Efficient O- and N-(β-fluoroethylation)s with NCA [ 18F]β-fluoroethyl tosylate under microwave-enhanced conditions

Article abstract of DOI:10.1002/jlcr.818

Reactions of no-carrier-added (NCA) [¹⁸F]β-fluoroethyl tosylate with amine, phenol or carboxylic acid to form the corresponding [ ¹⁸F]N-(β-fluoroethyl)amine, [¹⁸F]β-fluoroethyl ether or [¹⁸F]β-fluoroethyl ester,

Full text of DOI:10.1002/jlcr.818

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 289–297.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.818
Research Article
Efficient O- and N-(b-fluoroethylation)s with NCA
[18F]b-fluoroethyl tosylate under microwave-enhanced
conditions
Shui-Yu Lu*, Frederick T. Chin, Julie A. McCarron and Victor W. Pike
PET Radiopharmaceutical Sciences, Molecular Imaging Branch, National Institute of
Mental Health, National Institutes of Health, Building 10, Room B3 C346, 10 Center
Drive, Bethesda, MD 20892-1003, USA
Summary
Reactions of no-carrier-added (NCA) [18F]b-fluoroethyl tosylate with amine, phenol
or carboxylic acid to form the corresponding [18F]N-(b-fluoroethyl)amine, [18F]b-
fluoroethyl ether or [18F]b-fluoroethyl ester, were found to be rapid (2–10 min) and
efficient (51–89% conversion) under microwave-enhanced conditions. These condi-
tions allow reactants to be heated rapidly to 1508C in a low boiling point solvent, such
as acetonitrile, and avoid the need to use high boiling point solvents, such as DMSO
and DMF, to promote reaction. The microwave-enhanced reactions gave about
20% greater radiochemical yields than thermal reactions performed at similar
temperatures and over similar reaction times. With a bi-functional molecule, such as
dl-pipecolinic acid, [18F]b-fluoroethyl tosylate reacts exclusively with the amino
group. Copyright # 2004 John Wiley & Sons, Ltd.
Key Words: fluorine-18; [18F]b-fluoroethylation; amine; phenol; ester; pipecolinic
acid; microwave
Introduction
In the field of labeling compounds with fluorine-18 (t1/2=109.8 min;
b+=96.9%) for positron emission tomography (PET), no-carrier-added
(NCA) [18F]b-fluoroethyl tosylate is widely used as a reagent for O-, N- and
S-fluoroalkylations.1–13 This reagent is attractive for several reasons, including
its (a) ease of preparation, (b) good stability, (c) wide applicability and (d)
suitability for one-pot radiosyntheses.13 However, applications of this labeling
agent are restricted by some disadvantages, including lower reactivity
*Correspondence to: S.-Y. Lu, PET Radiopharmaceutical Sciences, Molecular Imaging Branch, National
Institute of Mental Health, National Institutes of Health, Building 10, Room B3 C346, 10 Center Drive,
Bethesda, MD 20892-1003, USA. E-mail: shuiyu.lu@mail.nih.gov
Copyright # 2004 John Wiley & Sons, Ltd.
Received 22 January 2004
Accepted 10 February 2004

290
S.-Y. LU ET AL.
