A self-assembled complex with a Titanium(IV) catecholate core as a potential bimodal contrast agent

Article abstract of DOI:10.1002/chem.201101413

A ditopic chelating ligand (H₆4) that bears catechol and diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) has been designed and shown to specifically bind lanthanide(III) ions at the DTPA core ([Ln(H ₂4)(H₂O)]^-

Full text of DOI:10.1002/chem.201101413

FULL PAPER
DOI: 10.1002/chem.201101413
A Self-Assembled Complex with a Titanium(IV) Catecholate Core as a
Potential Bimodal Contrast Agent
Geert Dehaen,[a] Svetlana V. Eliseeva,[a] Kristof Kimpe,[a] Sophie Laurent,[b]
Luce Vander Elst,[b] Robert N. Muller,[b, c] Wim Dehaen,[a] Koen Binnemans,[a] and
Tatjana N. Parac-Vogt*[a]
Abstract: A ditopic chelating ligand
(H64) that bears catechol and diethyl-
onance imaging (MRI) agent has been
evaluated. Nuclear magnetic relaxation
dispersion (NMRD) measurements for
plex to bind to human serum albumin
(HSA) was also examined by relaxo-
metric measurements. In addition,
upon UV irradiation the [(Gd4)3Ti-
ACHTUNGTRENNUNG
the [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ complex have
G
demonstrated an enhanced r1 relaxivity
that corresponds to 36.9 sꢀ1 mmꢀ1 per
metallostar molecule at 20 MHz and
310 K, which is a result of a decreased
tumbling rate. The ability of the com-
(H2O)3]5ꢀ complex exhibits broad-band
ACHTUNGTRENNUNG
A
U
green emission in the range 400–
750 nm with a maximum at 490 nm.
Taking into account the high relaxivity
and luminescence properties, the
ACHTUNGTRENNUNG
G
[(Gd4)3TiACTHNGUTERNNUG
(H2O)3]5ꢀ complex is a good
lead compound for the development of
efficient bimodal contrast agents.
Keywords: gadolinium
nides · magnetic resonance imaging ·
self-assembly · titanium
·
lantha-
ACHTUNGTRENNUNG
cacy of the metallostar complex as a
potential bimodal optical/magnetic res-
Introduction
of its relaxivity, r1, which is defined as the longitudinal relax-
ation rate in sꢀ1 measured in a solution of GdIII with a con-
centration of 1 mm. The currently used contrast agents have
relaxivities of about 4 to 5 mmꢀ1 sꢀ1, but according to the So-
lomon–Bloembergen theory, relaxivities up to 100 mmꢀ1 sꢀ1
can be achieved.[5] The water proton relaxivity is mainly
characterized by four parameters: the number of water mol-
ecules in the first coordination sphere of GdIII (q), the ex-
change rate for these water molecules (tMꢀ1), the relaxation
behavior of the electron spin of GdIII (tS1), and the rotation-
al diffusion of the complex in solution (tR).[6] One of the
ways to achieve a higher proton relaxivity is to slow down
the rotational motion of the contrast agent. This can be
achieved by binding the GdIII complex by means of covalent
or noncovalent bonds to a large macromolecule such as a
polymer or a protein.[7–9] Another approach is achieved by
incorporating the GdIII complex into slowly tumbling supra-
molecular assemblies such as micelles or liposomes.[10–12]
Recently, Livramento et al.[13–15] presented a compound
they named metallostar, which is a self-assembled GdIII che-
late around a central d-block metal ion. The concept of met-
allostars as potential MRI contrast agents was initially de-
scribed by Jacques and Desreux.[16,17] Because of the higher
molecular weight of the metallostar compounds, higher
proton relaxivities may be obtained after formation of a
supramolecular polymetallic complex. Furthermore, these
compounds show a lower degree of internal flexibility than
GdIII chelates in micelles. The higher rigidity and the multi-
ple GdIII ions within one molecule could also reduce the re-
Over the last three decades, magnetic resonance imaging
(MRI) has gained a great importance and is currently rou-
tinely used as a diagnostic tool in various medical proce-
dures. Since its introduction, a continuous interest has
grown in the development of more efficient, more tissue-
specific, and recently, more responsive contrast agents.[1,2]
Complexes of gadoliniumACTHUNRGTNE(NUG III) ions act as contrast agents for
T1-weighted MR images because they decrease the longitu-
dinal relaxation time T1 by increasing the relaxation rate of
the spins of the surrounding water protons.[3] This enhances
the image contrast between normal and diseased tissue or
indicates the status of organ function or blood flow.[4] The
effectiveness of an MRI contrast agent is expressed in terms
[a] G. Dehaen, Dr. S. V. Eliseeva, Dr. K. Kimpe, Prof. W. Dehaen,
Prof. K. Binnemans, Prof. T. N. Parac-Vogt
Katholieke Universiteit Leuven
Department of Chemistry, Celestijnenlaan 200F
P.O. Box 2404, 3001 Heverlee (Belgium)
E-mail: tatjana.vogt@chem.kuleuven.be
[b] Dr. S. Laurent, Prof. L. Vander Elst, Prof. R. N. Muller
NMR and Molecular Imaging Laboratory
Department of General, Organic and Biomedical Chemistry
University of Mons-Hainaut, 7000 Mons (Belgium)
[c] Prof. R. N. Muller
Center for Microscopy and Molecular Imaging
Rue Adrienne Bolland 8, 6041 Charleroi (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101413.
