CH,F is passed through a preparative gas chromatography column before transfer to a reactor and addition of carrier fluorine. The exchange reaction is then initiated either with UV-irradiation by using a low-pressure mercury lamp, or by initiating an electric
678
J. Bergman and 0. Solin
1OOOOO
Synthesis
m -Maximum [‘*F]F SA
10000 1000
Specific radioactivities for [‘*F]F2
100
.
f-
Measured [‘*F]Fz SA
10
and [‘*F]F,
[GBqWoll
1
: e
SA for [‘8F]Fz in Ref. 11
0.1 0.01
radioactivity (SA) of “F displayed on a FIG. 1. Specific logarithmic scale. The arrows point at (a) the theoretical maximum for the SA of [ ‘sF]F-; (b) the highest SA measured for [ ‘sF]F-,, (24); (c) the SA of [ “F]F, achieved with our new method; and (d) the highest SA for [ “F]F2 found in the literature ( 11). discharge through the gas. Subsequently, the gas is bubbled through a receiving vessel, where the labeling reaction takes place. All gases used in this work, except where otherwise stated, were acquired from Aga Special Gases (Helsinki, Finland).
Production
of [18F]F-
The [“Flfluoride was produced by irradiating -400 p,L 94-99% ‘so-enriched water (Isotec Inc., Miamisburgh, Ohio) in a nonpressurized silver target chamber. The target chamber construction is similar to the one described by Solin et al. (24), except it is modified for the use with 16.7-MeV protons instead of 10.5-MeV protons. The irradiations were made with the isochronous cyclotron (MGC20) at the Abe Akademi Accelerator Laboratory using 17-MeV protons with a beam current of lo-12 PA on the target. The saturation yield under these conditions is 7.2-7.8 GBq/kA. For high activity runs, the irradiation time was 2 h.
and
isolation of [18F]CH,F
The irradiated water was transported via silicon tubing (i.d. 0.8 mm, Masterflex 6411-13, Cole-Parmer Instrument Co., Chicago, IL) to a reaction vessel containing 3 mg potassium carbonate (Merck AG, Darmstadt, Germany), 12 mg kryptofix 2.2.2 (Merck AG., Darmstadt, Germany) and 1 mL acetonitrile (Rathbum Chemicals Ltd., Scotland). Evaporation with helium (99.998%) flow under reduced pressure, generated by a Teflon membrane pump (Leybold-Heraus AG, Kaln, Germany), was carried on for 2 min. During evaporation, the vessel was heated to a temperature of 80°C in a sonic bath. Acetonitrile (1 mL) was added and the evaporation continued for a further 2 min, after which the vessel was evacuated to a pressure of -10 mbar. Fifty microliters CH,I (p.a., Merck AG, Darmstadt, Germany) in 1 mL acetonitrile was added to the dry residue. The formation of [18F]CH,F was completed in less than 1 min. The product was flushed with 35 mL neon, through a cooling tower at 10°C into a 60-mL syringe and injected onto a Haysep Q (80/100 mesh, Ohio Valley Specialty Co., Marietta, OH) gas chromatography column (i.d. 0.8 cm, length 30 cm). Neon was used as carrier gas. A radioactivity detector on the outlet of the column monitored the elution of the [“F]CH,F. When eluted, the product was trapped in a l/16” stainless steel loop at liquid nitrogen temperature (-196°C). The isolation took less than 10 min.
Formation of Electrophilic
[18F]Flmrine
From the loop, the [“FJCH,F was transferred to a reaction chamber h ar g e excitation) or quartz (both (see fig. 3) made ofT efl on (f or d’LSC for discharge and UV-excitation) using known amounts of carrier fluorine (150 nmol-1.5 prnol) in neon as sweep gas. The exact amount of carrier gas was achieved by filling a standard volume, connected via a valve to the discharge chamber, to a calibrated pressure with a gas mixture of 0.8% F, in neon (Spectra Gases Inc., Alpha, NJ). This gas was then released through the stainless steel loop containing the [“FJCH,F. Filling the standard volume to a pressure of 4 bar absolute with the undiluted gas mixture resulted in the introduction of 1.5 p,rnol carrier fluorine in the discharge chambers. When using lower amounts of carrier fluorine, the gas mixture was diluted with neon. The lower energy and flux of UV-photons as compared to energy and flux of fast electrons generated during the electric discharge allows the time-resolved study of intermediate products formed
u
Vacuum,
FIG. 2. Schematic diagram of the apparatus for conversion of “F-fluoride to electrophilic “Ffluorine. Valves l-3 are 3.way Teflon solenoid valves (1116” connections, Asco Controls BV, Scherpentzel, The Netherlands), valves 4-8 are 3. or 2.way airoperated SS-41XSl valves (1116” connections, Nupro Co., Willoughby, OH); and valves 9-11 SS.4BK are hand-operated valves (l/4” connections, Nupro Co., Willoughby, OH).
Cold trap
l.,..._.... 0 +
o”-
.._ .i
-
High voltage 30 kV
Sonic bath/Heating
Fluorine-18-Labeled
Fluorine
679
Gas
with a spectral resolution of h/AX = 3800. The exposure times used were 1 to 30 sec. The light from the discharge chamber was conducted to the spectrograph inlet slit via a quartz fiber (o.d. 1 mm).
Calculations of a Simplified
Kinetic Model
Initiating an electric discharge through the gas mixture, or irradiation with intense UV-light, breaks the chemical bonds of the constituents, and the subsequent fate of the “F-label can be followed experimentally (Fig. 4a) by analyzing the formation of labeled fluoromethanes. The exchange process can be simulated using a Monte Carlo model, where in an ideal case the formation of [‘sF]Fz can be studied as a function of the relative concentrations of the constituents (Fig. 4b), subject to the constraints imposed by the model used. In the simplest case, assuming that all the chemical bonds are broken in the discharge plasma, the following equation holds for m * n:
I
:
:
:
:
I mFz + n[“F]
5cm
CH,F
4
(m - 3n)[“F]Fz
+ 3n[ ‘*F]HF FIG. 3. Cutaway chamber is above;
drawings of discharge chambers: quartz chamber is below.
