Synthesis of [18F]-labeled adenosine analogues as potential PET imaging agents

Article abstract of DOI:10.1002/jlcr.712

The syntheses of adenosine analogues, 2′-deoxy-2′-[ ¹⁸F]fluoro-9-β-D-arabinofuranosyladenine ([¹⁸F]-FAA) and 3′-deoxy-3′-[¹⁸F]fluoro-9-β -D-xylofuranosyladenine ([¹⁸F]-FXA) are reported. Adenosine (1) was converted to its methoxytrityl derivatives 2 and 3 as a mixture. After separation, these derivatives were converted to their respective triflates 4 and 5. Each triflate was reacted with tetrabutylammonium[¹⁸F] fluoride to produce 6b or 7b, which by acidic hydrolysis yielded compounds 8b and 9b. Crude preparations were purified by HPLC to obtain the desired pure products. The radiochemical yields were 10-18 % decay corrected (d.c.) for 8b and 30-40% (d.c.) for 9b in 4 and 3 runs, respectively. Radiochemical purity was > 99% and specific activity was > 74 GBq/μmol at the end of synthesis (EOS). The synthesis time was 90-95 min from the end of bombardment (EOB). Copyright

Full text of DOI:10.1002/jlcr.712

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 805–814.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.712
Research Article
Synthesis of [18F]-labeled adenosine analogues as
potential PET imaging agents
Mian M. Alauddin, John D. Fissekis, and Peter S. Conti*
University of Southern California, PET Imaging Science Center, Los Angeles,
CA 90033, USA
Summary
The syntheses of adenosine analogues, 20-deoxy-20-[18F]fluoro-9-b-d-arabino-
furanosyladenine ([18F]-FAA) and 30-deoxy-30-[18F]fluoro-9-b-d-xylofuranosyl-
adenine ([18F]-FXA) are reported. Adenosine (1) was converted to its
methoxytrityl derivatives 2 and 3 as a mixture. After separation, these
derivatives were converted to their respective triflates 4 and 5. Each triflate was
reacted with tetrabutylammonium[18F]fluoride to produce 6b or 7b, which by
acidic hydrolysis yielded compounds 8b and 9b. Crude preparations were
purified by HPLC to obtain the desired pure products. The radiochemical
yields were 10-18% decay corrected (d.c.) for 8b and 30–40% (d.c.) for 9b in 4
and 3 runs, respectively. Radiochemical purity was >99% and specific activity
was >74 GBq/mmol at the end of synthesis (EOS). The synthesis time was
90–95 min from the end of bombardment (EOB). Copyright # 2003 John
Wiley & Sons, Ltd.
Key Words: fluorine-18; nucleoside; adenosine; PET.
Introduction
Many fluorinated analogues of adenosine nucleoside have been
synthesized and studied as potential antitumor and antiviral agents.1–11
*Correspondence to: Peter S. Conti, USC, PET Imaging Science Center, 2250 Alcazar St., # 101,
Los Angeles, CA 90033, USA. E-mail: pconti@hsc.usc.edu
Contract/grant sponsor: National Cancer Institute; contact/grant number: CA 72896
Copyright # 2003 John Wiley & Sons, Ltd.
Received 13 January 2003
Revised 4 February 2003
Accepted 6 March 2003

806
M. M. ALAUDDIN ET AL.
Among these, 20-deoxy-20-fluoro-2-chloro-9-b-d-arabinofuranosylade-
nine has been found to be active against human colon tumor
xenografts.6,7 The 20-deoxy-20-fluoro-arabino compounds gained much
6–8
attention as anticancer agents,
while the 30-deoxy-30-fluoro-ribo
compounds have shown antiviral activity.9–11 Little information is
available regarding the biological properties of the xylo-derivative, 30-
fluoro-9-b-d-xylofuranosyladenine.1,12,13 Most recently a synthesis of
[11C]-adenosine monophosphate has been reported in order to
investigate its potential use for imaging cancer.14 [18F]-Labeled
analogues of adenosine, particularly those that are non-catabolized,
also have potential for PET imaging of cancer and/or viral infection.