compared to alternative labeling agents (e.g. [18F]b-fluoroethyl triflate14,15
)
and its sensitivity to some solvents and bases that are used in the labeling
reactions. For example, it was observed that reactions with some secondary
aliphatic and aromatic amines were particularly sluggish in acetonitrile and
that polar, high boiling point solvents, such as DMF or DMSO, were required
to complete reactions.14 Consequently, alternative labeling agents,14,15
catalysts16,17 or new radiochemistry18,19 have been explored to overcome the
lack of reactivity. Another noted drawback of this labeling reagent is its lack
of selectivity in reactions with multi-functional molecules. For example, a
base-supported [18F]b-fluoroethylation of an H-acidic group, like a phenolic
hydroxyl or carboxyl group, may be accompanied by the alkylation of a
coexisting nucleophilic amino group, making the use of appropriate protection
necessary.19
Microwave dielectric heating transforms electromagnetic energy directly to
heat in reaction media. In recent years, microwaves have had a huge impact on
how experimental organic or medicinal chemistries are performed.20,21
Microwave-enhanced radiochemistry can provide a faster, cleaner, more
selective and highly atom-efficient methodology. The shorter reaction time
coupled with other benefits, such as higher product purity, due to reduced
reaction mixture decomposition and the promotion of otherwise sluggish
reactions, make it an ideal tool to be explored in radiochemistry with short-
lived positron-emitters.22–24 Here we report how improved radiochemical
yields and practical convenience derive from the use of microwaves when using
[18F]b-fluoroethyl tosylate to prepare [18F]N-b-fluoroethyl-amines, ethers and
esters. We also report that, under microwave conditions, [18F]b-fluoroethyl
tosylate is chemoselective in reacting exclusively with the amino group of bi-
functional dl-pipecolinic acid.
Results and discussion
Benefits of using microwaves extend to a wider choice of solvents, including
acetonitrile. Acetonitrile is an attractive aprotic polar solvent for use in PET
radiochemistry, because it is easy to maintain in a dry state and is easily
removable. Thus, in this work, acetonitrile was first used for the azeotropic
removal of the proton-irradiated [18O]water and recovery of the reactive
‘naked’ [18F]fluoride ion for the preparation of [18F]b-fluoroethyl tosylate.
Acetonitrile was also a component of the mobile phase for the preparation and
purification of the [18F]b-fluoroethyl tosylate with solid phase extraction.
Under microwave conditions, it was possible to heat reaction mixtures
containing [18F]b-fluoroethyl tosylate rapidly to 1508C in low boiling point
(b.p. 828C) acetonitrile. This avoids the need for high boiling point solvents,
such as DMF or DMSO, to drive reactions to completion under thermal
conditions. Such solvents are more difficult to remove and indeed quite
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EFFICIENT O- AND N-(
291
Scheme 1. Examples of the preparation of NCA [18F]N-b-fluoroethylamine,
[18F]b-fluoroethyl ether and [18F]b-fluoroethyl ester using [18F]b-fluoroethyl
tosylate as labeling agent in a microwave-enhanced procedure
unwieldy extraction techniques have been required for this purpose.13
Although acetonitrile is not considered a good microwave solvent on its
own, mainly due to its small dielectric loss ðe00Þ to dielectric constant (e0) ratio
(tan d=0.062)21, dissolved metal salts (Cs+ or Na+) dramatically improve the
absorption and transfer of the microwave energy to heat by the ionic
conduction mechanism.25,26
3-(3-Pyridyl)propionic acid (1), 4-nitrophenol (2), 2b-carbomethoxy-3b-(4-
chlorophenyl)nortropane (3) and 1-(4-nitrophenyl)piperazine (4) were selected
as examples of compounds containing carboxyl, hydroxyl and amino groups,
as commonly encountered in substrates to be labeled with fluorine-18.
Reaction of [18F]b-fluoroethyl tosylate with the acid, phenol and amines
proceeded smoothly in acetonitrile under microwave-enhanced conditions
(Scheme 1). The standard Pyrex reaction vessel (10 ml), which can be crimp-
sealed,y was used and no loss of solvent or radioactivity was observed during
the microwave irradiation. The procedure was safe and reliable; no vessel
failure incident occurred. Improvement in decay-corrected radiochemical
yields (RCY) of the [18F]b-fluoroethylated compounds under microwave-
enhanced conditions compared to thermal heating in acetonitrile are
y Radiation exposure to the worker is reduced by replacing the screw-capped vials, which require more hand
manipulation during radiosynthesis, with the simpler, crimp-sealed microwave reaction tube.
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S.-Y. LU ET AL.