Procedures
A gas chromatograph (GC-15A, Shimadzu Co., Kyoto, Japan) equipped with a flame ionization detector (FID) and a radioactivity detector (NaI, 2 X 2”) was used for the determination of [18F]CH3F, [“F]CH,F,, [‘sF]CHF,, and [“F]CF4. A 3-m (o.d. l/8”, i.d. 2 mm)-long column filled with Porapak Q (SO/l00 mesh, Alltech, Arlington Heights, IL) was used for the separations. The column temperature was 50°C; nitrogen (99.999%) was used as carrier gas. Retention times for all the fluoromethanes were determined; an absolute calibration was done with authentic standards of CH,F (Fluorochem Ltd., Old Glossop, UK), CHzF, (L’Air Liquide, Alphagaz, France), CHF,, and CF, (Union Carbide SA, Westerloo, Belgium). GAS CHROMATOGRAPHY.
Spectrometric analyses of the light emission from the discharge chamber during discharge were made with an optical spectrometer (Multichannel Echelle Spectrograph, MES@ 30K, NOW-Optics, Kista, Sweden) able to cover the spectral range from 195 nm to 1100 nm in 30,000 channels simultaneously SPECTROMETRIC
ANALYSES.
(1)
Teflon
during the 18F for 19F exchange reaction. However, during UVillumination, the major part of the formed [‘*F]F, is lost in reactions with the chamber walls, apparently due to the temperature rise in the chamber materials associated with the relatively long illumination times needed. Therefore, further experimentation was done utilizing the considerably more energetic fast electrons generated in a discharge plasma. The bulk gas in the discharge chambers is chemically inert neon. The discharge is supported at 20-30 kV and 280 PA through a 50-Mohm load resistor (EH series high-voltage power supply, Glassman Europe Ltd., Hampshire, UK). The anode and cathode are stainless steel capillaries (o.d. l/16”, i.d. 0.2 mm) that also serve as the gas inlet/outlets of the chamber. The volume of the chamber is 1.6 cm3 and the distance between the electrodes is 15 mm. The discharge is normally run for 10 sec.
Analytical
+ n[‘sF]CF4
Calculations for [I ‘F]F2
of Specific Radioactiwity
and Reaction Yields
We determined the SA of [“F]F* both directly by iodometric titration of oxidizing material and measurement of the radioactivity of the [“F]KF formed and indirectly by radiochromatographic determinations of amounts of mass and radioactivity of substances labeled with “F. Note that the SA of the product in the labeling synthesis is decreased by half as compared to [‘sF]F, as there is only a 50% chance for the introduction of the 18F-atom. The decay of the “F will also decrease the SA in proportion to the half-life of 109.8 min. When the amount of methyl fluoride used in the exchange reaction is known, the theoretical specific radioactivity and yield of [18F]F, can be calculated and compared to the measured time-corrected specific radioactivity of the synthesis product. From these numbers the yield in the exchange reaction can be determined.
RESULTS
[“F]FIn a series of 10 irradiations the following yield was measured for the radioactivity collected at the methyl fluoride synthesis apparatus: activity corrected to end of bombardment was 38.5 ? 1.4 GBq (irradiation time 120 + 4.5 min; beam current 10.0 + 0.33 kA). The enrichment grade of the 180-water was 99%. Based on earlier measurements with similar targetry, we estimate the specific radioactivity of the [“F]Fproduced to be in excess of 5.5 TBq/ p-mol (24).
[18F]CH,F The total mass of methyl fluoride formed in a synthesis was 8-12 nmol as analyzed by gas chromatography. Starting a synthesis with about 37 GBq [“F]Fand an average radiochemical yield of 75 + 9% (n > 100) for the methyl fluoride synthesis gives 25 + 3 GBq (EOB + 20 min) of methyl fluoride with a specific activity of 2.5 + 0.3 TBq/pmol.
680
J. Bergman and 0. Solin
a
b
4 n
3
I
100
2 1 80
I 4 s3 12
I
[‘BFICpP
II
[“FJCF,
Y C* .L 5
1
.-8 J
4 3
\ : III
2 1
10
I
100 200 300 400 500 600
0
I.-
Dose [arb. units]
Retention time [set]
FIG. 4. (a) Intermediate “F-labeled carbon&uorine compounds formed in the exchange reaction between [ “F]CH,F and F, as analyzed by gas chromatography. The gas samples were collected before (I), during (II), and after (III) illumination of the gas mixture with UV-light from a low-pressure mercury lamp (6 W). (b) Computer-generated curves for the formation of [ ‘sF]Fz in the exchange of “F for laF between [ ‘*F]CH,F and laI-19F fluorine gas. The calculations were made by a Monte Carlo routine, taking into account the successive formation of partially and totally fluorinated C, and C,-species. The curves displayed have molar ratios (m/n) of 1000, 20, and 5 for F, and [‘sF]CH,F.
Electrophilic
[‘8F]Fluorine
The [18F]CH,F/[‘8F]F, conversion efficiency was studied as a function of the amount of carrier F, used, while the discharge time was held constant at 10 sec. The conversion efficiencies were about 60% when -500 nmol or more carrier fluorine was used. The conversion was about 30% when 150 nmol carrier fluorine was used
(Fig. 5). No significant difference was observed between the Teflon and quartz chambers. Lengthening the discharge time did not increase the conversion yield. Starting from 37 GBq [t8F]FP and by using 150 nmol carrier fluorine, more than 7.5 GBq [‘sF]F, can be produced with a specific radioactivity of > 50 GBq/p,mol (EOB + 20 min). Using larger
FIG. 5. Amount of ‘8F-atoms, recovered as electrophilic “F, as a function of the amount of F, used in the exchange reaction.
800
1000
1200
Carrier fluorine [mol]
Fluorine-18-Labeled
Fluorine
681
Gas
630
636 I I
‘t
200
400
600
800
1000
FIG. 6. Light emission, in the wavelength range 200-1050 nm, of the discharge in the quartz chamber. Atomic and molecular species show their characteristic atomic or molecular emissions. Most of the emission lines seen here are from atomic neon and fluorine, created in the discharge volume. In the insets, atomic emission lines from silicon, oxygen, hydrogen, and carbon can be seen. The exposure time for the recording was 5 set on a parallel registering optical spece trometer, using an optical fiber to conduct the light from outside of the chamber to the spectroe graph inlet slit.