Chem. Eur. J. 2012, 18, 293 – 302
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
293

quired concentration of the contrast agent. For certain appli-
cations of MRI, such as cellular imaging, it is favorable to
limit the amount of contrast agents to prevent cell damage.
Catechol is known to act as a bidentate chelating ligand
that has a high affinity for metal ions in high oxidation
states or with a high charge-to-ionic-radius ratios.[18] As a
pioneer of metal–catecholate chemistry, Raymond et al. re-
ported in 1984 that due to its high Lewis acidity, the titani-
whereas catechol is able to self-assemble with a TiIV ion to
form a heteropolymetallic metallostar complex, [(Ln4)3Ti-
A
N
ACHTUNGTRENNUNG
(H2O)]ꢀ
and [(La4)3TiCAHTUNGTRENNNUG
scopic characterization of these metallostars, the GdIII ana-
logues were used for relaxivity studies. In this context, the
ability of catechol to bind to human serum albumin (HSA)
was examined by relaxometric measurements. To gain more
information about the coordination environment and the hy-
dration numbers, the photophysical properties of the corre-
sponding EuIII complexes have also been studied. In addi-
ACHTUNGTRENNUNGum(IV) ion is able to stabilize the catecholate anion over a
broad pH range.[19] At physiological pH, a stable complex
(logb130 ꢁ60) is formed by coordination of three catechol
entities to a central TiIV ion.[19,20] Later on, taking advantage
of this strong affinity, catechol derivatives have been widely
used for synthesis of TiIV complexes and even as binding
agents for TiO2 nanoparticles.[21–24]
tion, to test the feasibility of [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ to act as a
bimodal contrast agent, its luminescent properties were in-
vestigated. Bimodal imaging is presently gaining a great
deal of interest since it can take advantage of great spatial,
temporal resolution, and unlimited tissue penetration of
MRI and high sensitivity of optical imaging.[25–28] Different
classes of compounds have been designed as bimodal con-
trast agents, for example, GdIII chelates derivatized with lu-
minescent dyes or transition-metal complexes,[29–32] as well as
functionalized Fe3O4,[33] polymer,[34] or silica[35] nanoparticles.
In this paper, we describe the synthesis of a new ligand
H64, which bears a catechol and a diethylenetriaminepenta-
acetic acid (DTPA) moiety linked together through an
amide bond (Scheme 1). The DTPA unit provides a stable
chelating environment for LnIII ions ([Ln (H2O)]ꢀ),
ACTHNUTRGENNUG(H24)ACHTUTGNRENNUGN
Results and Discussion
The ligand and complexes: The synthesis of the catechol-
DTPA-based ligand started from N,N-bis(2-ACHTNUTRGNEUNG{bis[2-(1,1-dime-
thylethoxy)-2-oxoethyl]amino}ethyl)glycine (1),[36] of which
only the central carboxylic group remained unprotected.
Compound 1 was coupled with 3,4-(dibenzyloxy)phenethyla-
mine (2) in the presence of ortho-benzotriazol-1-yl-
N,N,N’,N’-tetramethyluronium tetrafluoroborate (TBTU)
and dry triethylamine to yield the protected ligand 3. For
the coupling of both entities, an amide bond was chosen be-
cause of its high in vivo stability. After deprotection of the
phenyl and tert-butyl groups, the final ligand H64 was ob-
tained as a white solid (Scheme 1). A proton NMR spec-
trum of ligand H64 was recorded in D2O; its peaks corre-
sponded to the labeled molecule (Figure S1 in the Support-
ing Information). Further, a full assignment was achieved by
a two-dimensional COSY experiment (Figure S2 in the Sup-
porting Information).