Table 1. RCYs of [18F]b-fluoroethyl derivatives under microwave-enhanced conditions or
thermal heating in acetonitrile
Substrate
Base
Microwave
Conditions
Thermal heating
Conditions
RCY (%)a
RCY (%)a
1
2
3
4
Cs2CO3
Cs2CO3
NaHCO3
NaHCO3
300 W, 2 min
300 W, 6 min
300 W, 1508C, 10 min
300 W, 1508C, 10 min
89
77
78
51
1208C, 10 min
1208C, 10 min
1208C, 45 min
708C, 25 min
66
59
60
5b
a RCY based on [18F]b-fluoroethyl tosylate.
b This data is from Ref. 31 for similar reaction.
Scheme 2. Reactions of [18F]b-fluoroethyl tosylate with DL-pipecolinic acid and
its ethyl ester under microwave-enhanced conditions
summarized in Table 1. Generally, the microwave-enhanced reactions gave
about 20% greater RCYs than thermal reactions under similar conditions of
temperature (the highest achievable with a heating block) and reaction time.
dl-Pipecolinic acid (5a) was selected as a model substrate for examination
of the reactivity and selectivity of [18F]b-fluoroethyl tosylate towards a bi-
functional compound. In the presence of sodium bicarbonate or cesium
carbonate a single radioactive product, the [18F]N-(b-fluoroethyl)amine 6a,
was obtained in very high RCY (90% or 96%, respectively, by radio-TLC
analysis) within 5–10 min of microwave heating at 1308C. In the absence of
base the RCY was around 10% (Scheme 2). In reactions of dl-pipecolinic acid
(5a) with one equivalent of non-radioactive b-fluoroethyl tosylate in the
presence of sodium bicarbonate, mono-substituted ester 7 was the major
product after 10 min, and the di-substituted compound 8 appeared if the
reaction was extended for another 20 min. When cesium carbonate was used as
base, di-substituted compound 8 was the major product at 10 min (Scheme 3).
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EFFICIENT O- AND N-(
293
Scheme 3. Influence of base on the reaction of one molar equivalent of non-
radioactive b-fluoroethyl tosylate with DL-pipecolinic acid under microwave-
enhanced conditions
Table 2. [18F]b-Fluoroethylation of pipecolinic acid, salts and ethyl ester, under
microwave-enhanced conditions
Entry
Substrate
Base
Irradiation time (min)
RCY (%)a
1
2
3
4
5
6
7
5a
5a
5a
5a
5b
5b
5b
}
}
5
10
10
10
5
10
11
Cs2CO3
NaHCO3
}
Cs2CO3
Cs2CO3
96 ꢀ 1 (n=3)
90 ꢀ 1 (n=3)
28
54
95
5
10
a By radio-TLC, n=1 unless otherwise stated.
Under the described microwave conditions, whether the carboxylic acid group
is blocked, as with an ethyl group in 5b27–29 (Table 2, entries 6 and 7), or not
(Table 2, entries 3 and 4), [18F]b-fluoroethyl tosylate reacts exclusively with the
amino group.
Experimental
Materials
2b-Carbomethoxy-3b-(4-chlorophenyl)nortropane and its N-fluoroethyl deri-
vative (3) were obtained from Dr. M. Goodman (Emory University). Ethylene
glycol di-p-tosylate (99%), 1-(4-nitrophenyl)piperazine (97%), 4-nitrophenol
(99+%), 3-(3-pyridinyl)propionic acid (98%), dl-pipecolinic acid (98%) (5a),
ethyl pipecolinate (98%) (5b), sodium hydrogen carbonate (99.7%), cesium
carbonate (99.95%), sodium hydroxide (97%) and Kryptofix 2.2.21
(4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo-[8,8,8]hexacosane), all from Aldrich,
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plus ammonium formate (96%; J.T. Baker), ethyl acetate (HPLC grade; Fisher
Scientific), hexane (OmniSolv; EMD), methanol (HPLC grade; Fisher
Scientific) and acetonitrile (high purity solvent; Burdick & Jackson) were all
used as received. b-Fluoroethyl tosylate was prepared using a literature
method.30
General analytical methods
1H-NMR spectra were recorded on an Avance-400 spectrometer (Bruker). LC-
MS analysis was performed on a Surveyor LC system (Thermo Finnigan)
equipped with a Quest LC QDECA ESI probe (Finnigan).