Wavelength [nm]
amounts of carrier F, gives higher yields of [“F]Fz tional decrease in the specific radioactivity.
with
a propor-
Spectroscopy In addition to expected signals from atomic transitions of atomized neon and fluorine, the optical spectra recorded during the discharge also showed atomic lines from hydrogen, oxygen, silicon, and carbon. These stem from the chamber materials and from the radiolabeled methyl fluoride purposefully introduced into the chamber. No molecular features were seen during recordings of lo-set discharges in pure gases. However, if the discharge is continued for longer times, spectral features belonging to the Swan-bands of diatomic carbon (Cz) are observed from the Teflon chamber. Prolonged discharge in both chambers showed that the signals from fluorine decreased as compared to neon. Unidentified molecular features then showed in the spectra. No signals from ionic species were seen in any of the spectra recorded from these chambers.
DISCUSSION We utilize [‘sF]F-,a (>37 GBq) produced from a water target to make [“F]CHsF, the most simple fluorinated organic compound. The synthesis is facile, and radiochemical yields of 75% are reached in less than 6 min after end of bombardment at the accelerator (3). The specific radioactivity of the [“F]F-,, is ~5.2 TBq/p,mol (24) (Fig. l), as stable fluoride is unavoidably introduced into the preparations. We have measured the specific radioactivity of the [‘sF]CH,F to be 22.2 TBq/kmol. The [“FJCHsF is separated chromatographically, and after cryogenic isolation transferred to a quartz chamber together with carrier fluorine gas. Spectroscopic observation of the discharge plasma (Fig. 6) shows, in addition to the atomic emissions from neon and fluorine, emissions from several other atomic constituents (impurities) present in the plasma. These will, in proportion to their amounts, interfere with the desired course of the reactions. Therefore, the elimination of the impurities is important. The spectroscopic method of studying the discharge allows us to optimize the discharge chamber construction with reference to materials and shape, as well as to discharge power.
Figure 5 shows results from yield measurements of the incorporation of “F into the fluorine molecule. These results apply to the reaction chambers displayed in Figure 3. Fluorinated polymers seem to work equally well as quartz as chamber materials. The specific radioactivity and yield of [“F]F, are functions of the amount [“F]CH,F used, the amount of carrier fluorine gas introduced, and the efficiency of the exchange reaction between these two. A practical limit, at present, is set by the amount of [‘sF]CH,F we can produce (25-30 GBq, SA > 2.2 TBq/pmol) and a reasonable efficiency in the conversion, 30% at a level of 150 nmol fluorine carrier (Fig. 5). This gives us a maximal specific radioactivity of -55 GBq/p,mol for -7.5 GBq of [“F]Fz. The maximum value in the exchange reaction approaches 60%, as the amount of carrier F, is increased. According to theoretical calculations (Fig. 4) this value should approach 100%. The calculations do not, however, take into account the introduction of foreign materials, the losses to chamber materials, and other handling losses of this very reactive molecule. Also, the volume of interaction, where the electrons created in the discharge reach the gas molecules, is not the same as the total gas space in the handling system. Radiolabeling with [r8F]F, is simple: An inert carrier gas containing the labeled fluorine is bubbled through a receiving vessel containing an organometallic precursor molecule dissolved in a suitable solvent. The fluorination reaction is essentially instantaneous, after which the crude reaction mixture is injected on a semipreparative high-performance liquid chromatographic (HPLC) column. The purified substance is collected on the column outlet in a few minutes, formulated for injection, and is then ready for use at the hospital site. We have applied this method of making [‘“F]F, for the synthesis of several radiopharmaceuticals (see Fig. 7). In most cases we first synthesized [“fiacetylhypofluorite ( [r8F]CH,COOF) and used this as the labeling reagent (23). We have synthesized [r8F]CFT (4, 14) (precursor 2-P-carbomethoxy-3@(4-t nmethyl-stannyl-phenyl)tropane), a marker for the dopamine transporter, [r8F]fluoroatipamezole (26) (precursor 4-(2.ethyl-2,3-dihydro-5-tributhylstannyl-lH2-indenyl)-1-acetyl-imidazole), an alpha-2 adrenergic antagonist, [“Floxoquazepam (5) (precursor 7-chloro-l-(2,2,2-trifluoroethyl)-
682
J. Bergman and 0. Solin
YH2 FHzCHCOOH
OH OH
FIG. 7. Fluorine-184abeled used.
compounds
synthesized
via electrophilic
1,3-dihydro-5-(2-trimethylstannylphenyl)-2H~l,4-benzodiazepine~ 2-one) a bentzodiazepine, as well as 6[18F]FDOPA (2, 15) (precursor N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-Lphenylalanine ethyl ester) a marker for endogenous DOPA. The specific radioactivities for the first three mentioned pharmaceuticals have been about 15 GBq/p,mol at the end of synthesis. The radiopharmaceuticals have usually been ready for injection in 50 to 60 min after the end of accelerator bombardment. [“F]CFT is routinely synthesized with a specific radioactivity exceeding 15 GBq/pmol at EOS in amounts high enough for two PET studies on human subjects (400-800 MBq). The method has proved to be reliable: In less than 0.5% (n > 200) of the labeling syntheses made with the nucleophilic-electrophilic conversion system has any failure occurred, resulting in unexpected low synthesis yield. The mass and the specific radioactivity of the methyl fluoride will eventually put limits on this method. The mechanism is an exchange reaction demanding an excess of electrophilic carrier fluorine. The discharge chamber in use has a practical lower limit of
fluorination.
In all syntheses
the present
method
was
about 150 nmol carrier fluorine. Research will continue so as to improve mainly the discharge chamber in order to increase the efficiency with low amounts of carrier fluorine.
CONCLUSIONS Recent advances in PET technology, i.e., high-resolution 3-D cameras, as well as multipurpose PET/SPECT-devices, have created a situation where numerous hospitals and research institutions have need for positron emitting tracers, but have no in-house capabilities to produce radionuclides. Regional distribution centers for the delivery of t8F to these sites, mostly in the form of [r8F]F-,, or [‘*F]fluorodeoxy-D-glucose, are now being developed in several countries. Utilizing this new method to produce [r’F]F, from [‘*F]F-,a makes it possible for these sites to have available relatively complex fluorinated tracers in an essentially kit-like formulation, without the large monetary investment that a modern PET cyclotron/radiopharmaceutical lab requires.
