Selective fluorination of m-tyrosine by OF2

Article abstract of DOI:10.1016/j.jfluchem.2007.08.004

Fluorine-18 labeled aromatic amino acids are routinely used as tracers in positron emission tomography (PET) to study in vivo metabolic processes. The most versatile method for the production of such radiotracers is electrophilic fluorination of the aroma

Full text of DOI:10.1016/j.jfluchem.2007.08.004

Journal of Fluorine Chemistry 129 (2008) 22–27
www.elsevier.com/locate/fluor
Selective fluorination of m-tyrosine by OF2
Babak Behnam Azad a,b, Rezwan Ashique a, Raman Chirakal a,b, , Gary J. Schrobilgen
*
b,**
a Nuclear Medicine, McMaster University Medical Centre, Hamilton Health Sciences, Hamilton, ON L8N 3Z5, Canada
b Department of Chemistry, McMaster University, Hamilton, ON L8S 4M1, Canada
Received 25 June 2007; received in revised form 6 August 2007; accepted 6 August 2007
Available online 10 August 2007
Abstract
Fluorine-18labeledaromatic aminoacids are routinely usedastracersinpositronemission tomography (PET)tostudy invivo metabolicprocesses.
The most versatile method for the production of such radiotracers is electrophilic fluorination of the aromatic amino acid with [18F]F2, which is most
commonly produced by the gas-phase nuclear reaction 18O(p, n)18F. Although [18F]F2 is the major product, considerable amounts of [18F]OF2 (up to
20%) are also produced. Electrophilic fluorination reactions of L-phenylalanine, 3-nitro-L-tyrosine, 4-nitro-DL-phenylalanine, 3,4-dihydroxyphenyl-L-
alanine (L-DOPA), 3-O-methyl-L-DOPA, 3,4-dimethoxy-L-phenylalanine, p-tyrosine and o-tyrosine in H2O and of m-tyrosine in anhydrous HF (aHF),
CF3SO3H, CF3COOH, CH3COOH, HCOOH and H2O using OF2 were investigated. Although F2 is an efficient fluorinating agent in aHF, electrophilic
fluorination reactions using OF2 were shown to be most efficient in less acidic media such as H2O. In addition, and contrary to reports that OF2 and F2
have similar reactivities, m-tyrosinewas the only aromatic system studied that was fluorinated by OF2 and this was optimum in H2O for the fluorinated
m-tyrosine isomers (total yield, 4.35 ꢀ 0.04%). The presence of [18F]OF2 byproduct has no significant impact on the fluorination of aromatic amino
acids investigated in this study and the subsequent production of their corresponding 18F-labeled radiotracers for patient use.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Oxygen difluoride; Electrophilic fluorination; Fluorine-18; PET; Fluoro-m-tyrosine
1. Introduction
in organic and inorganic syntheses. For example, OF2 has been
employed in the oxidation of primary aliphatic amines [3],
fluorination of aromatic systems through fluorodestannylation
reactions [4], and addition reactions, where OF2 adds across
carbon–carbon or sulfur–oxygen double bonds [5–13]. More-
over, the direct fluorination of 3,4,6-tri-O-acetyl-D-glucal
(TAG) by OF2 (Eq. (1)) has been shown to result in the
production of 2-deoxy-2-fluoro-D-glucose (2-FDG). Fluorine-
18 labeled 2-FDG is currently the most widely used radiotracer
in diagnostic imaging [14]:
Four fluorides of oxygen have been synthesized and
structurally characterized, namely O4F2, O3F2, O2F2, and
OF2, all of which are powerful oxidants and fluorinating agents
[1]. It has been shown that the stabilities of the aforementioned
compounds decrease with increasing number of oxygen atoms,
making OF2 the most stable oxygen fluoride known.
Since its initial preparation by Lebeau and Damiens in 1927
[2], OF2 has been utilized as an oxidizing or fluorinating agent
(1)
Several synthetic routes have been used to prepare OF2,
including the reaction of fluorine with aqueous alkali solutions
[15], 60%HClO4 [16], H5IO6 [17], hydrated alkali fluorides[18],
or HOF [19]. More recently, Satyamurthy et al. [20] reported the
* Corresponding author. Tel.: +1 905 521 2100x76893; fax: +1 905 546 1125.
