Syntheses of [18F]5-fluoro-3-nitro-L-tyrosine

Article abstract of DOI:10.1016/S0022-1139(02)00334-2

The detection of 3-nitro-L-tyrosine has been used as a biomarker of "reactive nitrogen species" in biological matrices and has been an ongoing challenge in analytical chemistry. In this work, fluorine-18 labelled 5-fluoro-3-nitro-L-tyrosine (FNT) was synthesized as a potential radiotracer to probe the biological fate of 3-nitro-L-tyrosine. The synthesis of [¹⁸F]FNT was carried out by reaction of [¹⁸F]3-fluoro-L-tyrosine with NaNO₃ in TFA solvent for 5min at 4 °C. The radiochemical yield (RCY) of [¹⁸F]FNT was 96±2% and [¹⁸F]3-fluoro-l-tyrosine, was 29±1%, relative to [¹⁸F]3-fluoro-l-tyrosine and [¹⁸F]F₂, respectively. The syntheses of [¹⁸F]FNT were also accomplished by direct fluorination of 3-nitro-L-tyrosine with [¹⁸F]F ₂ and by nitration of L-tyrosine with NaNO₃, followed by fluorination, in TFA (4 °C) or anhydrous HF (-65 °C) solvent. The latter two synthetic routes produced [¹⁸F]FNT in 13.5±1.5% RCY, within 1h. Products were characterized by use of ¹H, ¹³C and ¹⁹F NMR spectroscopy and mass spectrometry.

Full text of DOI:10.1016/S0022-1139(02)00334-2

Journal of Fluorine Chemistry 121 (2003) 9–14
Syntheses of [18F]5-fluoro-3-nitro-L-tyrosine
Neil Vasdeva,b, Raman Chirakala,b,*, Rezwan Ashiquea,b,
Gary J. Schrobilgena,*, Karen Gulenchynb
aDepartment of Chemistry, McMaster University, Hamilton, Ont., Canada L8S 4M1
bDepartment of Nuclear Medicine, Faculty of Health Sciences, McMaster University,
Hamilton Health Sciences, Hamilton, Ont., Canada L8N 3Z5
Received 10 October 2002; accepted 11 November 2002
Abstract
The detection of 3-nitro-L-tyrosine has been used as a biomarker of ‘‘reactive nitrogen species’’ in biological matrices and has been an
ongoing challenge in analytical chemistry. In this work, fluorine-18 labelled 5-fluoro-3-nitro-L-tyrosine (FNT) was synthesized as a potential
radiotracer to probe the biological fate of 3-nitro-L-tyrosine. The synthesis of [18F]FNTwas carried out by reaction of [18F]3-fluoro-L-tyrosine
with NaNO3 in TFA solvent for 5 min at 4 8C. The radiochemical yield (RCY) of [18F]FNT was 96 ꢀ 2% and [18F]3-fluoro-L-tyrosine, was
29 ꢀ 1%, relative to [18F]3-fluoro-L-tyrosine and [18F]F2, respectively. The syntheses of [18F]FNT were also accomplished by direct
fluorination of 3-nitro-L-tyrosine with [18F]F2 and by nitration of L-tyrosine with NaNO3, followed by fluorination, in TFA (4 8C) or anhydrous
HF (ꢁ65 8C) solvent. The latter two synthetic routes produced [18F]FNT in 13:5 ꢀ 1:5% RCY, within 1 h. Products were characterized by use
1
of H, 13C and 19F NMR spectroscopy and mass spectrometry.
# 2002 Published by Elsevier Science B.V.
Keywords: Nitrotyrosine; Fluoronitrotyrosine; L-Tyrosine; Fluorine-18; Positron emission tomography; Reactive nitrogen species
1. Introduction
tyrosines in proteins [8] as new NMR probes for nitrotyr-
osines. Thus, a radiolabelled derivative of 3-nitro-L-tyrosine
could also be useful for the detection and quantification of
3-nitro-L-tyrosine.
The goals of the present work were to develop rapþid
methods for the synthesis of fluorine-18 (18F, 97% b ,
Emax ¼ 0:635 MeV, t1=2 ¼ 109:7 min) labelled 3-nitro-L-
tyrosine, which could be used as a probe in studies of the
biological function of 3-nitro-L-tyrosine by means of posi-
tron emission tomography (PET). The present study reports
three synthetic routes to [18F]5-fluoro-3-nitro-L-tyrosine
([18F]FNT).
Aromatic nitration is one of the most extensively studied
reactions in synthetic and theoretical chemistry [1,2]. Aro-
matic nitration also occurs in vivo by the action of ‘‘reactive
nitrogen species’’, which are being increasingly proposed as
contributors to tissue injury in several human diseases. The
detailed mechanisms by which these species cause modifi-
cations in biomolecules is not completely understood [3].
The in vivo detection of 3-nitro-L-tyrosine is considered to be
a biomarker for ‘‘reactive nitrogen species’’ in a biological
matrix, however, the in vivo formation and fate of 3-nitro-L-
tyrosine is a controversial subject [3–5].
A number of analytical procedures for the separation,
detection and quantification of 3-nitro-L-tyrosine have been
developed including UV, HPLC, GC, MS and biochemical
techniques [6]. Labelled compounds have also been consid-
ered for the detection and quantification of 3-nitro-L-tyrosine.
For example, 15N-labelled tetranitromethane has been used
to synthesize [15N]3-nitro-L-tyrosine [7] and [15N]-labelled
2. Results and discussion
Mixtures of nitric acid and sulfuric acid continue to be
the most widely used nitrating agents, however, the strongly
oxidizing natures of these systems and environmental con-
siderations have led to the development of more selective
reagents and methods [1]. Acid-catalyzed electrophilic aro-
matic nitration [9] often has the advantage that the solvents
are recyclable and nitrations can be achieved under anhy-
drous conditions. Nitroaromatics that contain fluorine are an
interesting class of compounds and have applications in the
* Corresponding authors. Tel.: þ1-905-521-2100x76893/
þ1-905-525-9140x23306; fax: þ1-905-546-1125/þ1-905-522-2509.
E-mail addresses: chiraklr@mcmaster.ca (R. Chirakal),
schrobil@mcmaster.ca (G.J. Schrobilgen).
0022-1139/02/$ – see front matter # 2002 Published by Elsevier Science B.V.
doi:10.1016/S0022-1139(02)00334-2