We have been exploring the radiofluorination of pyrimidine furanosyl
derivatives as potential agents for imaging cell proliferation and gene
expression using PET.15,16 More recently, we have begun to explore
radiofluorination of furanosyl purines. One synthesis of 20-deoxy-20-
fluoro-9-b-d-arabinofuranosyladenine involves the incorporation of
fluorine in the arabino configuration at C-2 of the sugar followed by
coupling with the purine base.2,17 An alternative approach involves the
direct fluorination of an appropriate precursor of the nucleoside with
various fluorinating agents followed by de-protection of the reacting
intermediate.4,8 The direct fluorination of the purine nucleoside appears
to be convenient and superior to the three-step method in which the
fluorinated glycosyl moiety is prepared first, converted to its 1-bromo-
derivative and then coupled with the purine. This contrasts our
experience within the pyrimidine series where the direct fluorination
fails to provide the desired product.4,15,16
The high yield synthesis of 20-deoxy-20-fluoro-9-b-d-arabinofurano-
syladenine involves treatment of N6,30,50-tritrityladenosine with (diethy-
lamino)-sulfur trifluoride (DAST).4,13 DAST is not a suitable reagent
for radiochemical synthesis of these compounds due to the unavail-
ability of the 18F-labeled reagent and the required long reaction time 6–
16 h. One synthesis of [18F]-labeled FAA involves the fluorination of a
20-tosylate of a protected 9-b-d-ribofuranosyladenine.8 However, this
synthesis was reported without detailed characterization of the product.
In a continuing effort towards the development of PET imaging agents
we have synthesized 20-deoxy-20-[18F]fluoro-9-b-d-arabinofuranosylade-
nine. Since little biological information of FXA is available, we have
synthesized a new agent, 30-deoxy-30-[18F]fluoro-9-b-d-xylofuranosyla-
denine ([18F]-FXA), in order to study its biological properties in vivo
with PET.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 805–814

SYNTHESIS OF [18F] ADENOSINE ANALOG
807
Results and Discussion
Figure 1 represents the scheme for the [18F]-labeled synthesis of the
adenosine nucleoside analogues, [18F]-FAA and [18F]-FXA. Com-
pounds 2 and 3 were prepared from adenosine following a literature
method.4 Reaction of adenosine with methoxytrityl chloride in pyridine
produced a mixture of three compounds, which were separated by
column chromatography. The early eluting compound (not shown), a
methoxytrityl derivative of adenine as reported earlier,4 was discarded.
Compounds 2 and 3 were isolated in 28% and 50% yields, respectively.
1
Both compounds were characterized by H NMR spectroscopy.
NHMTr
NH 2
N
NHMTr
N
N
N
N
N
N
N
N
N
MTrCl
+
N
O
N
O
MTrO
HO
MTrO
O
HO OMT r
HO OH
MTrO OH
1
2
3
NHMTr
NHMTr
N
NH2
N
N
-
N
HCl
(TfO )2O
N
X
N
N
2
N
N
N
N
N
MTrO
MTrO
HO
O
O
X
O
X
MTrO OTf
OMTr
OH
8a X = 19F
8b X = 18
6a X = 19
6b X = 18
F
F
4
F
NHMTr
N
NHMTr
NH2
N
N
N
(TfO )2O
-
N
N
N
X
HCl
3
N
N
N
N
N
X
MTrO
MTrO
HO
O
O
O
X
TfO OMTr
OMTr
OH
7a X = 19
7b X = 18F
F
9a X = 19F
9b X = 18
5
F
Figure 1. Synthetic scheme of [18F]-fluoro-adenosine analogues
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 805–814

808
M. M. ALAUDDIN ET AL.
Compounds 4 and 5 were prepared by reaction of 2 and 3 with
trifluoromethanesulfonic acid anhydride in pyridine at low temperature.
