D. Parker, I. Kuprov et al.
17O NMR spectroscopy: Variable-temperature 17O NMR spectra were re-
corded by using a JEOL ECP-400 (9.4 T) spectrometer equipped with a
5 mm probe and a standard temperature control unit. Aqueous solutions
of the complexes (ꢄ20–30 mm) containing 2.8% of the 17O isotope
(Cambridge Isotope) were used. The observed transverse relaxation rates
subsequently left to boil under reflux for 3 h. Once cooled, the solvent
was removed under reduced pressure and the complex purified by alumi-
na chromatography (eluent: gradient, (5% MeOH/CH2Cl2!20%
MeOH/CH2Cl2) (0.07 g, 77%). 19F NMR (376 MHz, D2O): d=ꢂ62.8 ppm
(CF3); MS (ESI): m/z: 701.3 [MꢂH]ꢂ, 725.2 [M+Na]+, 741.2 [M+K]+;
HRMS (ESI): m/z calcd for C23H28O7N5F3155Gd: 698.1172; found:
698.1169.
(R2obs) were calculated from the signal width at half height (Dn1/2): Ro2bs
pꢄDn1/2
=
.
The following complexes were prepared as described for [L2Gd]:
19F MRI: Fluorine-19 imaging data were collected by using a 7 T Varian
Unity Inova micro-imaging system (Varian Inc., Palo Alto, California,
USA) equipped with broadband capability, actively shielded gradients
(180 ms rise time to 400 mT/m) and a purpose-built two-turn circular 19F
surface coil (i.d. 12 mm, 281 MHz 19F frequency), which was used for
both excitation and reception of the signal. Aqueous samples of the
[Y(L3)] and [Er(L3)] complexes (200ml, 4 mm) were prepared, placed in
5 mm NMR tubes and positioned on the axis of the coil. Conventional
proton MRI was used to localise and shim the samples based on the
proton water signal. Following 19F pulse calibration, R1 values were deter-
mined for each sample by using a saturation recovery sequence (35 ms
pulse, 22 experiments, 128 scans) to calculate Ernst angle pulses for opti-
mal imaging sensitivity. Fluorine MR images were then collected by
using a RF spoiled, gradient echo imaging sequence with a repetition
time (TR) of 20 ms, an echo time of (TE) 1.56 ms, a 0.5 ms sinc pulse for
selection of a 6 mm thick slice, a 48ꢄ48 mm field of view, a 32ꢄ32
matrix and a 50 kHz receiver bandwidth. Relative imaging sensitivity for
the two complexes was determined by region-of-interest analysis of the
signal-to-noise ratio in each image.
[Ho(L2)]: 1H NMR (200 MHz, D2O, pD =5.5) partial: d=ꢂ93.5, ꢂ79.3,
ꢂ69.1, ꢂ58.23, ꢂ47.4, ꢂ36.0, ꢂ32.1, ꢂ12.4, ꢂ1.3, ꢂ1.1, 4.6, 7.6, 11.0, 12.9,
13.9, 14.9, 18.7, 23.0, 28.9, 44.2, 55.3, 86.3, 92.5 ppm; 19F NMR (376 MHz,
D2O): d=ꢂ64.2 (CF3, major species), ꢂ62.7, ꢂ62.1, ꢂ60.5, ꢂ57.9, ꢂ56.2,
ꢂ54.2, ꢂ50.8 ppm (CF3, minor species); MS (ESI): m/z: 732.1 [M+Na]+,
708.2 [MꢂH]ꢂ; HRMS (ESI); m/z calcd for C23H28O7N5F3165Ho:
708.1250; found: 708.1250.