The electrospray mass spectrum (ESI-MS) in the positive
mode showed molecular peaks [M+H]+ and [M+Na]+ at
m/z 529.6 and 551.9, respectively. Lanthanide
were obtained by treating the ligand H64 with a lanthanide-
(III) chloride (Ln=La, Eu, Gd) under slightly alkaline con-
ditions. All [Ln(H24)
(H2O)]ꢀ complexes were purified by
ACHTUNGTREN(NGNU III) complexes
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Chelex 100 to remove the free lanthanide ions and their
purity was checked by a test with an arsenazo indicator solu-
tion. Positive-mode ESI-MS of the complexes showed mo-
lecular peaks [M+2Na]+ at m/z 709.2, 723.0, and 728.0,
which correspond to the LaIII, EuIII, and GdIII complexes, re-
spectively. Complexation of H64 with LaIII resulted in a sig-
1
nificant change in the aliphatic region of the H NMR spec-
trum. The aliphatic resonances of [La
a small shift to lower ppm values and a large broadening in
(H2O)]ꢀ showed
ACHUTGTNRENNUG(H24)ACHTUTGNRENNUGN
Scheme 1. Synthesis of ligand H64. Conditions: i) TBTU, dry triethyl-
amine, dry DMF; ii) H2 gas, Pd/C 5%, methanol; iii) HCl 6n.
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Chem. Eur. J. 2012, 18, 293 – 302

Titanium(IV) Catecholate Core
FULL PAPER
comparison with those of the ligand, while the aromatic res-
onances remained sharp and unchanged. This indicates the
selective coordination of the LaIII ion to the carboxylic
groups of the DTPA moiety. The broadening of the aliphatic
resonances is consistent with the occurrence of several inter-
converting isomers, which is characteristic for lanthanide-
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
showed severe broadening, whereas the aromatic resonances
remained sharp (Figure S3 in the Supporting Information).
To form stable metallostar complexes, FeIII, GaIII, and TiIV
ions were used as central metal ions. However, because mix-
tures of bis and tris complexes were formed at physiological
pH in the presence of FeIII or GaIII ions, these complexes
will not be discussed further in this work. In the presence of
TiIV, the color changed from colorless to red, thereby indi-
cating that TiIV had formed a supramolecular structure with
three catechol moieties (Scheme 2).[38] Total-reflection X-ray
fluorescence (TXRF) measurements on this complex con-
firmed a 3:1 ratio of LnIII versus TiIV. Hence, we can repre-
Figure 1. Framework molecular model of the [(Gd4)3Ti(H2O)3]5ꢀ com-
plex. Hydrogen atoms have been omitted for clarity.
sent the structure of the metallostar compound as
1
[(Ln4)3Ti
[(La4)3Ti
G
wards lower ppm values after the complexation of the
ligand with TiIV was observed (Figure S4 in the Supporting
Information). The strongest shifts of d=0.51 and 0.48 ppm
are attributed to protons g and i, respectively (see Scheme 1
for atom labeling). The aromatic proton h underwent a
smaller shift of d=0.23 ppm. The appearance of only three
proton resonances of the aromatic entity of [(La4)3Ti-
(H2O)3]5ꢀ, a shift of the aromatic resonances to-
AHCTUNGTRENNUNG
(H2O)3]5ꢀ also indicate the formation of only one type of
the complex in solution. Although no single crystals suitable
for X-ray diffraction analysis could be obtained, the data
gained from IR, ESI-MS, NMR, spectroscopic (see below),
and TXRF analyses are consistent with the formation of a
supramolecular complex with three lanthanide
one titanium(IV) ion (Figure 1).
ACHTUNGTREN(NUNG III) ions and
AHCTUNGTRENNUNG
Photophysical properties: The absorption spectrum of
ligand H64 is similar to that of the nonderivatized catechol[39]
and displays a band at 281 nm (e=7185mꢀ1 cmꢀ1; Figure 2).
Figure 2. Absorption spectra of ligand H64 (10ꢀ4 m, c), of the complex
[Gd(H24)(H2O)]ꢀ (10ꢀ4 m, g), and of the metallostar complex
[(Gd4)3Ti(H2O)3]5ꢀ (3.3ꢁ10ꢀ5 m, a) in H2O. The absorption spectra of
the EuIII complexes are similar and shown in the Supporting Information
(Figure S5).