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N. Vasdev et al. / Journal of Fluorine Chemistry 121 (2003) 9–14
Table 1
Proton, 13C and 19F NMR parameters for FNTa
1H chemical shift (ppm)
Coupling constant (Hz)
13C chemical shiftc (ppm)
Coupling constant (Hz)
5-Fluoro-3-nitro-tyrosineb
H7A 3.03
2JðH7A-H7BÞ, ꢁ14.6
3JðH7A-H8XÞ, 5.72
3JðH7B-H8XÞ, 7.31
3JðH6-FÞ, 10.7
C-1 132.3 (132.0)
C-2 128.1 (125.5)
C-3 142.5 (139.5)
C-4 148.9 (143.8)
C-5 159.0 (159.1)
C-6 130.2 (129.3)
C-7 41.1
3JðC1-FÞ, 6.9
4JðC2-FÞ, 2.3
3JðC3-FÞ, 3.1
2JðC4-FÞ, 16.1
1JðC5-FÞ, 246.9
2JðC6-FÞ, 19.2
H7B 3.16
H8X 4.18
H6 7.31
H2 7.67
5JðH2-FÞ, 2.0
4JðH2-H6Þ, 2.0
C-8 60.2
C-9 177.5
a Spectra recorded in D2O solvent.
b The 19F chemical shift is ꢁ130.7 ppm with respect to external CFCl3 at 30 8C.
c Calculated values using fluorine substituent parameters [24] are shown in parentheses.
agrochemical and pharmaceutical industries [10]. Chambers
and Skinner [10] have patented a synthetic route to mono-
and polyfluoronitrated aromatic compounds by reacting
aromatic compounds with a nitrating agent (e.g. aqueous
HNO3) in the presence of elemental fluorine. In the pre-
sent work, three synthetic approaches to [18F]FNT were
explored: (1) nitration of [18F]3-fluoro-L-tyrosine (2) direct
fluorination of 3-nitro-L-tyrosine, and (3) a one-pot nitration
of L-tyrosine followed by fluorination. Anhydrous HF and
TFA were chosen as the solvents for these reactions because
they have proven to be useful for acid-catalyzed electro-
philic nitration [9] and for the direct fluorination of aromatic
amino acids [11–17].
was >98% after 5 min. Characterization of 5-fluoro-3-nitro-
tyrosine was accomplished by use of 1H, 13C and 19F NMR
spectroscopy (Table 1).
We have previously reported the synthesis of [18F]3-
fluoro-L-tyrosine by direct fluorination of L-tyrosine with
a 29 ꢀ 1% radiochemical yield (RCY) [17]. The nitration of
3-fluoro-DL-tyrosine, described above, was applied to the
nitration of [18F]3-fluoro-L-tyrosine (Scheme 1) and pro-
duced [18F]FNT with a RCY of 96 ꢀ 2% with respect to
[18F]3-fluoro-L-tyrosine. Analytical HPLC analysis of the
reaction mixture after nitration of [18F]3-fluoro-L-tyrosine
with NaNO3 in TFA (Scheme 1) is shown in Fig. 1. The
peaks eluting at 5.5 and 7.5 min correspond to unconverted
3-fluoro-L-tyrosine and [18F]FNT, respectively, as confirmed
by 19F NMR spectroscopy. Furthermore, the peak assigned
to 3-fluoro-L-tyrosine in the reaction mixture showed an
increase in peak area when spiked with 3-fluoro-DL-tyrosine.
2.1. Nitration of 3-fluoro-DL-tyrosine and
[18F]3-fluoro-L-tyrosine
In previous work [18], 5-fluoro-3-nitro-DL-tyrosine was
synthesized by reaction of an ice-cold suspension of 3-
fluoro-DL-tyrosine in water with concentrated HNO3 and
by allowing the reaction to proceed below 25 8C overnight.
In the present work, nitration of 3-fluoro-DL-tyrosine was
carried out using an equimolar quantity of NaNO3 in TFA
(4 8C) or HF (ꢁ65 8C) solvent. Analysis of the reaction
mixture using HPLC (UV, l ¼ 275 nm) showed that the con-
versionof3-fluoro-DL-tyrosineto5-fluoro-3-nitro-DL-tyrosine
2.2. Fluorination of 3-nitro-L-tyrosine
The direct fluorination of 3-nitro-L-tyrosine using [18F]F2
(Scheme 2) resulted in RCYs of 13 and 15% in TFA and
HF, respectively, for [18F]FNT. Structural characterization
1
of FNT was accomplished by use of H, 13C and 19F NMR
spectroscopies and positive ion electrospray mass spec-
trometry, which showed a protonated molecular ion at
Scheme 1.