** Corresponding author. Tel.: +1 905 525 9140x23306; fax: +1 905 522 2509.
E-mail addresses: chiraklr@mcmaster.ca (R. Chirakal),
schrobil@mcmaster.ca (G.J. Schrobilgen).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.08.004

B. Behnam Azad et al. / Journal of Fluorine Chemistry 129 (2008) 22–27
23
formation of [18F]OF2 as a reaction byproduct (up to 5% for
double shoot and up to 20% for the single shoot irradiation
methods) under the high-pressure and high-energy irradiation
conditions of a proton cyclotron gas target using the nuclear
reaction, 18O(p, n)18F and according to Eqs. (2)–(4). Prior studies
from our laboratory have also indicated the presence of [18F]OF2
(up to 5%) in the double shoot irradiation method [21]:
gram-scale synthesis reported by Pullen et al. [18]. Parameters
reported by these workers could not be replicated in our
laboratory owing to the scale and reaction conditions required
for the production of radiotracers having applications in
diagnostic imaging. Formation of OF2 can be confirmed by its
reaction with TAG in CFCl3 which, unlike the reaction of TAG
with F2, results in the formation of 6-deoxy-6,6-difluoro-D-
glucose (6-DDFG) [14]. The attempted syntheses did not,
however, result in OF2 formation which was confirmed by the
absence of 6-DDFG in the 19F NMR spectra when the effluent
gas was passed through CFCl3 solutions of TAG. Consequently,
fluorinations of the aromatic systems investigated in this study
were carried out using unlabeled OF2.
(2)
Oꢁ þ Fꢁ ! OFꢁ
OFꢁ þ Fꢁ ! OF2
(3)
(4)
The increasing popularity of the ‘‘double shoot’’ method
[21,22] for the production of electrophilic agents used for the
syntheses of PET imaging agents requires a fuller under-
standing of the electrophilic fluorination properties of OF2.
Positron emission tomography is commonly used for the in vivo
visualization of brain functions such as blood flow, metabolism,
enzyme activity, neuroreceptors and neurotransporters [23]. An
important category of PET tracers for brain imaging are 18F-
labeled aromatic amino acids such as [18F]6-fluoro-3,4,-
dihydroxy-L-phenylalanine (6-FDOPA) [24] and [18F]6-
fluoro-L-meta-tyrosine [25]. It is therefore important to
investigate the fluorinating ability of OF2 towards aromatic
amino acids and to establish whether or not OF2 gives rise to
other fluorinated aromatic amino acids occurring in the product
mixture that may prove difficult to separate, thus contributing to
PET image background noise.
2.2. Solvent and isomer effects
Solvent acidity has been shown to play an important role in
the direct fluorination reactions of aromatic amino acids [26]. In
attempts to find a suitable solvent medium for the fluorination
of aromatic amino acids by OF2, the effect of solvent acidity
was also studied using m-tyrosine (MT) as the substrate. Direct
fluorination of MT using F2 results in the formation of 2-, 4-, 5-
or 6-fluoro-m-tyrosine (6-FMT), the degree of which varies
with solvent acidity [27].