Scheme 2. Formation of the [(Gd4)3Ti(H2O)3]5ꢀ complex: i) GdCl3·6H2O,
pyridine; ii) [TiO(acac)2], Na2CO3.
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295

T. N. Parac-Vogt et al.
This band slightly shifts to the blue region and a tail that ex-
tends to the red region appears upon complexation with
the EuIII ion occupies a position with Cn, Cnv, or Cs symme-
try. As expected, the crystal-field splitting patterns of the
transitions are similar to the ones observed for other EuIII
complexes of DTPA derivatives.[42–44]
GdIII in [Gd
G
ACHTUNGTRENNUNG
(H2O)]ꢀ (e=6950mꢀ1 cmꢀ1). In the absorp-
AHCTUNGTRENNUNG
(H2O)3]5ꢀ, apart from the ligand-
attributed absorption at 277 nm (e=19375mꢀ1 cmꢀ1), the
ligand-to-metal charge transfer (LMCT) band appeared at
378 nm (e=8430mꢀ1 cmꢀ1). The position of the LMCT band
is typical for TiIV complexes of catechol.[23,39] Due to the
high affinity of TiIV ions to catechol ligands,[19,21,40] the for-
To determine the number of water molecules coordinated
5
to the EuIII ion, the luminescence lifetimes of the D0 level
were measured in H2O (tH O =0.51(1) ms) and in D2O
2
(tD O =1.67(2) ms) solutions (Table 1). Calculations were
2
carried out according to the following equation [Eq. (1)]:[45]
mation of [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ in solution at low concentra-
tion remains preserved.
Table 1. Photophysical parameters of the [Eu(H24)(H2O)]ꢀ complex (c=
(H2O)]ꢀ displays a
The excitation spectrum of [EuACTHNUTRGENNUG(H24)ACHTUTGNRENNUGN
10ꢀ4 m, lex =270 nm, room temperature).
broad band at wavelengths shorter than 350 nm, which is at-
tributed to the electronic transitions of the ligand along with
Eu
Eu
tobs [ms]
trad [ms][a]
Q
[%][a]
QLEu [%]
hsens [%][a]
0.51(1)
5.05
10
0.042
0.42(6)
7
characteristic f–f transitions of the EuIII ion from the F0,1
[a] The refractive index was set equal to that of the neat solvents, nH O
1.34 ; nD O =1.328. See Equations (2a), (2b), and (3) for definitions.
=
3
5
5
5
2
levels to P0 (307 nm), HJ (313–325 nm), D4 (363 nm), GJ,
5L7 (370–390 nm), and 5L6 (396 nm) (Figure 3, top). Upon
excitation into the ligand levels at 270–280 nm,
2
qðEuÞ ¼ 1:11 ꢂ ðDkꢀ0:31ꢀ0:075 ꢂ qNÞ
[EuACHTUNGTRENNUNG(H24)ACHTUNGTRENNUNG
(H2O)]ꢀ exhibits a red luminescence on account of
ð1Þ
the 5D0! FJ (J=0–4) transitions. (Figure 3, bottom). It is
well documented that lanthanide luminescence, particularly
in the case of EuIII, is very sensitive to the nature of the co-
ordination environment and its symmetry.[41] The integral
relative intensities of the transitions are listed in Table S1 in
7
in which qN =1 is the number of coordinated amide groups,
thus resulting in q(Eu)=1.1. These results indicate that in
(H2O)]ꢀ, the EuIII ions are hydrated by one water
[EuACTHNURTGENN(UG H24)ACHTUTGNRENNUGN
molecule and that they are nine-coordinated.
The luminescence quantum yield of [EuCATHNUGTREN(NNUG H24)ACHTUNGTRENNUNG
(H2O)]ꢀ
under ligand excitation is 0.042%. The intrinsic quantum
the Supporting Information. The 5D0! F2 and 5D0! F4
transitions have almost equal integral intensities and repre-
sent approximately 40% of the total emission. The highly
forbidden D0! F0 transition has a relatively high integral
intensity (13% of D0! F1 transition), which suggests that
7
7
yield could not be measured because of the low absorption
5
7
!