N. Vasdev et al. / Journal of Fluorine Chemistry 121 (2003) 9–14
11
Fig. 1. HPLC trace of the reaction mixture after the nitration of [18F]3-fluoro-L-tyrosine (A) using NaNO3 in TFA solvent at 4 8C for 5 min to produce
[
18F]FNT (B) (Scheme 1): (a) UV, l ¼ 275 nm and (b) [18F]-radioactivity trace.
Inview ofthesignificantly lower RCYinScheme2, compared
with that resulting from direct nitration of [18F]3-fluoro-L-
tyrosine in Scheme 1, the development of HPLC methods to
optimize this separation were not pursued further.
2.3. One-pot nitration and fluorination of L-tyrosine
One-pot nitrations of L-tyrosine in TFA and HF solvents,
followed by fluorination using [18F]F2, were also carried
out in the present study (Scheme 3). The conversion of
L-tyrosine to 3-nitro-L-tyrosine was >98% (determined by
HPLC; UV, l ¼ 275 nm). The products of these reactions
were characterized by 1H, 13C and 19F NMR spectroscopies
and by positive ion electrospray mass spectrometry,
Scheme 2.
m=z ¼ 245 [M þ H]þ. The syntheses and preparative HPLC
purifications of [18F]FNT were completed within 1 h.
It should be noted that 3-nitro-L-tyrosine was not separated
from [18F]FNT under the HPLC conditions used in this study.
Scheme 3.