Fluorine- 1S-Labeled Fluorine Gas
683
References
Pike V. W. (1991) Recommendations for fluorine-18 production. Appl. R&r. Isot. 42, 749-762. 14. Haaparanta M., Bergman J., Laakso A., Hietala J. and Solin 0. (1996) [‘*FjCFT ([‘8FjW1N 35,428), a radioligand to study the dopamine transporter with PET: Biodistribution in rats. Synapse 23, 321-327. 15. Hietala J., Syvdahti E., Vuorio K., R%kk&inen V., Bergman J., Haaparanta M. et al. (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346, 1130-l 131. 16. Kilboum M. R. (1990) Fluorine-18 labelling of radiopharmaceuticals. Nucl. Sci. Ser. NAS-NS-3203, National Academy Press, Washington
1. Bergman J., Kallman K-M., Solin O., DeJesus 0. T., Oakes T. R. and Nickles R. J. (1993) A new method for the production of electrophilic F-18 starting from aqueous [18F]fluoride. I. Nucl. Med. 34(Suppl), 69P. 2. Bergman J., Haaparanta M., Lehikoinen P. and Solin 0. (1994) Electrophilic synthesis of 6-[18F]fl uoro-L-dopa starting from aqueous [‘sF]fluoride. J. Label. Compd. Radiophann. 35, 476-477. 3. Bergman J. and Solin 0. (1994) Automated synthesis of [‘sF]-fluoromethane ([‘sFjCH,F). J. Label. Compd. Radiophann. 35, 174-175. 4. Bergman J., Haaparanta M. and Solin 0. (1995) Synthesis of 2p-carbomethoxy-3P-([4-‘sF]-fluorophenyl)tropane ([‘sF]CFr or [‘8FjWIN 35428). 1. Labelled Cumpd. Radio@arm. 37,46-48. 5. Bergman J., JohnstrZjm P., Haaparanta M., Solin O., Duelfer T. and Stone-Elander S. (1995) Radiolabelling of 2-oxoquazepam with electrophilic ‘sF prepared from [“Fjfluoride. Appl. Radiar. Isot. 46, 10271034. N., Bida G., Phelps M. and Barrio J. R. (1996) 6. Bishop A., Satyamurthy Chemical reactivity of the 18F electrophilic reagents from the ‘80(p,n))‘8F gas target system. Nucl. Med. Biol. 23, 559-565. N., Bida G., Phelps M. and Barrio J. R. (1996) 7. Bishop A., Satyamurthy Identification and quatitation of gaseous compounds of fluorine generated in [‘sF]F, target systems. Nucl. Med. Biol. 23, 391-405. N., Bida G., Phelps M. and Barrio J. R. (1996) a. Bishop A., Satyamurthy Metals suitable for fluorine gas target bodies: First use of aluminum for the production of [‘sF]F,. Nucl. Med. Biol. 23, 181-188. N., Bida G., Phelps M. and Barrio J. R. (1996) 9. Bishop A., Satyamurthy Production of [18F]F, using the ‘60(3He,p)‘8F reaction. Nucl. Med. Biol. 23,385-389. R. R. and Ruth 10. Casella V., Ido T., Wolf A. P., Fowler J. S., MacGregor T. (1980) Anhydrous F-18-labeled elemental fluorine for radiopharmaceutical preparation. J. Nucl. Med. 21, 750-757. G. J., Coates G. and 11. Chiracal R., Adams R. M., Fimau G., Schrobilgen Garnett E. S. (1995) Electrophilic “F from a Siemens ll-MeV proton-only cyclotron. Nucl. Med. Biol. 22, 11 l-l 16. 12. DeJesus 0. T., Murali D., Kitchen R., Endres C., Oakes T. R., Shelton S. E. et al. (1994) Evaluation of 3-[“F]fl uoro-u-fluoromethyl-p-tyrosine as a tracer for striatal tyrosine hydroxylase activity. Nucl. Med. Biol. 21, 663-667. M., Luxen A., Nebeling B., Argentini M., Clark J. C. and 13. Guillaume
17. Luxen A., Guillaume M., Melega W. P., Pike V. W., Solin 0. and Wagner R. (1992) Production of 6-[“Fjfluoro-L-DOPA and its metabolism in v&--a critical review. Nucl. Med. Biol. 19, 149-158. 18. Murali D., DeJesus 0. T., Sunderland J. J. and Nickles R. J. (1992) [‘sF]Fluoro-P-fluoromethylene-m-tyrosine analogs, potential PET agents for presynaptic dopamine terminals: Synthesis and spectroscopic characterization. Appl. R&at. lsot. 43, 969-977. 19. Namavari M., Bishop A., Satyamurthy N., Bida G. and Barrio J. R. (1992) Regioselective radiofluorodestannylation with [“F]F, and [‘8F]CH,CCOF: A high-yield synthesis of 6-[‘*F]fluoro-L-dopa. Appl. Radiar. Isot. 43, 989-996. 20. Nickles R. J., Daube M. E. and Ruth T. J. (1984) An 0, target for the Isot. 35, 117-122. production of [‘*F]F,. ht. J. Appl. R&at. 21. Park B. K. and Kitteringham N. R. (1994) Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications. Drug Metab. Reo. 26, 605-643. 22. Roberts A. D., Daniel L. C. and Nickles R. J. (1995) A high-power target for the production of [lsF]fl uoride. Nucl. Instrum. Methods B99, 797-799. 23. Rozen S. (1988) Elemental fluorine as a “legitimate” reagent for selective fluorination of organic compounds. AccountsChem. Res. 21, 307-312. 24. Solin O., Bergman J., Haaparanta M. and Reissell A. (1988) Production of 18F from water targets: Specific radioactivity and anionic contaminants. A@. Radiar. Isot. A 39, 1065-1071. 25. Solin O., Aho K., Bergman J., Kallman K-M. and Oakes T. R. (1993) Synthesis of [‘sF]F, from [18F]F-(aq). J. Label. Compd. Radiopharm. 32, 137-138. 26. Solin O., Enas J. D., Bergman J., Haaparanta M., VanBrocklin H. F. and Budinger T. F. (1996) Synthesis of [F-18lfluoroatipamezole: Biodistribution in rats. J. Nucl. Med. 37(Suppl), 51P. 27. Straatman M. G., Schlyer D. J. and Chasko J. (1982) Synthesis of F18-fluorine gas from no-carrier-added F18-HF. J. Label. Compd. Radiopharm. 19, 1373. 28. Wilkinson J. A. (1992) Recent advances in the selective formation of the C-F bond. Chem. Rev. 92, 505-519.