5
7
coefficients of the D0 F0,1 transitions, thus it was estimat-
ed to be 10% by using the following equations [Eqs. (2a)
and (2b)]:
5
7
tobs
Eu
Eu
Q
¼
ð2aÞ
ð2bÞ
trad
ꢀ
ꢁ
1
trad
Itot
IMD
¼ AMD;0 ꢂ n3
in which AMD,0 is a constant equal to 14.65 sꢀ1 and (Itot/IMD
)
7
the ratio of the total integrated 5D0! FJ emission (here
5
7
taken as J=0–4) to the integrated intensity of the D0! F1
Eu
Eu
magnetic dipole transition. The value of Q is comparable
with other hydrated EuIII complexes with 1,4,7,10-tetraaza-
cyclododecane-1,4,7,10-tetraacetic acid (DOTA; 10%)[46] or
DTPA (13%)[42] derivatives. However, these complexes dis-
play much higher overall quantum yields, 0.4 or 1.9%, re-
spectively, in comparison to
a value of 0.042% for
[Eu(H24)
N
ACHTUNGTRENNUNG
efficient energy transfer from the organic ligand, which
could be expected because of the absence of chromophoric
groups close to the EuIII ion. Indeed, the sensitization effi-
ciency calculated as the ratio [Eq. (3)]:
QLEu
ð3Þ
hsens
¼
Q
Eu
Eu
Figure 3. Top: Excitation (lem =614 nm), and (bottom) emission (lex
=
is equal to only 0.42% for [Eu
the formation of low-lying charge-transfer state in
(H2O)]ꢀ. In addition,
ACHUTGTNRENNUG(H24)ACHTUTGNRENNUGN
270 nm) spectra of the [Eu(H24)(H2O)]ꢀ complex in aqueous solution
(10ꢀ4 m).
a
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Chem. Eur. J. 2012, 18, 293 – 302

Titanium(IV) Catecholate Core
FULL PAPER
5
7
[Eu
G
G
sharp features due to the D0! FJ (J=0–4) transitions (Fig-
quenching.[47,48]
ure S6 in the Supporting Information). Upon excitation at
It is known that the TiIV ion in an inorganic matrix can ex-
hibit intensive blue, green-blue, or even near-infrared broad-
band luminescence (depending on the host matrix), due to
270 nm, the luminescence spectrum of [(Eu4)3TiACTHNGUTERNNUG
(H2O)3]5ꢀ is
dominated by the f–f transitions, but the broad emission in
the range 400–750 nm still present. The relative integral in-
7
7
O
2ꢀ!TiIV charge-transfer transitions.[49–53] However, reports
tensities of 5D0! F2 and 5D0! F4 transitions in
that describe the luminescence of TiIV in complexes with or-
ganic ligands are very scarce.[54] On the other hand, whereas
A
E
are
slightly
larger
than
in
C
(H2O)]ꢀ (Table S1 in the Supporting Information),
ACHTUNGTRENNUNG
Gd–DTPA does not show intra
whereas the crystal-field splitting of the bands is very similar
for the two complexes (Figure S7 in the Supporting Informa-
tion), thus confirming that the coordination of the catechol
moiety to TiIV does not influence the environment around
the EuIII ion. This is further confirmed by measurement of
the luminescence lifetimes of the 5D0 level, which remain
the same within the limits of the experimental error for
echol itself is luminescent and under excitation at 274 nm
exhibits broad-band emission centered at 320 nm.[56] To es-
tablish the possibility of [(Gd4)3Ti
dal optical/MRI contrast agent, its luminescence properties
were investigated. The excitation spectrum of
[(Gd4)3Ti
(H2O)3]5ꢀ resembles its absorption spectrum, but it
G
is slightly redshifted and it displays two bands at 310 and
400 nm (Figure 4, top). Upon excitation either into the
[EuACHTNUGRTEG(NUNN H24)ACHUTNRTGENNUNG ACTHNUGTRENNUGN
(H2O)]ꢀ and [(Eu4)3Ti(H2O)3]5ꢀ in H2O and D2O:
0.51(1) versus 0.52(2) ms and 1.67(2) versus 1.65(4) ms, re-
spectively. The EuIII ions are thus monohydrated in
[(Eu4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ , as evidenced by calculations of q(Eu)=
1.1 by using Equation (1).
Relaxometric studies: The efficacy of a GdIII complex as an
MRI contrast agent is usually assessed through its relaxivity,
which is defined as the increase of the proton relaxation
rate induced by one mm per liter of complexed GdIII. The
relaxivity arises mainly from the contributions of short-dis-
tance interactions between the paramagnetic GdIII ion and
the coordinated water molecules exchanging with bulk
water, the so-called inner-sphere interaction,[57,58] and from
the long-distance interactions related to the diffusion of
water molecules near the paramagnetic GdIII center, that is,
the outer-sphere interaction.[59] The first contribution de-
pends mainly on the number of water molecules coordinated
in the first hydration sphere of the complexed ion (q), on
the electronic relaxation times of GdIII (tS1 and tS2), on the
residence time of the coordinated water molecules (tM), and
on the rotational correlation time (tR).