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N. Vasdev et al. / Journal of Fluorine Chemistry 121 (2003) 9–14
Scheme 4.
which showed protonated molecular ions at m=z ¼ 227 and
245 [M þ H]þ corresponding to 3-nitro-L-tyrosine and
[18F]FNT, respectively.
2.4. Relative reactivity of [18F]F2 towards L-tyrosine
and 3-nitro-L-tyrosine
Substitutions at positions 3- and 5- on the aromatic ring
of L-tyrosine were expected in view of the higher electron
densities at these positions that arise from the electron donat-
ing properties of the hydroxyl group. We have recently shown
that the same sites are susceptible to electrophilic aromatic
substitution in L-tyrosine and L-a-methyltyrosine [17]. The
RCYof [18F]FNT, after a one-pot nitration of L-tyrosine using
NaNO3 followedbyfluorinationwith[18F]F2 (Scheme3), was
14 and 12% in TFA and HF, respectively.
The RCYs of [18F]FNT resulting from the direct fluorina-
tion of 3-nitro-L-tyrosine (Schemes 2 and 3; 13:5 ꢀ 1:5%)
are lower than those resulting from the direct fluorination
of L-tyrosine in TFA (28%) and HF (30%). The lower RCYs
in the present work are not surprising because the electron
withdrawing nitro group renders the aromatic ring less
susceptible to electrophilic aromatic substitution. Cacace
and Wolf [19] have reported that the relative reactivity
of aromatic substrates with F2 increases with increasing
Fig. 2. HPLC trace showing the relative reactivity of [18F]F2 towards three-fold molar excesses of both L-tyrosine and 3-nitro-L-tyrosine in TFA solvent at
4 8C (Scheme 4). The labels A, B, and C correspond to unidentified fluorine-containing species, [18F]3-fluoro-L-tyrosine and [18F]FNT, respectively: (a) UV,
l ¼ 275 nm and (b) [18F]-radioactivity trace.

N. Vasdev et al. / Journal of Fluorine Chemistry 121 (2003) 9–14
13
activation of the aromatic ring in the order: nitrobenzene
<< benzene < toluene << anisole. Because the RCY of an
18F-labelled fluoroaromatic compound is indicative of the
efficiency of fluorine substitution on the aromatic ring, it was
of interest to determine the relative reactivity of [18F]F2
towards three-fold molar excesses of both L-tyrosine and
3-nitro-L-tyrosine in TFA at 4 8C (Scheme 4). The results of
this competition experiment revealed that the reactivity of
fluorine towards L-tyrosine was considerably higher than
towards 3-nitro-L-tyrosine, which was determined from the
distribution of radioactivity and peak integration after
preparative HPLC and from integration of the 19F NMR
spectrum of the reaction mixture. The combined RCY of
[18F]3-fluoro-L-tyrosine and [18F]FNT was 26% (relative to
[18F]F2), with >95% of the activity arising from [18F]3-
fluoro-L-tyrosine. Fig. 2 shows HPLC traces of the reaction
mixture resulting from this competition experiment. The
peaks eluting at 4, 5.5 and 7.5 min correspond to (an)
unknown fluorine-containing species, [18F]3-fluoro-L-tyro-
sine and [18F]FNT, respectively. These results clearly show
that the aromatic ring of L-tyrosine is more susceptible to
substitution by fluorine, under the present experimental
conditions, than the relatively deactivated aromatic ring
of 3-nitro-L-tyrosine, accounting for the lower RCY after
fluorination of 3-nitro-L-tyrosine when compared with that
of L-tyrosine in TFA [17].
with respect to [18F]3-fluoro-L-tyrosine within 5 min. This
method offers the highest radiochemical purity and yields
of [18F]FNT at this time and is well suited for the routine
production of [18F]FNT in a hospital environment. The
present work also establishes that [18F]FNT can be synthe-
sized by direct fluorination of 3-nitro-L-tyrosine in TFA or
HF solvent using [18F]F2 in a RCYof 13:5 ꢀ 1:5% relative to
[18F]F2.
4. Experimental
4.1. General experimental procedures
Precautionary measures should be established prior to
repeating aspects of this work, particularly when 18F and
anhydrous HF are employed. Before commencing work with
anhydrous HF, first-aid treatment procedures [21–23] should
be available and known to all laboratory personnel.
4.1.1. Materials
Enriched [18O]O2 (18O, min 99 atom%, Isotec), neon
(99.999%, Air Products), anhydrous hydrogen fluoride
(Air Products), 1% F2 in neon (Canadian Liquid Air), helium
(99.9999%, Matheson), L-tyrosine (Fisher), 3-nitro-L-tyro-
sine (Aldrich), 3-fluoro-DL-tyrosine (Aldrich), sodium nitrate
(Caledon), trifluoroacetic acid (Caledon), glacial acetic acid
(BritishDrugHouses),andHPLCgradeacetonitrile(Caledon)
were used without further purification.
2.5. Comparison of the synthetic routes to [18F]FNT
Of the three new synthetic methods for [18F]FNT that are
described in the present study (Schemes 1–3), the direct
nitration of [18F]3-fluoro-L-tyrosine (Scheme 1) is the pre-
ferred route because the nitration of [18F]3-fluoro-L-tyrosine
is fast (5 min) and efficient (96 ꢀ 2% conversion to
[18F]FNT). This method also produces [18F]FNT of high
radiochemical purity because all of the L-tyrosine precursor
is easily removed immediately following fluorination with
[18F]F2. The present study also showed that fluorination of
L-tyrosine is more efficient than fluorination of the relatively
deactivated aromatic ring of 3-nitro-L-tyrosine. However,
the one-pot method of nitration followed by fluorination of
L-tyrosine (Scheme 3) offers an alternative general route
to the syntheses of nitrofluoroaromatic compounds. For
18F-labelled nitrofluoroaromatic compounds requiring high
specific activities for PETapplications, nucleophilic methods
using no-carrier-added 18Fꢁ can be used for the syntheses
of 18F-aromatics [20], and the resulting compounds should
prove to be easily nitrated, as established by the present study.
4.1.2. Synthetic methods
The general experimental procedures for the fluorination
of aromatic amino acids in the present work were conducted
as previously described [17]. Separation of L-tyrosine from
[18F]3-fluoro-L-tyrosine by preparative HPLC was carried
out using a reverse-phase column (Phenomenex M9 Partisil
10/50, ODS-3) and an aqueous solution of 5% CH3CN with
0.1% TFA (v/v) as the mobile phase and a flow rate of
3.0 mL minꢁ1. The eluate from the column was monitored
with a fixed wavelength UV detector (280 nm) and a Geiger-
Mu¨ller counter (Bicron SWGM B980C) coupled to a rate
meter (Bicron Erik-TechTM). Preparative HPLC analysis of
the reaction mixture (Scheme 1) showed one major UV peak
having the same retention time as L-tyrosine at 13.5 min and
another major peak at 16 min. The radiochromatogram of
the same sample showed peaks at 8, 9.5, 11, 13 and 16 min.
The peak eluting at 16 min contained the majority of the
radioactivity and was collected, evaporated to dryness and
redissolved in 0.5 mL of 0.1% HOAc and the evaporation
process was repeated. Sodium nitrate (2 mg, 24 mmol) in
1 mL of TFA was added to the dry residue and reacted at
4 8C for 5 min. The products were confirmed to be [18F]3-
fluoro-L-tyrosine and [18F]FNT by use of HPLC and 19F
NMR spectroscopy. The present separation method offers
the advantage, over our previous method [17], of avoiding
the use of a buffered mobile phase and a second HPLC
3. Conclusions
Efficient synthetic methods leading to the syntheses of
[18F]FNT have been developed in the present study. The
direct nitration of [18F]3-fluoro-L-tyrosine using NaNO3 in
TFA at 4 8C produced [18F]FNT with a RCY of 96 ꢀ 2%

