F. Zhuravlev et al.
0.1m NaOH at 1.0 mLminꢀ1. Radio-TLC was performed with a Raytest
MiniGita TLC scanner.
Fluorination: general procedure: The substrate (0.18 mmol), P2Et·HF
(1.5 equiv), and naphthalene (15 mg) were added to a 1 mL volumetric
flask and the solvent (tmeu/Mes, 46:54) was added to the mark. The reac-
tion mixture was transferred to a glass pressure tube and heated at
1208C. The initial and final concentrations were determined by GC fol-
lowing the GC response factor determination protocol.
Materials and apparatus for [18F]HF production and radiofluorination:
The PE, glassy carbon (SIGRADUR) reaction vials, and glass pressure
tubes were purchased from Kartell (Italy), HTW Hochtemperatur-Werk-
stoffe GmbH (Germany), and Aldrich, respectively. The PE tubing
(I.D.=3 mm, O.D.=4.5 mm) was purchased from Buch & Holm and
proved superior to natural rubber Suprene (New Age Industries) in
terms of chemical resistance and [18F]fluoride absorption, and was used
throughout. The stoppers were made of either PE or Teflon and fitted to
the tubing via appropriately sized orifices; no valves were used. All radi-
ochemistry was performed without automation equipment.
General procedure for [18F]HF generation, transfer, and the synthesis of
R [18F]HF: [18F]Fluoride (cyclotron target wash, 1 mL, 15–1100 MBq)
Pn ·ACHTNUTGRNUEGN
was added to a reaction vial (PE or glassy carbon) containing H2SO4
(98%, 5 mL). The vial was heated for 30 min at 808C in an ultrasound
bath while being irradiated at 35 kHz. [18F]HF was carried by an argon
R
flow (300–400 sccminꢀ1) to a receiving vial (glassy carbon) containing Pn
(30 mmol) in toluene or MeCN (2 mL) at 08C. The [18F]HF transfer yield
Computational methods: The DFT calculations were performed by using
the Gaussian 09 suite of programs.[34] All structures were verified to be
minima on the potential energy surfaces by vibrational analyses. The op-
timized structures are given in the Supporting Information as .xyz files.
The electron densities were visualized by using VESTA.[35]
was 16–82% measured by the dose calibrator.
Radiosynthesis of 2-[18F]fluoro-2-deoxyglucose ([18F]FDG): The content
Et [18F]HF in 2 mL MeCN) was transferred to a
of the receiving vial (P2 ·ACHTUNTGNRUEGN
glass pressure tube containing mannose triflate (25 mg, 52 mmol) through
a stainless steel cannula and the reaction was carried out at 1208C for
20 min. The reaction mixture was added to a C18 (Waters) cartridge pre-
conditioned with EtOH and H2O. NaOH (0.70 mL, 2n) was added to the
column and the tetraacetate intermediate was hydrolyzed at room tem-
perature for 5 min. The hydrolyzed product was eluted using H2O
(2 mL). The decay-corrected radiochemical yield was 82%; the radio-
General procedure for the synthesis of phosphazene hydrofluorides,
PnR·HF: A flame-dried 50 mL round-bottomed flask was charged with
R
the corresponding phosphazene base Pn (19.69 mmol). The flask was
connected to a vacuum line, evacuated, and Et2O (20 mL) was vacuum-
transferred onto the liquid. The flask was then backfilled with Ar, fitted
with a rubber septum, and Et3N·3HF (1.061 g, 6.581 mmol) was added.
The reaction mixture was stirred for 1 h, and the product was either fil-
tered under partial vacuum using a double-ended frit or removed by a sy-
ringe (P2Et·HF).
chemical purity was 98%.
Radiosynthesis of [18F]NpEtF: The content of the receiving vial (P2
Et
·
[18F]HF in 2 mL toluene) was transferred to a reaction vial (glassy carbon
or a glass pressure tube) containing the substrate NpEtOMs (Np: naph-
thalene, Ms: methanesulfonyl), NpEtOTs (Ts: p-toluenesulfonyl), NpE-
tOTf, NpEtCl, NpEtBr, or NpEtI (52 mmol). [18F] fluorination was car-
ried out at 1208C for 20 min and [18F] fluorinated product was purified
by passing through a Silica Plus (Waters) cartridge. The corresponding
radiochemical purities determined by radio-TLC were higher than 99%.
(tert-Butylimino)tris(dimethylamino)phosphonium
hydrofluoride
(P1tBu·HF): A white solid (54%). 1H NMR (500 MHz, [D6]benzene): d=
2.47 (d, J=9.5 Hz, 18H), 1.25 ppm (s, 9H); 13C NMR (126 MHz,
[D6]benzene): d=32.01 (s, 3C), 37.85 (d, J=3.6 Hz, 6C), 51.91 ppm (s,
1C); 31P NMR (202 MHz, [D6]benzene): d=35.40 ppm (s); 19F NMR
(235 MHz, [D6]benzene): d=ꢀ151.18 ppm (br s); MS: m/z: (P1tBuH+)
235.2 (100%), 236.0 (4%).