The residence time of the coordinated water molecules
(tM), a key factor of the relaxivity, can be estimated through
the analysis of the temperature dependence of the trans-
verse relaxation rate of the 17O NMR spectroscopic reso-
nance of water in the GdIII complex solutions.[60–64] The data
obtained for [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ are shown in Figure 5.
Figure 4. Top: Excitation (solid line, lem =500 nm) and superimposed ab-
sorption (dashed line) spectra. Bottom: Emission (lex =380 nm) spectrum
of [(Gd4)3Ti(H2O)3]5ꢀ complex in aqueous solution (3.3ꢁ10ꢀ5 m).
The theoretical treatment of the experimental data was
performed as previously described.[60,61,65] The following pa-
rameters were determined: tV, the correlation time that
modulates the electronic relaxation of GdIII; EV, the activa-
tion energy related to tV; B, related to the mean-square of
LMCT band at 380 or at 270 nm, [(Gd4)3Ti
A
the zero-field splitting energy DACTHNGUTERNNUG
(B=2.4D2); and DH# and
its a green broad-band emission in the range 400–750 nm
with a maximum of 490 nm (Figure 4, bottom), which might
DS#, respectively, the enthalpy and entropy of activation of
the water-exchange process. The number of coordinated
water molecules was set to one in accordance with the data
derived from the luminescence lifetime measurements on
the EuIII complex, and A/ꢀh, the hyperfine coupling constant
between the 17O nucleus of the bound water molecule and
the GdIII ion, was fixed to the typical value of ꢀ3.6ꢁ
106 radsꢀ1. The calculated parameters are shown in Table 2.
be attributed to intraACTHNUGRTENNUGliACHUTGTNRENNUG
gand and/or ligand-to-TiIV charge-
transfer transitions. However, the absolute quantum yield is
relatively low (0.054%).
When it comes to the EuIII derivative, excitation at
380 nm resulted in a similar broad-band emission as in the
case of [(Gd4)3TiACHTUNGTRENNUNG
(H2O)3]5ꢀ, however with the characteristic
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297

T. N. Parac-Vogt et al.
Figure 6. 1H NMRD relaxivity profiles of [Gd(H24)(H2O)]ꢀ
(
)
and
Figure 5. Reduced transverse relaxation rate of 17O (1/T2R =55.55/(Tp2ara
[Gd])) as function of the reciprocal of the temperature for
[(Gd4)3Ti(H2O)3]5ꢀ
ꢁ
*
[(Gd4)3Ti(H2O)3]5ꢀ
(
) in water at 310 K. The relaxivity is expressed by
*
a
mm per liter of GdIII. The solid lines correspond to the theoretical fittings
of the data points. The dashed line corresponds to the fitting of Gd–
DTPA data.
.
Table 2. Parameters obtained by the theoretical adjustment of the 17O
transverse relaxation rates versus the reciprocal of the temperature.
[(Gd4)3Ti(H2O)3]5ꢀ
Gd–DTPA[a]
Table 3. Parameters obtained by the theoretical adjustment of the proton
NMRD data in water at 310 K.
t3M10 [ns]
(212ꢃ33)
(45.2ꢃ0.3)
(28.4ꢃ0.5)
ꢀ3.6
(143ꢃ25)
(51.5ꢃ0.3)
(52.1ꢃ0.6)
(ꢀ3.4ꢃ0.1)
(2.6ꢃ0.1)
(12.3ꢃ0.3)
(4.5ꢃ4.2)
¼
DH [kJmolꢀ1
]
Gd–
[Gd(H24)(H2O)]ꢀ [(Gd4)3Ti(H2O)3]5ꢀ
¼
DS [Jmolꢀ1 Kꢀ1
]
DTPA[a]
A/ꢀh [106 radsꢀ1
]
t3M10 [ns][b]
143
212[c]
212
B [1020 sꢀ2
t2V98 [ps]
]
(6.3ꢃ0.4)
(20ꢃ1)
t3R10 [ps]
(54ꢃ14)
(87ꢃ3)
(25ꢃ3)
(104ꢃ24)
(69ꢃ1)
(29ꢃ2)
(371ꢃ6)
(108ꢃ1)
(46ꢃ2)
(12.3ꢃ0.6)
310
SO
t3V10 [ps]
t
[ps]
EV [kJmolꢀ1
]
(10ꢃ4)
[a] From Ref. [67].
r1 [sꢀ1 mmꢀ1] at
20 MHz
(3.8ꢃ0.2) (5.2ꢃ0.3)
[a] From Ref. [67]. [b] t3M10 was fixed to the value obtained by 17O relax-
ometry. [c] Fixed to the value obtained for [(Gd4)3Ti(H2O)3]5ꢀ
As expected, the calculated value of the water residence
time at 310 K is larger than that of the parent compound.