Several protic solvent media, namely, aHF (Hammett acidity,
Ho = ꢃ15.1) [28], CF3SO3H (Ho = ꢃ13.8) [28], CF3COOH,
CH3COOH, HCOOH and H2O, were utilized for the fluorination
of MT (Table 1). It was shown that, unlike F2, fluorination by OF2
was less efficient in superacidic media. Fewer byproducts and
higher ratios of fluorinated MT isomers were formed in solvent
media of lower acidity as determined by analytical HPLC
(Fig. 1). After analysis of the reaction mixtures by 19F NMR
spectroscopy, each sample was spiked with known quantities
(1.03 and 2.07 ꢀ 0.04 mmol) of the internal standard, m-fluoro-
DL-tyrosine. Fluorine-19 NMR peak integrations of the spiked
reaction mixtures were then used to calculate reaction yields
(Table 1). It was shown that the highest yield (4.35 ꢀ 0.04%) and
lowest amounts of fluorinated byproducts were obtained when
H2O was used as thesolvent for fluorinationof MTwith OF2. The
19F NMR spectrum of 6-FMT (ꢃ129.3 ppm, complex multiplet),
4-FMT (ꢃ138.4 ppm, doublet of doublet of doublets,
3J(F ꢃ H5) = 11.3 Hz, 4J(F ꢃ H6) = 4.2 Hz, 4J(F ꢃ H2) =
7.4 Hz), and 2-FMT (ꢃ142.2 ppm, doublet of doublets,
2. Results and discussion
2.1. Fluorine-18 labeled OF2
The formation of [18F]OF2 in the gas target of an 11 MeV
proton cyclotron in the nuclear reaction, 18O(p, n)18F, occurs
simultaneously with that of [18F]F2, making the separation of
the two species very difficult to impossible. Moreover, the
isolation of [18F]OF2 has not been reported. In order to quantify
the relative amounts of 18F-labeled products that result from the
fluorination of aromatic amino acids using OF2, attempts were
made to synthesize and isolate [18F]OF2. The method used in
this study involved the direct fluorination of anhydrous KF/
KFꢂ2H2O in micromolar quantities and is a modification of the
4
4J(F ꢃ H4) ꢄ J(F ꢃ H6) = 7.1 Hz) agree with those reported
in the literature [29].
Table 1
Effect of solvent acidity on the fluorination of m-tyrosine by OF2
Solvent
Temperature (8C)
Product
Relative
Yield ꢀ 0.04%a
Fluorinated
by-productsb (%)
amounts (2:4:6)
H2O
23
23
2-, 4-, and 6-FMT
2-, 4-, and 6-FMT
2- and 6-FMT
33:20:47
26:8:66
30:0:70
30:0:70
9:0:91
–
4.35
2.17
2.19
2.60
1.41
–
0
60
67
74
85
–
HCOOH
CH3COOH
CF3COOH
CF3SO3H
aHF
23
23
2- and 6-FMT
23
2- and 6-FMT
ꢃ60
FMT not formed
a
Yields are reported with respect to OF2.
Percentages of fluorinated byproducts were calculated from the total integrated peak intensities in 19F NMR spectra.
b

24
B. Behnam Azad et al. / Journal of Fluorine Chemistry 129 (2008) 22–27
towards different ring sites using electron withdrawing and
electron donating ring substituents. The solvent medium used
for this study was H2O because it produced the highest isomeric
ratios of 6- and 4-fluoro-m-tyrosine and smallest amounts of
fluorinated byproducts in the fluorination of MT.
Initially, L-phenylalanine, which contains the ortho- and
para-directing electron donating alanine group, was examined.
Although direct fluorination of L-phenylalanine results in the
formation of 2-, 3-, and 4-fluoro-L-phenylalanine isomers [29],
analytical HPLC and 19F NMR spectroscopy indicated that
fluorination with OF2 did not result in the formation of
fluorinated phenylalanine.
The fluorination of DL-tyrosine, which contains two
electron donating (alanine and hydroxyl) groups, was also
studied with the aim to further localize the electron density in
the p-system in order to promote the electrophilic fluorina-
tion by enhancing the nucleophilicity of the phenyl ring at the
activated sites. The direct fluorination of DL-tyrosine has been
shown to result in the formation of 3-fluoro-DL-tyrosine [30],
however, fluorination using OF2 did not yield any fluorinated
tyrosine isomers.