Yields in this step were quite high, ꢀ90% for both compounds. These
1
compounds were characterized by H and 19F NMR spectroscopy, and
high resolution mass spectrometry. 19F NMR spectra showed a singlet
at –73.16 and –73.58 ppm for compound 4 and 5, respectively.
Fluorination of the triflate precursor 4 with n-Bu4NF produced the
desired 20-deoxy-20-fluoro-9-b-d-arabinofuranosyladenine derivative 6a
in 20% yield. Reaction of the triflate precursor 5 with n-Bu4NF on the
other hand produced the corresponding 30-deoxy-30-fluoro-9-b-d-
xylofuranosyladenine derivative 7a in 50% yield. Low yield of 6a
compared 7a may be due to steric hindrance exerted by the purine ring.
Both compounds were purified, and characterized by 1H and 19F NMR
spectroscopy and high resolution mass spectrometry. 19F NMR
spectrum of 6a was more complex compared to that of 7a, which was
2,5
a clean doublet of triplet. Consistent with the earlier reports
on 20-
fluoro-arabinoadenosine there is a long range coupling between the
20-fluorine and C8H in compound 6a (J=ꢀ1 Hz). Furthermore
nucleophilic substitution of the 20-(ribo) triflate of adenosine with
acetate or thiol is known to produce the respective arabino epimer.4,8,18
The major by-products in these fluorination reactions with n-Bu4NF
are the 20-hydroxy-arabino- and 30-hydroxy-xylo-derivatives, respec-
tively. The Rf value (TLC) of 20-hydroxy-arabino compound differs
from that of the corresponding 20-hydroxy-ribo compound, which
further confirms the epimerisation at the 20-position during nucleophilic
substitution. Competition between hydroxide and fluoride ions has been
observed in our earlier studies on fluorination of a protected sugar and
acycloguanosine.15,19,20
Compounds 8a and 9a were prepared by acid hydrolysis of the
protecting groups from the respective methoxytrityl derivatives 6a and
7a following the method reported earlier.20 The NMR spectra of the
products were compared with known compounds, reported earlier.4,13
Radiolabeled compounds 6b and 7b were prepared by fluorination of
the respective triflate precursors with n-Bu4N18F, prepared in situ from
n-Bu4NHCO3 and aqueous H18F. In this reaction ꢀ50 ml (4% soln,
ꢀ7 mmol) of n-Bu4NHCO3 was used based on our earlier experience as
an optimum quantity.15,19 As observed in the cold synthesis the
radiochemical yield was much higher for compound 7b compared to
6b. Unreacted fluoride was removed by passing the crude reaction
mixture through a Sep-Pak cartridge (silica) and the product was eluted
Copyright # 2003 John Wiley & Sons, Ltd.
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SYNTHESIS OF [18F] ADENOSINE ANALOG
809
with 10% methanol in dichloromethane. The protected [18F]-labeled
compounds 6b and 7b were neither purified nor characterized, how-
ever, the unlabeled products 6a and 7a were isolated and purified.
After solvent evaporation the recovered labeled compounds 6b and 7b
could be easily hydrolyzed with acid, and the desired labeled nucleosides
8b and 9b isolated by high performance liquid chromatography (HPLC)
purification using 9% MeCN. Figure 2 represents a typical purifica-
tion trace of [18F]-FAA. The uv peak at 9 min corresponds to the by-
product, 20-hydroxy-arabinoadenosine, and the radioactive peak
between 15-16 min corresponding to the desired [18F]-FAA. The
apparent split of the radioactive peak is an artifact due to the saturation
of the detector.
The radiochemical yield of this synthesis was 10-18% (d.c.) for 8b and
30-40% for 9b. The radiochemical purity was >99% with specific
activity >74 GBq/mmol. The synthesis time was 90-95 min from the
EOB. In representative syntheses, 518 MBq of labeled product 8b was
obtained starting from 6.88 GBq of [18F]-fluoride, and 3.07 GBq of 9b
was obtained from 8.54 GBq of [18F]-fluoride.