Indeed, the replacement of a carboxylic acid function by an
amide is known to increase the residence time of the coordi-
nated water molecules. The proton nuclear magnetic relaxa-
tion dispersion (NMRD) profiles of the complexes
.
value of [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ agrees with the size of the com-
plex and is responsible of the enhanced relaxivity. It should
be emphasized that the relaxivity expressed in mM per liter
[Gd
Figure 6. The NMRD profile of [Gd
for a low-molecular-weight complex, whereas the profile of
[(Gd4)3Ti
(H2O)3]5ꢀ has a hump around 20 MHz, which is
A
E
N
of the [(Gd4)3TiACTHNGUTERNNUG
(H2O)3]5ꢀ complex is 36.9 sꢀ1 mmꢀ1 at
A
U
20 MHz and 37.7 sꢀ1 mmꢀ1 at 60 MHz and 310 K.
The interaction of a small GdIII complex with human
serum albumin (HSA) results in an increase of the paramag-
netic relaxation rate as a result of the increase of its rota-
tional correlation time. The change of the observed relaxa-
tion rate depends on the intensity of the magnetic field and
on the proportion of bound contrast agents, and therefore,
on the strength of the interaction. The proton NMRD pro-
files of the paramagnetic relaxation rate of solutions that
contain 1 mm per liter of complexed GdIII and 4% of HSA
are shown in Figure 7.
A
ACHTUNGTRENNUNG
typical of a higher-molecular-weight complex.
The theoretical adjustment of the NMRD profiles takes
into account the inner-sphere[57,58] and the outer-sphere[59]
contributions to the paramagnetic relaxation rate. Some pa-
rameters were fixed during the fitting procedure: q, the
number of coordinated water molecules (q=1); d, the dis-
tance of closest approach (d=0.36 nm); D, the relative dif-
fusion constant (D=3.3ꢁ10ꢀ9 m2 sꢀ1 for [Gd
(H2O)]ꢀ
ACHUTGTNRENNUG(H24)ACHTUTGNRENNUGN
and 3.0ꢁ10ꢀ9 m2sꢀ1 for [(Gd4)3Ti(H2O)3]5ꢀ);[66] tM310, the
G
The slight increase of paramagnetic relaxation rate in the
presence of HSA is partly explained by the viscosity in-
crease induced by HSA (0.87 MPasꢀ1 with HSA relative to
0.69 MPasꢀ1 without HSA at 310 K). This change of viscosi-
ty results in an increased value of tR and a decreased value
of the relative diffusion constant D. Theoretical fittings per-
formed with the parameters of the free GdIII complexes, but
which take into account these viscosity effects on tR and D,
water residence time was set to the value determined by
17O NMR spectroscopy; and r, the distance between the
GdIII ion and the proton nuclei of water (r=0.31 nm). The
results of these fittings are shown in Table 3 and Figure 6.
The tSO values at 310 K are close to that of the Gd–DTPA
complex, and as expected, the tR value of [Gd
is larger than the value for the Gd–DTPA complex. The tR
(H2O)]ꢀ
ACHUTGTNRENNUG(H24)ACHTUTGNRENNUGN
298
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Chem. Eur. J. 2012, 18, 293 – 302

Titanium(IV) Catecholate Core
FULL PAPER
and further self-assemble with TiIV, thereby giving rise to
stable metallostar molecules, [(Ln4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ. The forma-
tion of such a supramolecular complex in case of the GdIII
analogue induces a decrease of the tumbling rate by a factor
of 4 to 7.4 relative to the monomer and currently used com-
mercial MRI contrast agent Gd–DTPA (Magnevist), respec-
tively. This, in turn, leads to an enhanced r1 relaxivity up to
12.3 sꢀ1 mmꢀ1 per GdIII ion at 20 MHz and 310 K that corre-
sponds to 36.9 sꢀ1 mmꢀ1 per metallostar molecule. In addition
to these high relaxivities, the [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ complex
shows interesting photophysical properties. Under UV exci-
IV
tation, the GdIII Ti metallostar exhibits broad-band green
ꢀ
emission with a quantum yield of 0.054%. Although the
latter value is rather low, the ligand was not specifically opti-
mized to give highly luminescent complexes. However, ap-
propriate functionalization should make such ditopic ligands
promising candidates for the successful design of bimodal
optical/MRI contrast agents.
