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140.2, 140.4, 166.0, 173.2, 175.3 ppm; HRMS (ESI): m/z calcd for
[C37H47N6O8Pꢀ2H+K]ꢀ: 771.26790; found: 771.26539.
the array of functionalities prone to metal coordination on the
adjacent DOTA cage. Subsequent labeling with radionuclides
occurs without problem. The prepared RuII(arene) complex
shows favorable stability and solubility profiles in biologically
relevant media. Pleasingly, it shows in vitro cytotoxicity in line
with that expected for this type of metallodrug and, just as im-
portantly, it is nontoxic to the organism as a whole. The radio-
labeled complex was tracked in the body to provide informa-
tion about drug uptake, biodistribution, and excretion. This
ability to obtain a big-picture idea of the location of the pre-
sented theranostic sets this work apart from the rest of the
field. As metallotherapeutics develop, a thorough understand-
ing of how biological activity is achieved will be imperative to
designing and improving future metallodrugs. Thus, we be-
lieve strategies such as that shown here will be essential to the
further development of this research field.
Dichloro[(h6-p-cymene)(2,2’,2’’-(10-(2-((2-(4-(diphenylphosphino)-
benzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclodode-
cane-1,4,7-triyl)triacetic acid)-ruthenium(II)] (4): Compound
1
(100 mg, 0.136 mmol) and [RuCl2(p-cymene)]2 (41.6 mg,
0.068 mmol) were dissolved in freshly distilled CH2Cl2 (3.5 mL)
under argon. The solution was stirred at room temperature for
19 h. The solution was concentrated under reduced pressure to
a volume of 1 mL. Freshly distilled pentane (5 mL) was added to
precipitate the product as an orange powder. The powder was fil-
trated under an inert atmosphere and washed with degassed ace-
tone (2ꢄ2 mL) to afford the desired product as an orange-red
solid (0.106 g, 78%). 1H NMR (300.13 MHz, D2O): d=1.09 (d, 6H,
3J=6.9 Hz; CHMe2), 1.87 (s, 3H; Me of p-cymene), 2.82 (brm, 1H;
3
CHMe2 (p-cymene)), 1.95–3.87 (brm, 24H; cyclen), 5.19 (d, 2H, J=
5.9 Hz; CHAr of p-cymene), 5.33 (d, 2H, 3J=5.9 Hz; CHAr of p-
cymene), 7.45–7.96 ppm (m, 14H; CHar), NH signal not observed;
31P{1H} NMR (121.5 MHz, CDCl3): d=24.9 ppm; 13C{1H} NMR
(75 MHz, CDCl3): d=124.3–128.2 (m), 58.2 (s), 52.6 (m), 48.4 (m),
30.3 (s), 22.4 (s), 22.0 (m), 18.4 (s), 17.9 ppm (m); HRMS (ESI): m/z
calcd for [C47H61Cl2N6O8PRuꢀ2H+K]ꢀ: 1077.21951; found:
1077.21750.
Experimental Section
Synthetic procedures
General information: All solvents were dried and distilled under
argon before use. The p-cymene–ruthenium dimer was obtained
by following the procedure of Bennett and Smith.[10] All other re-
agents were commercially available and used as received (DOTA-
derivative A was provided by Chematech). The analyses were per-
formed at the “Plateforme d’Analyses Chimiques et de Synthꢂse
Molꢀculaire de l’Universitꢀ de Bourgogne”. The identity and purity
(ꢂ95%) of the complexes were unambiguously established by
using high-resolution mass spectrometry and multinuclear NMR
spectroscopy. The exact masses of the complexes were obtained
on a Thermo LTQ Orbitrap XL ESI-MS mass spectrometer. 1H
(300.13, 500.13, or 600.23 MHz), 13C (75.5, 125.8, or 150.9 MHz), and
31P (121.5, 202.5, or 242.9 MHz) NMR spectra were recorded on
Bruker 300 Avance III, Bruker 500 Avance III, or Bruker 600 Avance II
spectrometers. Chemical shifts (d) are quoted in parts per million
Dichloro[(h6-p-cymene)(samarium-2,2’,2’’-(10-(2-((2-(4-(diphenyl-
phosphino)benzamido)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraa-
zacyclododecane-1,4,7-triyl)triacetate)-ruthenium(II)]
(5):
Sm(OTf)3 (22 mg, 0.038 mmol) dissolved in dry MeCN (10 mL) was
added to a solution of 4 (35 mg, 0.032 mmol) in dry MeCN (10 mL).