Analytical samples of 8b or 9b showed (HPLC) a single radioactive
peak that co-eluted with an authentic sample (Figure 3).
Experimental
Reagents and Instrumentation
All reagents and solvents were purchased from Aldrich Chemical Co.
(Milwaukee, WI), and used without further purification. Solid phase
Radioactivity
UV
20.5
0.0
Figure 2. Purification of [18F]-FAA: Semi-prep Column; 9% MeCN/H2O; flow
3.375 ml/min. Capacity factor = 4
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M. M. ALAUDDIN ET AL.
Radioactivity
UV
0.0
5.0
15.3
10.0
Figure 3. HPLC chromatogram of [18F]-FAA, co-injected with standard FAA:
Analytical C18 Column; 9% MeCN/H2O; flow 1.13 ml/min
extraction cartridges (Sep-Pak) were purchased from Waters Associates
(Milford, MA).
Thin layer chromatography (TLC) was performed on pre-coated
Kieselgel 60 F254 (Merck) glass plates. Proton and 19F NMR spectra
were recorded on a Brucker 360 or 500 MHz spectrometer using
tetramethylsilane as an internal reference and hexafluorobenzene as an
external reference, respectively. Mass spectra were obtained on a
Finnigan 400 mass spectrometer at the University of Minnesota using
the ammonia chemical ionization technique.
High performance liquid chromatography (HPLC) was performed on
a system using a 510 pump (Waters Associates, Milford, MA), UV
detector (Isco, Lincoln, NE) operated at 254 nm, and a radioactivity
detector with single-channel analyzer (Technical Associate, Woodland
Hills, CA) using a semi-preparative C18 reverse phase column (Alltech,
Econosil, 10 ꢁ 250 mm, Deerfield, IL) and an analytical C18 column
(Alltech, Econosil 4.6 ꢁ 250 mm). A acetonitrile/water (MeCN/H2O)
solvent system (9% MeCN) was used for purification of the
radiolabeled nucleosides and quality control analysis.
N6,30,50-Tri-methoxytrityl-20-hydroxy and N6,20,50-tri-methoxytrityl-
30-hydroxy-9-b-d-ribofuranosyladenine: 2 and 3
The title compounds were prepared following a literature method.4
Briefly, adenosine 1.35 g (5.0 mmol), dimethylaminopyridine 0.5 g
(1 equiv), and methoxytrityl chloride 5.45 g (17.6 mmol) were placed in
a dry flask under argon. Pyridine (80 ml) was added and the mixture was
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 805–814

SYNTHESIS OF [18F] ADENOSINE ANALOG
811
heated with stirring at 85–888C for 18 h when TLC showed no
significant starting material remained. Solvent was evaporated under
vacuum, the residue was dissolved in 50% EtOAc/hexane and the
solution washed with water. The organic phase was evaporated to
dryness and purified by column chromatography using 25% ethyl
acetate in hexane. Pure compound 2 and 3 were isolated in 28 and 50%
yields, respectively. 1H NMR (DMSO-D6) d: Compound 2: 8.27 (s, 1 H,
C8H), 7.78 (s, 1 H, C2H), 6.74–7.31 (m, 42 H, aromatic), 6.09 (d, 1 H,
J=7.25 Hz, 10H), 5.99 (d, 1 H, J=6.75 Hz, OH, exchangeable with
D2O), 4.88 (m, 1 H, 20H), 4.13 (d, 1 H, J=4.1 Hz, 30H), 3.71 (s, 3 H,
OMe), 3.70 (s, 3 H, OMe), 3.66 (s, 3 H, OMe), 3.09 (bs, 1 H, 40H), 2.63
(bs, 2 H, 50H).