[Tm(L2)]: 1H NMR (500 MHz, D2O, pD =5.5) partial: d=ꢂ246.3,
ꢂ215.5, ꢂ208.7, ꢂ150.7, ꢂ142.6, ꢂ119.6, ꢂ111.4, ꢂ92.6, ꢂ80.5, ꢂ71.9,
ꢂ25.3, ꢂ18.3, 18.9, 24.6, 35.9, 37.6, 40.0, 45.7, 49.3, 64.4, 79.3, 320.6, 325.7,
340.2, 380.0 ppm; 19F NMR (188 MHz, D2O): d=ꢂ75.9 (CF3, major spe-
cies), ꢂ88.1, ꢂ87.3, ꢂ80.77, ꢂ77.4, ꢂ66.8, ꢂ49.5 ppm (CF3, minor spe-
cies); MS (ESI): m/z: 736.2 [M+Na]+, 712.2 [MꢂH]ꢂ; HRMS (ESI): m/z
calcd for C23H28O7N5F3169Tm: 712.1289; found: 708.1286.
[Er(L2)]: 1H NMR (500 MHz, D2O, pD =5.5) partial: d=ꢂ101.7, ꢂ89.9,
ꢂ84.4, ꢂ80.4, ꢂ71.4, ꢂ66.5, ꢂ57.6, ꢂ56.0, ꢂ38.1, ꢂ32.1, ꢂ29.5, ꢂ8.0,
ꢂ2.9, 12.8, 14.6, 15.9, 18.7, 21.9, 33.4, 128.9, 136.4, 145.0, 153.9,
164.0 ppm; 19F NMR (188 MHz, D2O): d=ꢂ64.8 (CF3, major species),
ꢂ76.2, ꢂ70.4, ꢂ69.2, ꢂ62.7, ꢂ61.8, ꢂ58.3, ꢂ54.8 ppm (CF3, minor spe-
cies); MS (ESI): m/z: 709.3 [MꢂH]ꢂ, 751.2 [M+K]+; HRMS (ESI): m/z
calcd for C23H28O7N5166ErF3: 709.1249; found: 709.1240.
Preparation of L2 and its lanthanide
ACHTUNGTREN(NGNU III) complexes
ACHTUNGTRENNUNG{4,7-Bis(tert-butoxycarbonylmethyl)-10-[(2-trifluoromethylphenylcarba-
moyl)methyl]-1,4,7,10-tetraazacyclododec-1-yl}acetic acid tert-butyl ester:
2-Chloro-N-(2-trifluoromethylphenyl)acetamide (0.167 g, 0.91 mmol) was
[Tb(L2)]: 19F NMR (188 MHz, D2O): d=ꢂ51.9 (CF3, major species),
ꢂ60.2, ꢂ44.9, ꢂ39.8, ꢂ36.7 ppm (CF3, minor species); MS (ESI): m/z:
742.1 [M+Na]+, 702.2 [MꢂH]ꢂ; HRMS (ESI): m/z calcd for
added to
a stirred solution of 1,4,7-tris(tert-butoxycarbonylmethyl)-
1,4,7,10-tetraazacyclododecane (0.30 g, 0.58 mmol), KI (ꢄ10 mg, as cata-
lyst) and K2CO3 (0.80 g, 0.58 mmol) in anhydrous CH3CN (20 mL) at
858C under argon. The mixture was left to boil under reflux for 15 h, and
gave a pale orange solution and a white precipitate. The precipitate was
removed by filtration and the residue washed with CH2Cl2 (2ꢄ30 mL).
The solvent was removed under reduced pressure and the resulting oil
was purified by silica gel column chromatography (eluent: gradient,
100% CH2Cl2 !5% CH3OH/CH2Cl2) to give a pale brown oil (0.25 g,
C23H28O7N5F3159Tb: 702.1198; found: 702.1189; t
2.78 ms; qTb =0.75 (ꢁ0.1).
ACHUTGTNRNE(NUG H2O) 1.76 ms, ttACHTUNGTRENNUNG(D2O)
[Y(L2)]: 19F NMR (188 MHz, D2O): d=ꢂ62.0 ppm; MS (ESI): m/z: 656.2
[M+Na]+, 632.2
[MꢂH]ꢂ;
HRMS
(ESI):
m/z
calcd
for
C23H29F3N5O7Na89Y: 656.0969; found: 656.0970.