After 36 h, the resulting mixture was filtered and the solid was
washed with dry n-hexane. The desired product was obtained as
a bright orange powder after having been dried under vacuum
(32 mg, 73%). 1H NMR (300.13 MHz, DMSO): d=0.94 (d, 6H, 3J=
6.9 Hz; CHMe2),1.76 (s, 3H; Me of p-cymene), 1.05–3.25 (brm, 25H;
cyclen + CHMe2 (p-cymene)), 5.25 (d, 2H, 3J=5.4 Hz; CHar of p-
3
cymene), 5.32 (d, 2H, J=5.4 Hz; CHAr of p-cymene), 7.05–7.95(m,
14H; CHAr), 8.85 ppm (brs, 2H; HNCH2CH2NH); 31P{1H} NMR
(121.5 MHz, CDCl3): d=24.3 ppm; HRMS (ESI): m/z calcd for
[C48H61Cl2N6O8PRuSmꢀCl]ꢀ: 1154.19830; found: 1154.20347.
1
relative to tetramethylsilane (TMS; H and 13C), by using the residu-
al protonated solvent (1H) or the deuterated solvent (13C) as an in-
ternal standard. Alternatively, 85% H3PO4 (31P) was used as an ex-
ternal standard. The coupling constants are reported in Hertz. All
aromatic positions (ortho, meta, and para) are defined by using
phosphorus as the main group element. Infrared spectra were re-
corded on a Bruker Vector 22 FT-IR spectrophotometer (transmis-
sion mode) with 1% sample mixed with potassium bromide. The
melting points were determined on a BꢃCHI Melting Point B-545
instrument.
Synthesis of radiolabeled complexes
153Sm (T1/2 =46.8 h; bꢀ =0.67 MeV, 34%; 0.71 MeV, 44%; 0.81 MeV,
21%; g=0.103 MeV, 38%) was produced by irradiating isotopically
enriched 152Sm(NO3)3 at the ITN Portuguese Research Reactor. The
nitrate targets were prepared by dissolving 152Sm2O3 with HNO3
and then evaporating to dryness. Irradiation was performed at
1 MW, thermal neutron flux of ~0.8ꢄ1013 neutroncmꢀ2 sꢀ1, and epi-
thermal neutron flux of ~2ꢄ1011 neutroncmꢀ2 sꢀ1. The specific ac-
tivity after 2 h of irradiation and at end of bombardment was
185 MBqmgꢀ1 for 153Sm. After irradiation, the targets were recon-
stituted with water to produce stock solutions for the synthesis of
the complexes. The 153Sm activity was measured in an ionization
chamber (Aloka Curiemeter IGC-3).
2,2’,2’’-(10-(2-((2-(4-(diphenylphosphino)benzamido)ethyl)ami-
no)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triace-
tic acid (1): Compound 3 (0.6 g, 1.34 mmol) was dissolved in fresh-
ly distilled MeCN (30 mL) under argon. Diisopropylethylamine
(DIPEA; 2.3 mL, 13.44 mmol) was then added. The reaction was
stirred at room temperature for 1 h. Compound
2 (0.54 g,
1.34 mmol) was added and the solution was stirred at room tem-
perature overnight. After evaporation of the solvent, the resultant
solid was purified by silica gel column chromatography (eluent:
CHCl3/MeOH/25% NH3·H2O (6:3:1)) to afford the desired product as
The complex [153Sm]5 was prepared by dissolving 4 (4 mg) in
MeOH or DMSO (90 mL) and then adding water (500 mL) and an ad-
equate amount of 153Sm solution (30 mL) to achieve a 1:2 metal/
ligand molar ratio. The final pH value was ~5.5 and the final ligand
concentration was 6.3 mm. The radiolabeling efficiency and reac-
tion kinetics of the radiocomplexes were determined by RP-HPLC
and by ITLC-SG analysis by using silica gel (ITLC-SG) strips (Poly-
gram, Macherey–Nagel) with MeOH/H2O/conc. aq. NH3 (2:4:0.2)
and MeOH/6m HCl (95:5) as the eluents. The radioactive distribu-
1
a white solid (0.56 g, 57%). H NMR (300 MHz, MeOD): d=2.0–3.56
(brm, 24H; cyclen), 7.29–7.84 ppm (m, 14H; CHar), NH signal not
observed; 31P{1H} NMR (121.5 MHz, CDCl3): d=ꢀ5.7 ppm;
13C{1H} NMR (75.5 MHz, D2O): d=48.3, 52.5, 56.4, 59.6, 127.6, 127.7,
128.8, 128.9, 129.2, 132.6, 132.9, 133.2, 133.5, 134.7, 136.0, 136.1,
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1567 – 1573 1571