Compound 3: 8.06 (s, 1 H, C8H), 7.65 (s, 1 H, C2H), 6.60–7.32 (m,
42 H, aromatic), 5.87 (d, 1 H, J=5.85 Hz, 10H), 4.98 (m, 2 H, 20H and
OH, exchangeable with D2O), 3.99 (bs, 1 H, 30H), 3.70 (s, 3 H, OMe),
3.69 (s, 3 H, OMe), 3.63 (s, 3 H, OMe), 3.29 (bs, 1 H, 40H), 3.08 (m, 1 H,
50aH), 2.9 (m, 1 H, 50bH).
N6,30,50-Tri-methoxytrityl-20-trifluoromethanesulfonyl- and N6,20,50-tri-
methoxytrityl-30-trifluoromethanesulfonyl-9-b-d-ribofuranosyladenine: 4
and 5
Compounds 4 and 5 were prepared by the same general method. A
representative procedure is described here. Compound 2 or 3 (0.55 g,
0.5 mmol) was dissolved in pyridine (7 ml) under argon and cooled in ice
bath. Trifluoromethanesulfonic acid anhydride (0.2 ml, 1.3 equiv) was
added and the reaction mixture was stirred for 10 min in the cold and
subsequently for 30 min at room temperature. The reaction mixture was
quenched with cold water and extracted with 50% EtOAc/hexane. The
organic extract was evaporated to dryness and purified by chromato-
graphy on a silica gel column using 30% ethyl acetate in hexane. Pure
1
compound (560 mg) was obtained in 90% yield. H NMR (DMSO-D6)
d: Compound 4: 8.38 (s, 1 H, C8H), 7.62 (s, 1 H, C2H), 6.74–7.40 (m,
42 H, aromatic), 6.62 (d, 1 H, J=4.25 Hz, 10H), 5.93 (t, 1 H, J=5.0 Hz,
20H), 4.50 (t, 1 H, J=4.3 Hz, 30H), 3.81 (bs, 1 H, 40H), 3.71 (s, 3 H,
OMe), 3.70 (s, 3 H, OMe), 3.65 (s, 3 H, OMe), 2.87–2.93 (m, 2 H, 50H).
19F NMR (d): ꢂ73.16 (s). High resolution MS: M+, Calculated
1215.4064; found 1215.4028.
Compound 5: 8.46 (s, 1 H, C8H), 6.64–7.40 (m, 43 H, aromatic and
C2H), 6.43 (d, 1 H, J=8.1 Hz, 10H), 6.04 (m, 1 H, 30H), 4.26 (d, 1 H,
Copyright # 2003 John Wiley & Sons, Ltd.
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M. M. ALAUDDIN ET AL.
J=4.1 Hz, 40H), 4.13 (m, 1 H, 20H), 3.72 (s, 3 H, OMe), 3.65 (s, 3 H,
OMe), 3.58 (s, 3 H, OMe), 2.9 (m, 2 H, 50H). 19F NMR (d): ꢂ73.58 (s).
High resolution MS: M+, Calculated 1215.4064; found 1215.4034.
N6,30,50-Tri-methoxytrityl-20-fluoro-9-b-d-arabinofuranosyl- and N6,20,50-
tri-methoxytrityl-30-fluoro-9-b-d-xylofuranosyladenine: 6a and 7a
Compound 4 or 5 (30 mg) was dissolved in dry MeCN (1.5 ml) in a
sealed v-vial. To the above solution n-Bu4NF (1 M, 30 ml) was added
and the mixture was heated for 30 min at 72–748C in a heating block.
The reaction mixture was cooled to room temperature, the solvent
evaporated in a stream of air and the residue purified on a short silica
gel column using 30% ethyl acetate in hexane. Pure compound 6 (5 mg)
or 7 (12 mg) were obtained in 20 and 50% yields, respectively. 1H NMR
(DMSO-D6) d: Compound 6a: 7.87 (s, 1 H, C2H), 7.83 (bs, 1 H, C8H),
6.74–7.40 (m, 42 H, aromatic), 6.40 (dd, 1 H, J=24 and 2.1 Hz, 10H), 4.4
(m, 1 H, 40H), 4.22–4.38 (m, 2 H, 20H and 30H), 3.71 (s, 3 H, OMe), 3.70
(s, 3 H, OMe), 3.65 (s, 3 H, OMe), 3.01–3.12 (m, 2 H, 50H). 19F NMR
(d): ꢂ193.95–194.18 (m). High resolution MS: M+H, Calculated
1085.45276; found 1085.45402.