Compounds with greater electron localization in the p-
system were also investigated by the use of additional hydroxyl
substituents (L-DOPA) and utilization of the stronger electron
donating CH3O-group (3-O-methyl-L-DOPA and dimethoxy-L-
DOPA). As previously reported, direct fluorination of L-DOPA
in non-superacidic solvent media results in the formation of 2-
and 5-FDOPA [26], whereas direct fluorination of 3-O-methyl-
L-DOPA and dimethoxy-L-DOPA results in the formation of 3-
O-methyl-6-fluoro-L-DOPA and 2-, 5- and 6-fluoro-dimethoxy-
L-DOPA isomers [31]. The fluorination of L-DOPA, 3-O-
methyl-L-DOPA and dimethoxy-L-DOPA by OF2, however, did
not result in any fluorinated aromatic products as indicated by
analytical HPLC and 19F NMR spectroscopy. Similar results
were obtained when electron withdrawing NO2 substituted
derivatives were used as substrates, namely, 3-nitro-L-tyrosine
and 4-nitro-DL-phenylalanine.
3. Conclusion
Fig. 1. UV chromatograms for reaction mixtures resulting from the fluorination
of MT at 23 8C in (a) H2O, (b) CH3COOH and (c) CF3COOH. The asterisk (*)
denotes peaks corresponding to 4- and 6-FMT isomers which cannot be
specifically assigned because of overlap and more intense byproduct peaks.
The effect of solvent acidity on the fluorination of MT using
OF2 was studied and it was shown that, in contrast with the
reactivity of F2 in superacids, OF2 is a more efficient
fluorinating agent in less acidic solvent media. The use of
H2O as the solvent medium for fluorination of MT resulted in
the formation of FMT isomers in 4.35 ꢀ 0.04% yield.
The potential use of OF2 as a fluorinating agent for aromatic
amino acids was also investigated in the cases of L-
phenylalanine, 3-nitro-L-tyrosine, 4-nitro-DL-phenylalanine,
3,4-dihydroxyphenyl-L-alanine (L-DOPA), 3-O-methyl-L-
DOPA, 3,4-dimethoxy-L-phenylalanine, m-, p- and o-tyrosine.
In these studies, the only aromatic system fluorinated by OF2
was MT. These results indicate that the presence of [18F]OF2
(up to 20%) as a major byproduct resulting from the nuclear
reaction, 18O(p, n)18F, does not have a negative impact on the
syntheses of radiofluorinated aromatic amino acids having
applications in PET imaging.
The effect of the electron donating OH substituent at the
ortho-, meta- and para-positions on the fluorination of aromatic
amino acids by OF2 was studied using o-, m- and p-tyrosine as
the substrates. Contrary to expectations, MT was the only
isomer shown by 19F NMR spectroscopy and HPLC to be
fluorinated by OF2, showing that OF2 is, in this instance, a
highly selective fluorinating agent.
2.3. Fluorination by OF2
In order to investigate the suitability of OF2 as a fluorinating
agent for aromatic amino acids, several systems were studied in
which the electron density in the p-system was directed

B. Behnam Azad et al. / Journal of Fluorine Chemistry 129 (2008) 22–27
25
4. Materials and methods
method [21,22] in the Nuclear Medicine Department at
Hamilton Health Sciences. An aluminum target (11 mL) was
pressurized to 14–16 atm with 99% enriched [18O]O2 and
irradiated for 20 min using a 30 mA proton beam (production
shoot). After irradiation, the [18O]O2 was recovered from the
target by condensation at ꢃ196 8C into a cryo-trap consisting
of molecular sieves (Varian VacSorb) contained in a 316
stainless steel Whitey1 cylinder (75 mL). The target was
pumped to remove trace amounts of [18O]O2 and subsequently
filled with 1% F2 (40–50 mmol) in neon, pressurized to 20 atm
with neon, and irradiated for 10 min in a 15 mA proton beam
(recovery shoot). Portions of the [18F]F2/Ne mixture were
periodically released from the target into a continuous stream
of helium until the target pressure dropped to 2 atm. Helium
was used as the sweep gas to transfer [18F]F2 from the target
into the hot cell.