Radioactivity was measured with a calibrated dose calibrator (AtomlabTM
300; Biodex Medical Systems). Radio-TLC analysis was performed on silica
gel coated glass plates (Uniplates; AnalTech), which were developed in ethyl
acetate–hexane (2:1 v/v) and scanned with a sensitive quantitative g-detecting
instrument (Bioscan AR-2000). HPLC analysis was performed on a system
comprising a Gold HPLC module [System Gold 126 solvent module coupled
with a 166 UV absorbance detector (single wavelength); Beckman Coulter]
plus a Flow Count radioactivity detector (diode or PMT; Bioscan). The HPLC
(
system was equipped with a reverse phase column (Luna C18; 10 m; 100 A;
250 ꢁ 4.6 mm i.d.; Phenomenex) eluted with acetonitrile–ammonium formate
solution (0.1 M) at 1 ml/min.
Non-UV absorbing radioactive compounds were identified with radio-TLC
and UV absorbing compounds with radio-HPLC. In each method, co-
migration of radioactive product and reference compound was verified. RCYs
were estimated by integration of radioactive peaks and represent conversions,
not isolated yields. The area of the product peak (P, in units of V min) was
compared to the integral of radioactivity from all eluted peaks (T, in units of
V min) and the RCY calculated as [P/T ꢁ R2/R1 ꢁ 100%], where R2 is the total
activity transferred out of the reaction vessel and R1 was the starting activity
of 18FCH2CH2OTs, both decay corrected. In HPLC, no corrections were
made for radioactive decay in the short time between the first and last eluted
peak (ꢂ12 min). Regular checks were performed, confirming that all radio-
active compounds injected onto HPLC column were eluted during the course
of analysis.
Reference compounds
Non-radioactive counterparts of compounds 1, 2, 411, 6b, 7 and 8 were
prepared by treating the des-b-fluoroethyl compounds with b-fluoroethyl
tosylate (1:1 molar ratio). Each product was isolated by column chromato-
1
graphy, and characterized by TLC, LC-MS and H-NMR (Table 3).
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EFFICIENT O- AND N-(
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Table 3. 1H-NMR (400 MHz) and LC-MS data of the reference compounds
19F-Compound 1H-NMR
LC-MS [M+1]+
1
CD3CN, 8.52 (s, 1 H), 8.47 (d, 1H), 7.67 (d, 1H), 7.31 198
(dd, 1H), 4.62 (m, 2 H, JHF=47 Hz), 4.32 (m, 2 H,
HF=30 Hz), 2.99 (t, 2H), 2.75 (t, 2H)
CD3CN, 8.21 (d, 2 H), 7.08 (d, 2 H), 4.77 (m, 2 H, 185
HF=46 Hz), 4.35 (m, 2 H, JHF=29 Hz)
CD3CN, 8.08 (d, 2 H), 6.93 (d, 2 H), 4.57 (m, 2 H, 254
HF=47 Hz), 3.43 (t, 4 H), 2.69 (m, 2 H, JHF=29 Hz),
J
2
4
J
J
2.62 (t, 4 H)
6b
CDCl3, 4.56 (m, 2 H, JHF=47 Hz), 4.19 (q, 2 H), 3.23 204
(m, 1 H), 3.11 (m, 1 H), 2.86 (m, 2 H, JHF=29 Hz), 2.74
(M, 1 H), 2.38 (m, 1 H), 1.85 (m, 2 H), 1.66 (m, 2 H), 1.41
(m, 1 H), 1.26 (t, 3 H)
7
8
Mixture with fluoroethyl tosylate not isolated in a pure 176
state for NMR
CD3CN, 4.59 (m, 2 H, JHF=47 Hz), 4.47 (m, 2 H, 222
JHF=47 Hz), 4.31 (m, 2 H, JHF=29 Hz), 3.33 (t, 1 H),
3.27 (d, 1 H), 3.01 (m, 1 H), 2.80 (m, 2H, JHF=47 Hz),
2.70 (m, 1 H), 2.41 (m, 1 H), 1.77 (m, 2 H), 1.56 (m, 2 H)
Preparation of NCA [18F]fluoride ion
NCA [18F]fluoride ion was prepared through the 18O(p,n)18F nuclear reaction
by irradiating [18O]water (95 atom %) for 120 min with a proton beam
(17 MeV; 20 mA) from a commercial cyclotron (PETtrace; GE).