Compound 7a: 8.10 (s, 1 H, C8H), 7.65 (s, 1 H, C2H), 6.64–7.40 (m,
42 H, aromatic), 6.41 (s, 1 H, 10H), 4.39, (d, J=14.0 Hz, 20H, 4.24 (dt,
J=3.31 and 6.0 Hz, 40H), 3.82 (d, J=50.6 Hz, 1 H, 30H), 3.78 (s, 6 H,
OMe), 3.68 (s, 3 H, OMe), 3.42–3.45 (m, 1 H, 50aH), 3.28-3.30 (m, 1 H,
50bH). 19F NMR (d):ꢂ202.57, (dq). High resolution MS: M+,
Calculated 1085.45276; found 1085.44915.
20-Fluoro-9-b-d-arabinofuranosyladenine and 30-fluoro-9-b-d-xylofurano-
syladenine: 8a and 9a
Unlabeled compounds 8a and 9a were prepared by acid hydrolysis of
the protecting groups from the respective methoxytrityl derivatives 6a
and 7a in 80% yields, following the method reported earlier.20 The
products were characterized by 1H NMR spectroscopy, and found to be
consistent with the literature.12,17
20-[18F]-Fluoro-9-b-d-arabinofuranosyladenine and 30-[18F]-fluoro-9-b-
d-xylofuranosyladenine: 8b and 9b
[18F]-Labeled compounds were prepared as follows: Aqueous [18F]fluor-
ide (0.4 ml) was added to a solution of n-Bu4NHCO3 (50 ml, 4% by wt.)
Copyright # 2003 John Wiley & Sons, Ltd.
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SYNTHESIS OF [18F] ADENOSINE ANALOG
813
in a v-vial and the solution evaporated azeotropically to dryness
with acetonitrile (1.0 ml) at 72–74oC under a stream of argon. To
the dry residue, n-Bu4N18F, a solution of either 4 or 5 (1.5–2.0 mg,
1.2–1.6 mmol) in dry acetonitrile (0.5 ml) was added, and the reaction
mixture was heated at 72–74oC for 30 min. The reaction mixture was
cooled to room temperature, passed through a Sep-Pak cartridge (silica
gel), and eluted with 10% methanol in dichloromethane (2.5 ml). After
evaporation of the solvent with a stream of argon at ꢀ738C, the residue
was dissolved in methanol. 2N Hydrochloric acid solution in methanol
(0.1 ml) was added and the mixture was refluxed for 5 min.The crude
mixture was neutralized with 1N bicarbonate (0.2 ml), diluted with
HPLC solvent (1 ml) and purified by HPLC. The desired product was
isolated and the solvent evaporated under vacuum. The residue was re-
dissolved in sterile saline and the solution filtered through a Millex-GS
filter (Millipore Corp., Bedford, MA) into a sterile empty vial. The
product was co-injected with an authentic unlabeled sample onto an
analytical column to confirm its identity.
Conclusion
The syntheses of adenosine analogues, 20-deoxy-20-[18F]fluoro-9-b-d-
arabinofuranosyladenine ([18F]-FAA) and 30-deoxy-30-[18F]fluoro-9-b-
d-xylofuranosyladenine ([18F]-FXA) have been achieved. Radiochemi-
cal yield of [18F]-FXA and [18F]-FAA were 30–40 and 10–18% (d. c.),
respectively, with specific activities greater than 74 GBq/mmol. This
direct fluorination method is convenient, produces sufficient amounts of
activity, and is suitable for routine production for animal and human
studies with PET.
Acknowledgements
The authors wish to thank Mr. Alan Kershaw for assisting with
instrumentation on NMR spectroscopy. This work was supported by
the National Cancer Institute Grant CA 72896.
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