1
61%). H NMR (200 MHz, CDCl3): d=1.43, (27H; CH3), 2.02–3.66 (very
br, 24H; CH2 ring and CH2CO), 7.28 (d, J=8.0 Hz, 1H; ArH), 7.43 (d,
J=8.0, 1H; ArH), 7.56 (m, 2H; ArH), 9.97 ppm (s, 1H; NHCO);
13C NMR (125 MHz, CDCl3): d=28.11 (CH3), 49.04 (CH2 ring), 53.68
Acknowledgements
1
(CH2 ring), 55.89 (CH2CO), 56.72 (CH2CO), 82.13 (CCH3), 123.84 (q, J-
2
(C,F)=274 Hz, CF3), 126.13 (q, J
E
N
We thank ESF COST Action D38 and the EC networks of excellence
EMIL and DiMI for support. This work was supported by the EPSRC
(EP/F065205/1, EP/H003789/1) and the NSCCS.
5 Hz, Ar), 129.40 (Ar), 132.35 (Ar), 134.50 (Ar), 135.58 (Ar), 172.29
(CO), 172.73 (CO), 173.16 ppm (CO); 19F NMR (200 MHz, CDCl3): d=
ꢂ60.80 ppm (CF3); MS (ESI): m/z: 716.3 [M+H]+; HRMS (ESI): m/z
calcd for C35H56O7N5F3Na: 738.4024; found: 738.4026.
ACHTUNGTRENNUNG{4,7-Bis(carboxymethyl)-10-[(2-trifluoromethylphenylcarbamoyl)methyl]-
607; M. V. Knopp, F. L. Giesel, H. Marcos, H. von-Tengg-Kobligk,
[2] J. A. Bergwerff, A. A. Lysova, L. Espinosa-Alonso, I. V. Koptyug,
B. M. Weckhuysen, Chem. Eur. J. 2009, 15, 2363; I. V. Koptyug,
[3] S. J. Karlik, R. Bartha, K. Kennedy, R. Chhem, AJR 2007, 189, 105;
F. J. Ruhli, H. von Waldburg, S. Nielles-Vallespin, T. Boni, P. Speier,
H-J. Weinmann, W. Ebert, B. Misselwitz, H. Schmitt-Willich, Eur. J.
Radiol. 2003, 46, 33.
1,4,7,10-tetraazacyclododec-1-yl}acetic acid: Trifluoroacetic acid (3 mL)
was added to a solution of {4,7-bis(tert-butoxycarbonylmethyl)-10-[(2-tri-
fluoromethylphenylcarbamoyl)methyl]-1,4,7,10-tetraazacyclododec-1-yl}-
acetic acid tert-butyl ester (0.23 g, 0.32 mmol) in CH2Cl2 (5 mL). The so-
lution was stirred at RT for 2 h. The solvent was removed under reduced
pressure and the resulting solid repeatedly washed with CH2Cl2 (5ꢄ
5 mL) to give the product as a trifluoroacetate salt. The residue was dis-
solved in H2O (5 mL) and left to stir for 2 h with anion exchange resin
(DOWEX 1ꢄ8 200–400 Mesh, pre-treated with 1m HCl) in water to give
the chloride salt. The resin was removed by filtration and the solvent re-
moved under reduced pressure to give a light yellow oil (0.13 g, 74%).
1H NMR (400 MHz, CDCl3): d=3.09–3.92 (very br, 16H; CH2 ring),
7.25–7.94 ppm (brm, 4H; ArH); 19F NMR (200 MHz, CDCl3): d=
ꢂ62.31 ppm (CF3); MS (ES+) m/z: 570.4 [M+Na]+.
[Gd(L2)]:
moyl)methyl]-1,4,7,10-tetraazacyclododec-1-yl}acetic
0.13 mmol) was dissolved in H2O (3 mL) and the pH adjusted to ꢄ6.
[Gd(OAc)3] (0.05 g, 0.14 mmol) was added to the solution, which was
{4,7-Bis(carboxymethyl)-10-[(2-trifluoromethylphenylcarba-
acid (0.07 g,
[5] A. E. Merbach, E. Toth, E. eds. ꢅ The Chemistry of Contrast Agents
in Medical Magnetic Resonance Imaging’, Wiley, New York, 2001; P.
ACHTUNGTRENNUNG
146
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 134 – 148