We thank K.-M. Kiillman, U. H&ten, M. Haaparanta, and G. Solin for their help; R. J. Nickks, S. Stone-Ekmder, 0. T. Dejesus, T. R. Oakes, and P. Johnsctim for helpful discussions. The assistance of the technical staff at the Abo Akadxmi Accelerator Laboratory is gratefully acknowledged. This work was supported by the Technology Dewelopment Center of Finland (TEKES) .
DC.
ISSN 0969-8051/97/$17.00 + 0.00 PII SO969-8051(97)00078-4
1997
ELSEVIER
Fluorine+ 1&Labeled Fluorine Gas for Synthesis of Tracer Molecules JBrgen Berg-mm andOlaf Solin TURKU
PET CENTRE,
ACCELERATOR
LABORATORY,
LABORATORY,
i.BO
AKADEMI
UNIVERSITY
UNIVERSITY,
OF TURKU,
TURKU,
TURKU,
AND
MEDlCITYjPET
RESEARCH
FINLAND
ABSTRACT. The aim of this work was to develop a method to produce “F-labeled fluorine gas ([ ‘sF]F2) with high specific radioactivity (SA, radioactivity/mass-ratio). ‘sF-Labeled methyl fluoride ([ “F]CH3F) was synthesized from [18F]Fand mixed with carrier F, in an inert neon matrix. The constituents were atomized in an electric disc“it arge, after which a rearrangement and l*F for ‘9 exchange took place. [‘sF]F2 with a specific radioactivity of up to 55 GBq/p mo 1 is available for the labeling synthesis of tracers for positron NUCL MED BIOL 24;7:677-683, 1997. 0 1997 Elsevier Science Inc. emission tomography (PET). KEY WORDS. Fluorine-18. ceuticals,
ElectroDhilic
fluorine.
Fluorodestannylation,
Specific
radioactivity,
Radiopharma-
PET
INTRODUCTION Electrophilic fluorination of organic molecules with F, or its derivatives is efficient, controllable, and fast (16, 23, 28). F, is a very potent chemical agent; indeed, it is the most reactive pure element. The fluorine atom is about the same size as the hydrogen atom. This makes it possible for fluorine to mimic hydrogen with respect to steric requirements in molecules as well as at binding sites on receptors and enzymes. Fluorine substitution can also have a profound effect on the lipofilicity and biological activity of small molecules (21). The PET technique makes it possible to follow, in the living man, the binding of radiolabeled ligands to receptor sites, thus making it possible to quantitate the number of binding sites in both healthy and diseased states. Displacement of the labeled ligands makes it possible to measure the affinity to the binding site. Tracer studies with potent and/or toxic neuroreceptor ligands require high specific radioactivity for the tracer, as the amount of mass that can be injected into a human subject is limited by the toxicity of the substance and its affinity for the receptor site. For an injected dose of typically 185 MBq, the amount will be 10 nmol when the SA is 18.5 GBq/kmol. Electrophilic radiofluorine is particularly suitable for the synthesis of fluoroaryl compounds ([ “F]Ar-F) by cleavage of aryl-metal bonds of typically Ar-MR (M=Sn, Hg, Si, R=(CH,),) compounds either with [18F]Fz or [“F]CH,COOF (12, 17-19). The factor limiting the more widespread use of the method has been the low specific radioactivity of the labeled fluorine gas available through radionuclide production from gas phase target materials (10, 11, 20), typically neon or ‘sOz mixed with carrier Fz. Gas targetry for the production of [I’F]Fz has recently been extensively reported (6-9). Straatman et al. (27) describe a method where n.c.a. [18F]HF, in an exchange reaction with F,, is converted to [‘“F]F, by a microwave discharge. A facile way of producing 18F is to irradiate, with a particle Address rep@ requests to: Olof Solin, Turku PET Center, Accelerator Laboratory, Abo Akademi University, Porthansgatan 3, FIN-20500 Turku, Finland; E-mail: [email protected] Received 19 February 1997. Accepted 3 May 1997.
accelerator beam, highly “O-enriched water. Through the *‘O(p,n)“F nuclear reaction, up to several curies of radioactivity can be produced (13, 22). The radiolabeled fluoride ([‘sF]F-,,) recovered after charged particle irradiation can be used for the production of numerous labeled neurotracers (16). However, the synthetic chemistry with this anion is usually neither simple nor fast, especially if more complex molecules are needed. The aim of the present work has been to develop a method suitable for the routine use of [“F]F, for synthesis of radiotracers for PET. The SA of the product should be such that studies with receptor ligands are possible. Figure 1 shows some specific radioactivities for 18F. Initially, a semitheoretical model for gas phase exchange of fluorine between unlabelled fluorine gas and a radiolabelled inert gas was studied. Calculations showed that if rigorous purity of the reactants could be maintained and a suitable method of excitation found, the method was workable (1, 25). Radiolabelled methyl fluoride was considered to be a suitable vehicle for supplying the “F-atom to the reaction. Four different methods of excitation were considered: (a) excitation with the cyclotron particle beam, (b) excitation with hard UV-light, (c) excitation via an electric discharge through the gas, and (d) excitation with laser light (excimer lasers). Methods b and c were considered to be practical, and were therefore tested. As materials for the handling system, both quartz and Teflon were used.
MATERIALS Cjeneral
AND METHODS
An overview of the computer-controlled production system is shown in Figure 2. Starting from [“F]F-, [“F]CH,F is synthesized to get the radioactive fluorine into gas phase. The synthesis of [18F]CH,F has the advantage of being fast, and the radiochemical yield is high (3). To get rid of solvents and other impurities, the [18F]CH,F is passed through a preparative gas chromatography column before transfer to a reactor and addition of carrier fluorine. The exchange reaction is then initiated either with UV-irradiation by using a low-pressure mercury lamp, or by initiating an electric
678
J. Bergman and 0. Solin
1OOOOO
Synthesis
m -Maximum [‘*F]F SA
10000 1000
Specific radioactivities for [‘*F]F2
100
.
f-
Measured [‘*F]Fz SA
10
and [‘*F]F,
[GBqWoll
1
: e
SA for [‘8F]Fz in Ref. 11
0.1 0.01
radioactivity (SA) of “F displayed on a FIG. 1. Specific logarithmic scale. The arrows point at (a) the theoretical maximum for the SA of [ ‘sF]F-; (b) the highest SA measured for [ ‘sF]F-,, (24); (c) the SA of [ “F]F, achieved with our new method; and (d) the highest SA for [ “F]F2 found in the literature ( 11). discharge through the gas. Subsequently, the gas is bubbled through a receiving vessel, where the labeling reaction takes place. All gases used in this work, except where otherwise stated, were acquired from Aga Special Gases (Helsinki, Finland).