Automated radiochemical synthesis of 3-[18F]fluoro-1,2-di-hexadecylgly-
cerol: [18F]fluoride was recovered from [18O]-enriched water on a QMA
SepPak cartridge preconditioned with K2CO3. The activity was eluted
with 50% acetonitrile in water (0.6 mL) containing K2CO3 (7.0 mg,
50.8 mmol) and Kryptofix 2.2.2 (22.0 mg, 58.5 mmol). The eluate was
transferred to a ROTEM reactor vial and the acetonitrile/water solution
was evaporated under reduced pressure (60 mbar) by using a series of
temperature jumps and a helium stream (100 followed by 200 mLminꢀ1).
Residual water was removed by azeotropic evaporation with acetonitrile
(3ꢂ0.3 mL). MsO-1,2-di-hexadecylglycerol (5 mg, 8.0 mmol) was added in
toluene (0.5 mL) and the solvent was evaporated. Dry DMSO (1 mL)
was added and the mixture was allowed to react for 20 min at 1658C.
The reaction mixture was analyzed by radio-TLC, which showed the
target compound was obtained with a radiochemical conversion of 2.8%.
(1,1,3,3-Tetramethylbutylimino)tris(dimethylamino)phosphonium hydro-
fluoride (P1tOct·HF):
A
white solid (48%). 1H NMR (500 MHz,
[D6]benzene): d=1.04 (s, 9H), 1.28 (s, 6H), 1.64 (s, 2H), 2.50 ppm (d, J=
9.8 Hz, 18H); 13C NMR (126 MHz, [D6]benzene): d=30.69 (br s, 1C),
31.37 (s, 1C), 31.72 (s, 3C), 37.39 (d, J=4.5 Hz, 6C), 55.98 (brs, 2C),
56.68 ppm (br s, 1C); 31P NMR (202 MHz, [D6]benzene): d=34.87 ppm
(s); 19F NMR (235 MHz, [D6]benzene): d=ꢀ152.61 ppm (brs); MS: m/z:
(P1tOctH+) 291.2 (100%), 292.2 (17%).
TetramethylACHTUNGTRENNUNG[tris(dimethylamino)phosphoranylidene]phosphorictriamid-
Et-iminium hydrofluoride (P2Et·HF): A yellowish viscous oil (77%).
1H NMR (500 MHz, [D6]benzene): d=1.43 (td, J=7.2, 0.6 Hz, 3H), 2.41
(d, J=10.4 Hz, 18H), 2.59 (d, J=10.4 Hz, 12H), 2.89–2.98 ppm (m, 2H);
13C NMR (126 MHz, [D6]benzene): d=17.95 (d, J=9.1 Hz, 1C), 36.81 (s,
1C) 37.15 (d, J=4.5 Hz, 6C), 37.57 (d, J=4.5 Hz, 4C); 31P NMR
(202 MHz, [D6]benzene): d=17.66, 18.42 ppm (AB quartet); 19F NMR
(235 MHz, [D6]benzene): d=ꢀ150.38 ppm (brs); MS: m/z: (P2EtH+)
340.3 (100%), 341.2 (18%).
Acknowledgements
1-tert-Butyl-4,4,4-tris(dimethylamino)-2,2-bis-
This research was supported by the Hevesy Laboratory. We thank Palle
Rasmussen and Michael Jensen for discussions.
ACHTUNGTRENNUNG
[tris(dimethylamino)phosphoranylidenamino]-2L5,4L5-catenadiphospha-
zenium hydrofluoride (P4tBu·HF):
A
white solid (31%). 1H NMR
(500 MHz, [D6]benzene): d=1.34 (d, J=0.6 Hz, 9H), 2.53 ppm (d, J=
10.1 Hz, 54H); 13C NMR (126 MHz, [D6]benzene): d=32.27 (d, J=
5.5 Hz, 3C), 37.69 (d, J=4.5 Hz, 18C), 50.80 ppm (d, J=3.6 Hz, 1C);
31P NMR (202 MHz, [D6]benzene): d=ꢀ23.63 (q, J=49.8 Hz, 1P),
12.31 ppm (d, J=49.8 Hz, 1P); 19F NMR (235 MHz, [D6]benzene): d=
ꢀ153.20 ppm (d, J=119.8 Hz); MS: m/z: (P4tBuH+) 634.4 (100%), 635.3
(20%), 636.3 (4%).
[3] O. Jacobson, X. Chen, Curr. Top. Med. Chem. 2010, 10, 1048–1059.
[4] J. Talbot, Y. Petegnief, K. Kerrou, F. Montravers, D. Grahek, N.
b) H. H. Coenen, P. H. Elsinga, R. Iwata, M. R. Kilbourn, M. R. A.
Fluorination: GC response factor determination: The substrate
(0.18 mmol) and naphthalene (internal GC standard, 15 mg) were added
to a 1 mL volumetric flask and solvent (tmeu/Mes, 46:54) was added to
the mark. A portion (100 mL) of the solution was withdrawn and trans-
ferred to a 1 mL volumetric flask. n-Hexane was added to the mark and
the solution was filtered before injection. The experiment was carried out
in triplicate.
7804
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7796 – 7805