4.1. Reagents
Oxygen difluoride (1% in neon, Ozark-Mahoning), helium
(Matheson, 99.9999%), D2O (Cambridge Isotope Laboratories
Inc., 99.9%), CF3SO3H (Fluka, 99.8%), aHF (Air Products,
99.9%), CF3COOH (Caledon, 99.9%), glacial CH3COOH
¨
(BDH, 99.7%), HCOOH (Riedel-de Haen, 98%) and HPLC
grade CH3CN (Caledon), L-phenylalanine (Aldrich, 98%), m-
tyrosine (Aldrich, 98%), DL-tyrosine (Aldrich, 99%), o-tyrosine
(Aldrich, 96%), L-DOPA (Aldrich, 99%), 3-O-methyl-L-DOPA
(Aldrich), 3-nitro-L-tyrsoine (Aldrich, 98%), 4-nitro-DL-phe-
nylalanine (Aldrich, 98%), m-fluoro-DL-tyrosine (Aldrich),
3,4,6-tri-O-acetyl-D-glucal (Aldrich, 98%), anhydrous KF
(Aldrich, 99.99+%) and KFꢂ2H2O (Aldrich, 98%) were used
without further purification and/or drying. Sterile, deionized
water was used in all aqueous procedures.
4.3. Attempted preparation of [18F]OF2
4.2. Production of [18F]F2
In a typical reaction, 100 mg of KFꢂ2H2O and 300 mg of
anhydrous KF were loaded into a 1/2 in. o.d. FEP U-tube which
was attached to two PFA Whitey valves by means of stainless
steel Swagelok 1/2 to 1/4 in. reducing unions and lengths of 1/
4 in. FEP tubing (Fig. 2).
Fluorine-18 labeled F2 was produced by the nuclear
reaction, 18O(p, n)18F, using a Siemens RDS 112 proton
cyclotron, operating at 11 MeV, and the ‘‘double shoot’’
Fig. 2. Schematic diagram of the apparatus used in the attempted synthesis of [18F]OF2.

26
B. Behnam Azad et al. / Journal of Fluorine Chemistry 129 (2008) 22–27
One end of the U-tube was connected to the [18F]F2 target,
4.6. Analyses of reaction mixtures by HPLC and NMR
spectroscopy
while the other end was connected to a 5/16 in. o.d. ꢅ
5/32 in. i.d. FEP reaction vessel that was, in turn, attached to
an FEP Y-piece by means of a 1/4 in. Teflon Swagelok union.
A length of 1/16 in. o.d. ꢅ 1/32 in. i.d. FEP tubing,
connected to a valve of the U-tube, was fed through the
sidearm of the Y-piece into a reaction vessel containing
13 mg of TAG in 0.5 mL of CFCl3. The other arm of the Y-
piece was connected, through a 1/4 to 1/16 in. Teflon
reducing union, to a length of 1/16 in. o.d. FEP tubing that
was immersed in 1 M NaOH. The U-tube, containing an
equimolar mixture of anhydrous KF and KFꢂ2H2O, was
pressurized with [18F]F2 (typically 60 ꢀ 5 mmol of F2 was
used) and was agitated for 110 min at room temperature,
after which the gas was passed through the TAG solution.
The fluorinated reaction mixture was then analyzed by 19F
NMR spectroscopy after hydrolysis using 1.2 M HCl carried
out over 17 min at 130 8C.
The ring-fluorinated aromatic amino acids were analyzed
using a reverse-phase analytical HPLC column (Keystone,
Fluophase, 5 mm, 150 mm ꢅ 10 mm). A solution of 0.2%
CF3CO2H in water containing 7% CH3CN was used as the
mobile phase with a flow rate of 2.5 mL minꢃ1. The eluate from
the column was monitored by the use of a Waters 490E
Programmable Multi-wavelength Detector set at 280, 254 and
230 nm. A typical UV chromatogram of the FMT reaction
mixture showed peaks at 9.3 and 11.4 min corresponding to MT
and 6-FMT, respectively. The MT peak was identified by
injection of a standard solution which eluted at 9.9 min. The
peak eluting at 11.4 min was collected and was shown by 19F
NMR spectroscopy to be 6-FMT. In addition, the reaction
mixture was analyzed by 19F NMR spectroscopy to obtain the
relative molar amounts of products. The isomeric ratios of the
mono-fluorinated aromatic amino acids were determined by
peak integrations of the 19F NMR spectra.