Production
of [18F]F-
The [“Flfluoride was produced by irradiating -400 p,L 94-99% ‘so-enriched water (Isotec Inc., Miamisburgh, Ohio) in a nonpressurized silver target chamber. The target chamber construction is similar to the one described by Solin et al. (24), except it is modified for the use with 16.7-MeV protons instead of 10.5-MeV protons. The irradiations were made with the isochronous cyclotron (MGC20) at the Abe Akademi Accelerator Laboratory using 17-MeV protons with a beam current of lo-12 PA on the target. The saturation yield under these conditions is 7.2-7.8 GBq/kA. For high activity runs, the irradiation time was 2 h.
and
isolation of [18F]CH,F
The irradiated water was transported via silicon tubing (i.d. 0.8 mm, Masterflex 6411-13, Cole-Parmer Instrument Co., Chicago, IL) to a reaction vessel containing 3 mg potassium carbonate (Merck AG, Darmstadt, Germany), 12 mg kryptofix 2.2.2 (Merck AG., Darmstadt, Germany) and 1 mL acetonitrile (Rathbum Chemicals Ltd., Scotland). Evaporation with helium (99.998%) flow under reduced pressure, generated by a Teflon membrane pump (Leybold-Heraus AG, Kaln, Germany), was carried on for 2 min. During evaporation, the vessel was heated to a temperature of 80°C in a sonic bath. Acetonitrile (1 mL) was added and the evaporation continued for a further 2 min, after which the vessel was evacuated to a pressure of -10 mbar. Fifty microliters CH,I (p.a., Merck AG, Darmstadt, Germany) in 1 mL acetonitrile was added to the dry residue. The formation of [18F]CH,F was completed in less than 1 min. The product was flushed with 35 mL neon, through a cooling tower at 10°C into a 60-mL syringe and injected onto a Haysep Q (80/100 mesh, Ohio Valley Specialty Co., Marietta, OH) gas chromatography column (i.d. 0.8 cm, length 30 cm). Neon was used as carrier gas. A radioactivity detector on the outlet of the column monitored the elution of the [“F]CH,F. When eluted, the product was trapped in a l/16” stainless steel loop at liquid nitrogen temperature (-196°C). The isolation took less than 10 min.
Formation of Electrophilic
[18F]Flmrine
From the loop, the [“FJCH,F was transferred to a reaction chamber h ar g e excitation) or quartz (both (see fig. 3) made ofT efl on (f or d’LSC for discharge and UV-excitation) using known amounts of carrier fluorine (150 nmol-1.5 prnol) in neon as sweep gas. The exact amount of carrier gas was achieved by filling a standard volume, connected via a valve to the discharge chamber, to a calibrated pressure with a gas mixture of 0.8% F, in neon (Spectra Gases Inc., Alpha, NJ). This gas was then released through the stainless steel loop containing the [“FJCH,F. Filling the standard volume to a pressure of 4 bar absolute with the undiluted gas mixture resulted in the introduction of 1.5 p,rnol carrier fluorine in the discharge chambers. When using lower amounts of carrier fluorine, the gas mixture was diluted with neon. The lower energy and flux of UV-photons as compared to energy and flux of fast electrons generated during the electric discharge allows the time-resolved study of intermediate products formed
u
Vacuum,
FIG. 2. Schematic diagram of the apparatus for conversion of “F-fluoride to electrophilic “Ffluorine. Valves l-3 are 3.way Teflon solenoid valves (1116” connections, Asco Controls BV, Scherpentzel, The Netherlands), valves 4-8 are 3. or 2.way airoperated SS-41XSl valves (1116” connections, Nupro Co., Willoughby, OH); and valves 9-11 SS.4BK are hand-operated valves (l/4” connections, Nupro Co., Willoughby, OH).
Cold trap
l.,..._.... 0 +
o”-
.._ .i
-
High voltage 30 kV
Sonic bath/Heating
Fluorine-18-Labeled
Fluorine
679
Gas
with a spectral resolution of h/AX = 3800. The exposure times used were 1 to 30 sec. The light from the discharge chamber was conducted to the spectrograph inlet slit via a quartz fiber (o.d. 1 mm).
Calculations of a Simplified
Kinetic Model
Initiating an electric discharge through the gas mixture, or irradiation with intense UV-light, breaks the chemical bonds of the constituents, and the subsequent fate of the “F-label can be followed experimentally (Fig. 4a) by analyzing the formation of labeled fluoromethanes. The exchange process can be simulated using a Monte Carlo model, where in an ideal case the formation of [‘sF]Fz can be studied as a function of the relative concentrations of the constituents (Fig. 4b), subject to the constraints imposed by the model used. In the simplest case, assuming that all the chemical bonds are broken in the discharge plasma, the following equation holds for m * n:
I
:
:
:
:
I mFz + n[“F]
5cm
CH,F
4
(m - 3n)[“F]Fz
+ 3n[ ‘*F]HF FIG. 3. Cutaway chamber is above;
drawings of discharge chambers: quartz chamber is below.
Procedures
A gas chromatograph (GC-15A, Shimadzu Co., Kyoto, Japan) equipped with a flame ionization detector (FID) and a radioactivity detector (NaI, 2 X 2”) was used for the determination of [18F]CH3F, [“F]CH,F,, [‘sF]CHF,, and [“F]CF4. A 3-m (o.d. l/8”, i.d. 2 mm)-long column filled with Porapak Q (SO/l00 mesh, Alltech, Arlington Heights, IL) was used for the separations. The column temperature was 50°C; nitrogen (99.999%) was used as carrier gas. Retention times for all the fluoromethanes were determined; an absolute calibration was done with authentic standards of CH,F (Fluorochem Ltd., Old Glossop, UK), CHzF, (L’Air Liquide, Alphagaz, France), CHF,, and CF, (Union Carbide SA, Westerloo, Belgium). GAS CHROMATOGRAPHY.