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N. Vasdev et al. / Journal of Fluorine Chemistry 121 (2003) 9–14
purification step. The TFA was evaporated and the sample
was redissolved in 0.1% HOAc and used for characteriza-
tion. Preparative HPLC conditions used for the products of
fluorination of 3-nitro-L-tyrosine and for the study of the
relative reactivity of [18F]F2 towards L-tyrosine and 3-nitro-
L-tyrosine were identical to those described above except
that the mobile phase was an aqueous solution comprised
of 20% CH3CN and 0.1% TFA. Under these conditions,
L-tyrosine eluted at 8.5 min and [18F]FNT eluted at 9.5 min.
Aliquots of the reaction mixture and of purified [18F]FNT
were analyzed on a reverse-phase HPLC column (Phenom-
enex, ODS-2, 0:9 cm ꢂ 25 cm) and an aqueous solution of
20% CH3CN with 0.1% TFA as the mobile phase using a
flow rate of 3.0 mL minꢁ1. Under these conditions, 3-fluoro-
L-tyrosine and [18F]FNT eluted at 5.5 and 7.5 min, respec-
tively. The identity of the peak eluting at 5.5 min was
confirmed by spiking the reaction mixture with 3-fluoro-
DL-tyrosine. The eluate from the column was passed through
a Waters 490E programmable multiwavelength UV detector
(275 nm) and a Beckman radioisotope detector (Model 170).
Both detectors were connected to a Waters Millennium
Chromatography Manager.
(N.V.) and for support in the form of a research grant (G.J.S.).
We also thank Dr. Russell A. Bell and Dr. Frank J. Laronde for
helpful discussions.
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We thank the Natural Sciences and Engineering Research
Council ofCanada forthe award of a postgraduate scholarship