4.4. Electrophilic fluorination of aromatic amino acids in
H2O, HCOOH, CH3COOH, CF3COOH, CF3SO3H, and
aHF
Fluorinated MT isomers were also analyzed by the use of a
reverse-phase preparative HPLC column (Keystone, Fluophase,
5 mm, 250 mm ꢅ 10 mm). A solution of 17 mg of ascorbic acid
in 500 mL of 0.1% aqueous CH3CO2H was used as the mobile
phase with a flow rate of 3.5 mL minꢃ1. The eluate from the
column was monitored by means of a UV detector set at
280 nm. The 6- and 4-FMT isomers, typically appearing at 12.8
and 13.9 min on the UV chromatogram, were collected and
analyzed by 19F NMR spectroscopy.
The 19F NMR spectra were recorded on a Bruker Avance
200 (4.6976 T) or DRX-500 (11.7440 T) spectrometer using a
pulse width of 1 ms corresponding to a bulk magnetization tip
angle of ꢆ908. Fluorine-19 NMR spectra were obtained at
11.7440 T and were typically accumulated over a spectral
width of 14 kHz (acquisition time, 1.16 s), using 300 scans
and 32K memories, yielding data point resolutions of
0.35 Hz/point. Fluorine-19 NMR spectra obtained at
4.6976 T were accumulated over a spectral width of
17 kHz (acquisition time, 0.94 s), using 200 scans and 32K
memories, yielding a data point resolution of 0.53 Hz/point.
Spectra were referenced at 25 8C to external CFCl3. The
chemical shift convention used is that positive and negative
signs indicate chemical shifts to high and low frequencies
relative to that of the reference compound.
Substrates (13 mg), were each dissolved in 0.5 mL of
solvent and the solution was added to 5/16 in. o.d. ꢅ 5/32 in.
i.d. FEP reaction vessels connected to FEP Y-pieces. A
length of 1/16 in. o.d. ꢅ 1/32 in. i.d. FEP tubing, connected
to the OF2 source at one end, was fed through the sidearm of
the Y-piece into the reaction vessel. The other arm of the Y-
piece was connected to a separate length of 1/16 in. o.d. FEP
tubing, which was immersed in 1 M NaOH. In reactions
where aHF was utilized as the solvent medium, the reaction
vessel and contents were allowed to equilibrate for 30 min at
selected temperatures in a liquid nitrogen/CH3OH bath prior
to fluorination. Oxygen difluoride gas (typically 40 mmol)
was passed through the substrate solution and the effluent gas
was passed through 1 M NaOH before it was vented into the
hot cell.
Removal of CF3SO3H from the fluorinated MT reaction
mixtures were achieved using a 250 mm ꢅ 10 mm anion
exchange column (Bio-Rad AG 1-X8 in acetate form). The
reaction mixture was loaded onto the column and 20 mL of
0.1N HCl was used as the eluent. The eluate was then
evaporated on a rotary evaporator and was subsequently
analyzed by HPLC.
Acknowledgements
4.5. Determination of reaction yields for FMT isomers
We thank Dr. Karen Gulenchyn, Chief of Nuclear Medicine,
and Ms. Carol Dunne, Manager of Nuclear Medicine, Hamilton
Health Sciences, for granting permission to use hospital
facilities for this research.
A 10.3 mg sample of m-fluoro-DL-tyrosine was dissolved in
5.00 mL of 0.100 M HCl for use as an internal standard. Two
0.100 mL aliquots of 0.010 M m-fluoro-DL-tyrosine were then
added stepwise to each reaction mixture, which was analyzed
by 19F NMR spectroscopy after each addition. Each aliquot
contained 1.03 ꢀ 0.04 mmol of m-fluoro-DL-tyrosine, so that
19F NMR peak integrations could be used to calculate the FMT
isomer yields.
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