Spectrometric analyses of the light emission from the discharge chamber during discharge were made with an optical spectrometer (Multichannel Echelle Spectrograph, MES@ 30K, NOW-Optics, Kista, Sweden) able to cover the spectral range from 195 nm to 1100 nm in 30,000 channels simultaneously SPECTROMETRIC
ANALYSES.
(1)
Teflon
during the 18F for 19F exchange reaction. However, during UVillumination, the major part of the formed [‘*F]F, is lost in reactions with the chamber walls, apparently due to the temperature rise in the chamber materials associated with the relatively long illumination times needed. Therefore, further experimentation was done utilizing the considerably more energetic fast electrons generated in a discharge plasma. The bulk gas in the discharge chambers is chemically inert neon. The discharge is supported at 20-30 kV and 280 PA through a 50-Mohm load resistor (EH series high-voltage power supply, Glassman Europe Ltd., Hampshire, UK). The anode and cathode are stainless steel capillaries (o.d. l/16”, i.d. 0.2 mm) that also serve as the gas inlet/outlets of the chamber. The volume of the chamber is 1.6 cm3 and the distance between the electrodes is 15 mm. The discharge is normally run for 10 sec.
Analytical
+ n[‘sF]CF4
Calculations for [I ‘F]F2
of Specific Radioactiwity
and Reaction Yields
We determined the SA of [“F]F* both directly by iodometric titration of oxidizing material and measurement of the radioactivity of the [“F]KF formed and indirectly by radiochromatographic determinations of amounts of mass and radioactivity of substances labeled with “F. Note that the SA of the product in the labeling synthesis is decreased by half as compared to [‘sF]F, as there is only a 50% chance for the introduction of the 18F-atom. The decay of the “F will also decrease the SA in proportion to the half-life of 109.8 min. When the amount of methyl fluoride used in the exchange reaction is known, the theoretical specific radioactivity and yield of [18F]F, can be calculated and compared to the measured time-corrected specific radioactivity of the synthesis product. From these numbers the yield in the exchange reaction can be determined.
RESULTS
[“F]FIn a series of 10 irradiations the following yield was measured for the radioactivity collected at the methyl fluoride synthesis apparatus: activity corrected to end of bombardment was 38.5 ? 1.4 GBq (irradiation time 120 + 4.5 min; beam current 10.0 + 0.33 kA). The enrichment grade of the 180-water was 99%. Based on earlier measurements with similar targetry, we estimate the specific radioactivity of the [“F]Fproduced to be in excess of 5.5 TBq/ p-mol (24).
[18F]CH,F The total mass of methyl fluoride formed in a synthesis was 8-12 nmol as analyzed by gas chromatography. Starting a synthesis with about 37 GBq [“F]Fand an average radiochemical yield of 75 + 9% (n > 100) for the methyl fluoride synthesis gives 25 + 3 GBq (EOB + 20 min) of methyl fluoride with a specific activity of 2.5 + 0.3 TBq/pmol.
680
J. Bergman and 0. Solin
a
b
4 n
3
I
100
2 1 80
I 4 s3 12
I
[‘BFICpP
II
[“FJCF,
Y C* .L 5
1
.-8 J
4 3
\ : III
2 1
10
I
100 200 300 400 500 600
0
I.-
Dose [arb. units]
Retention time [set]
FIG. 4. (a) Intermediate “F-labeled carbon&uorine compounds formed in the exchange reaction between [ “F]CH,F and F, as analyzed by gas chromatography. The gas samples were collected before (I), during (II), and after (III) illumination of the gas mixture with UV-light from a low-pressure mercury lamp (6 W). (b) Computer-generated curves for the formation of [ ‘sF]Fz in the exchange of “F for laF between [ ‘*F]CH,F and laI-19F fluorine gas. The calculations were made by a Monte Carlo routine, taking into account the successive formation of partially and totally fluorinated C, and C,-species. The curves displayed have molar ratios (m/n) of 1000, 20, and 5 for F, and [‘sF]CH,F.
Electrophilic
[‘8F]Fluorine
The [18F]CH,F/[‘8F]F, conversion efficiency was studied as a function of the amount of carrier F, used, while the discharge time was held constant at 10 sec. The conversion efficiencies were about 60% when -500 nmol or more carrier fluorine was used. The conversion was about 30% when 150 nmol carrier fluorine was used
(Fig. 5). No significant difference was observed between the Teflon and quartz chambers. Lengthening the discharge time did not increase the conversion yield. Starting from 37 GBq [t8F]FP and by using 150 nmol carrier fluorine, more than 7.5 GBq [‘sF]F, can be produced with a specific radioactivity of > 50 GBq/p,mol (EOB + 20 min). Using larger
FIG. 5. Amount of ‘8F-atoms, recovered as electrophilic “F, as a function of the amount of F, used in the exchange reaction.
800
1000
1200
Carrier fluorine [mol]
Fluorine-18-Labeled
Fluorine
681
Gas
630
636 I I
‘t
200
400
600
800
1000
FIG. 6. Light emission, in the wavelength range 200-1050 nm, of the discharge in the quartz chamber. Atomic and molecular species show their characteristic atomic or molecular emissions. Most of the emission lines seen here are from atomic neon and fluorine, created in the discharge volume. In the insets, atomic emission lines from silicon, oxygen, hydrogen, and carbon can be seen. The exposure time for the recording was 5 set on a parallel registering optical spece trometer, using an optical fiber to conduct the light from outside of the chamber to the spectroe graph inlet slit.
Wavelength [nm]
amounts of carrier F, gives higher yields of [“F]Fz tional decrease in the specific radioactivity.
with
a propor-
Spectroscopy In addition to expected signals from atomic transitions of atomized neon and fluorine, the optical spectra recorded during the discharge also showed atomic lines from hydrogen, oxygen, silicon, and carbon. These stem from the chamber materials and from the radiolabeled methyl fluoride purposefully introduced into the chamber. No molecular features were seen during recordings of lo-set discharges in pure gases. However, if the discharge is continued for longer times, spectral features belonging to the Swan-bands of diatomic carbon (Cz) are observed from the Teflon chamber. Prolonged discharge in both chambers showed that the signals from fluorine decreased as compared to neon. Unidentified molecular features then showed in the spectra. No signals from ionic species were seen in any of the spectra recorded from these chambers.