Preparation of [18F]b-fluoroethyl tosylate
Non-automated method. The one-pot procedure was based on a literature
method with some modification.12 Cyclotron-produced NCA [18F]fluoride ion
was mixed with Kryptofix 2.2.2 (5 mg; 13.3 mmol) and potassium carbonate
(0.5 mg; 3.6 mmol) in acetonitrile-water (95:5 v/v; 0.1 ml) and dried azeotro-
pically by alternating evaporations and additions of acetonitrile (0.5 ml ꢁ 3).
Ethylene glycol di-p-tosylate (2 mg; 5.4 mmol) in acetonitrile (250 ml) was added
to the reaction mixture then heated at 1108C for 10 min to afford [18F]b-
fluoroethyl tosylate. The solution was used directly for the next reaction
without further purification.
Automated method. The automated procedure was carried out on a Tracerlab
FX module (GE). The preparation and azeotropic drying of the [18F]fluoride
ion-Kryptofix 2.2.2-K2CO3 complex were nearly identical to the manual
method but completed in the module. The reaction mixture containing [18F]b-
fluoroethyl tosylate was diluted in water (100 ml) and passed through a reverse
phase silica gel cartridge (C-18 Sep-Pak; Waters). The cartridge was
washed with water again (3 ml) and the radioactivity eluted off with
acetonitrile (1–1.5 ml).
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General procedure for [18F]b-fluoroethylation
To a standard Pyrex glass microwave reaction vessel containing substrate
(ꢂ0.01 mmol), base (1 equiv to substrate) was added [18F]b-fluoroethyl
tosylate solution in acetonitrile (radioactivity R1=0.2–2 mCi; 200–300 ml). The
contents were crimp sealed with a PTFE-coated septum and irradiated in a
single mode microwave cavity (DiscoverTM; CEM) for a pre-set period of time,
temperature and power. At the end of the microwave heating, the reaction
mixture was cooled to room temperature, transferred out of the reaction vessel
and further diluted by acetonitrile or methanol (radioactivity R2). A fraction
of the solution was injected into the radio-HPLC or spotted onto the radio-
TLC plate for analysis.
Conclusion
Examples of NCA [18F]N-b-fluoroethylamine, [18F]b-fluoroethyl ether and
[18F]b-fluoroethyl ester were obtained using [18F]b-fluoroethyl tosylate as
labeling agent in a microwave-enhanced, and reliable procedure. An otherwise
sluggish reaction in acetonitrile, a low boiling point and medium polar solvent,
became possible by changing the energy input mode, i.e. to microwave heating.
The use of high boiling point solvents, such as DMSO and DMF, which are
difficult to remove, is avoided. RCYs for these reactions are at least 20%
greater under microwave-enhanced condition than under thermal heating at
similar temperatures and reaction times. For reaction with a bi-functional
compound, such as dl-pipecolinic acid, [18F]b-fluoroethyl tosylate reacts
exclusively with the amino group.
Acknowledgements
The authors are grateful to Dr Umesha Shetty (MIB, NIMH) for LC-MS
measurements.
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