DISCUSSION We utilize [‘sF]F-,a (>37 GBq) produced from a water target to make [“F]CHsF, the most simple fluorinated organic compound. The synthesis is facile, and radiochemical yields of 75% are reached in less than 6 min after end of bombardment at the accelerator (3). The specific radioactivity of the [“F]F-,, is ~5.2 TBq/p,mol (24) (Fig. l), as stable fluoride is unavoidably introduced into the preparations. We have measured the specific radioactivity of the [‘sF]CH,F to be 22.2 TBq/kmol. The [“FJCHsF is separated chromatographically, and after cryogenic isolation transferred to a quartz chamber together with carrier fluorine gas. Spectroscopic observation of the discharge plasma (Fig. 6) shows, in addition to the atomic emissions from neon and fluorine, emissions from several other atomic constituents (impurities) present in the plasma. These will, in proportion to their amounts, interfere with the desired course of the reactions. Therefore, the elimination of the impurities is important. The spectroscopic method of studying the discharge allows us to optimize the discharge chamber construction with reference to materials and shape, as well as to discharge power.
Figure 5 shows results from yield measurements of the incorporation of “F into the fluorine molecule. These results apply to the reaction chambers displayed in Figure 3. Fluorinated polymers seem to work equally well as quartz as chamber materials. The specific radioactivity and yield of [“F]F, are functions of the amount [“F]CH,F used, the amount of carrier fluorine gas introduced, and the efficiency of the exchange reaction between these two. A practical limit, at present, is set by the amount of [‘sF]CH,F we can produce (25-30 GBq, SA > 2.2 TBq/pmol) and a reasonable efficiency in the conversion, 30% at a level of 150 nmol fluorine carrier (Fig. 5). This gives us a maximal specific radioactivity of -55 GBq/p,mol for -7.5 GBq of [“F]Fz. The maximum value in the exchange reaction approaches 60%, as the amount of carrier F, is increased. According to theoretical calculations (Fig. 4) this value should approach 100%. The calculations do not, however, take into account the introduction of foreign materials, the losses to chamber materials, and other handling losses of this very reactive molecule. Also, the volume of interaction, where the electrons created in the discharge reach the gas molecules, is not the same as the total gas space in the handling system. Radiolabeling with [r8F]F, is simple: An inert carrier gas containing the labeled fluorine is bubbled through a receiving vessel containing an organometallic precursor molecule dissolved in a suitable solvent. The fluorination reaction is essentially instantaneous, after which the crude reaction mixture is injected on a semipreparative high-performance liquid chromatographic (HPLC) column. The purified substance is collected on the column outlet in a few minutes, formulated for injection, and is then ready for use at the hospital site. We have applied this method of making [‘“F]F, for the synthesis of several radiopharmaceuticals (see Fig. 7). In most cases we first synthesized [“fiacetylhypofluorite ( [r8F]CH,COOF) and used this as the labeling reagent (23). We have synthesized [r8F]CFT (4, 14) (precursor 2-P-carbomethoxy-3@(4-t nmethyl-stannyl-phenyl)tropane), a marker for the dopamine transporter, [r8F]fluoroatipamezole (26) (precursor 4-(2.ethyl-2,3-dihydro-5-tributhylstannyl-lH2-indenyl)-1-acetyl-imidazole), an alpha-2 adrenergic antagonist, [“Floxoquazepam (5) (precursor 7-chloro-l-(2,2,2-trifluoroethyl)-
682
J. Bergman and 0. Solin
YH2 FHzCHCOOH
OH OH
FIG. 7. Fluorine-184abeled used.
compounds
synthesized
via electrophilic
1,3-dihydro-5-(2-trimethylstannylphenyl)-2H~l,4-benzodiazepine~ 2-one) a bentzodiazepine, as well as 6[18F]FDOPA (2, 15) (precursor N-formyl-3,4-di-t-butoxycarbonyloxy-6-(trimethylstannyl)-Lphenylalanine ethyl ester) a marker for endogenous DOPA. The specific radioactivities for the first three mentioned pharmaceuticals have been about 15 GBq/p,mol at the end of synthesis. The radiopharmaceuticals have usually been ready for injection in 50 to 60 min after the end of accelerator bombardment. [“F]CFT is routinely synthesized with a specific radioactivity exceeding 15 GBq/pmol at EOS in amounts high enough for two PET studies on human subjects (400-800 MBq). The method has proved to be reliable: In less than 0.5% (n > 200) of the labeling syntheses made with the nucleophilic-electrophilic conversion system has any failure occurred, resulting in unexpected low synthesis yield. The mass and the specific radioactivity of the methyl fluoride will eventually put limits on this method. The mechanism is an exchange reaction demanding an excess of electrophilic carrier fluorine. The discharge chamber in use has a practical lower limit of
fluorination.
In all syntheses
the present
method
was
about 150 nmol carrier fluorine. Research will continue so as to improve mainly the discharge chamber in order to increase the efficiency with low amounts of carrier fluorine.
CONCLUSIONS Recent advances in PET technology, i.e., high-resolution 3-D cameras, as well as multipurpose PET/SPECT-devices, have created a situation where numerous hospitals and research institutions have need for positron emitting tracers, but have no in-house capabilities to produce radionuclides. Regional distribution centers for the delivery of t8F to these sites, mostly in the form of [r8F]F-,, or [‘*F]fluorodeoxy-D-glucose, are now being developed in several countries. Utilizing this new method to produce [r’F]F, from [‘*F]F-,a makes it possible for these sites to have available relatively complex fluorinated tracers in an essentially kit-like formulation, without the large monetary investment that a modern PET cyclotron/radiopharmaceutical lab requires.
Fluorine- 1S-Labeled Fluorine Gas
683
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We thank K.-M. Kiillman, U. H&ten, M. Haaparanta, and G. Solin for their help; R. J. Nickks, S. Stone-Ekmder, 0. T. Dejesus, T. R. Oakes, and P. Johnsctim for helpful discussions. The assistance of the technical staff at the Abo Akadxmi Accelerator Laboratory is gratefully acknowledged. This work was supported by the Technology Dewelopment Center of Finland (TEKES) .
DC.