Figure 7. Proton paramagnetic relaxation rate of solutions of
[(Gd4)3Ti(H2O)3]5ꢀ (1 mm) in water and in aqueous solution of HSA
*
*
(4%, =HSA, =water, c=water fit). The dashed line through the
data obtained in HSA is drawn to guide the readersꢂ eyes. The dotted
line represents the data calculated, when the viscosity increase is taken
into account.
Experimental Section
are shown in Figure 7. The data indicate that the presence
of HSA does not induce significant modifications. This
result was confirmed by the analysis of the paramagnetic
proton relaxation rate of solutions that contain 4% of HSA
Materials: Reagents were obtained from Aldrich Chemical (Bornem,
Belgium) and Acros Organics (Geel, Belgium) and were used without
further purification. GadoliniumACTHNUTRGNE(NUG III) chloride hexahydrate was obtained
from GFS Chemicals (Powell, Ohio, USA).
Synthesis of N,N-bis[(tert-butoxycarbonyl)methyl]-2-bromoethylamine:[68]
Powdered KHCO3 (19.2 g, 192 mmol, 2.6 equiv) was added to tert-butyl
bromoacetate (33 g, 173 mmol, 2.3 equiv) dissolved in DMF (150 mL).
The suspension was cooled to 08C and ethanolamine (4.6 mL, 75 mmol,
1 equiv) was added dropwise over a period of five minutes. The reaction
mixture was stirred at 08C for 30 min and then for 24 h at room tempera-
ture. The semisolid residue obtained after removal of the solvent was dis-
solved in a sodium hydrogen carbonate solution and extracted three
times with diethyl ether. The combined ether layers were then washed
with brine, dried over MgSO4, and evaporated to give crude N,N-bis-
and increasing amounts of [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ (Figure 8).
The slight increase in paramagnetic relaxation over the con-
centration range investigated does not indicate the presence
of a significant interaction between [(Gd4)3TiACTHNUTRGNEUNG
(H2O)3]5ꢀ and
HSA.
[(tert-butoxycarbonyl)methyl]-2-ethanolamine as an oil (ꢁ18.6 g, 86%).
This crude dialkylated product was dissolved in dichloromethane
(200 mL), and triphenylphosphine (23.5 g, 89.6 mmol, 1.4 equiv) was
added. The solution was cooled to 08C and solid N-bromosuccinimide
(NBS; 15.95 g, 89.6 mmol, 1.4 equiv) was slowly added. The reaction was
continued for 2 h. The solvent was evaporated to yield a semisolid resi-
due, which was triturated three times with ether, and the remaining solid
was separated. The combined ether layers were concentrated and passed
through a column of silica using hexane/ether (5:1) as eluent, which re-
sulted in
a yellow oil (18.5 g, 82%). Rf =0.36 (5:1 hexane/ether);
1H NMR (300 MHz, CDCl3): d=1.45 (s, 18H; tert-butyl CH3), 3.1 (t, 2H;
BrCH2CH2N), 3.4 (t, 2H; BrCH2CH2N), 3.5 ppm (s, 4H; (tert-butoxycar-
bonyl-CH2)2N); ESI-MS: m/z calcd for C14H26BrNO4 [M]: 375.3
[M+Na]+; found: 375.6.
Synthesis of 1:[69] Benzyl glycinate p-toluenesulfonate (2 g, 6 mmol,
1 equiv) was dissolved in diethyl ether (40 mL), and an Na2CO3 solution
(1.89 g, 18 mmol, 3 equiv) in water (40 mL) was added. The ether layer
was separated from the water layer, dried, and evaporated to yield gly-
cine benzyl ester (0.5 g). This product is very unstable, and was therefore
immediately used in the next synthesis step. A phosphate buffer (10 mL,
2m, pH 8) was added to a solution of glycine benzyl ester (0.430 g,
2.6 mmol, 1 equiv) and N,N-bis[(tert-butoxycarbonyl)methyl]-2-bromo-
Figure 8. Proton paramagnetic relaxation rate of solutions of
[(Gd4)3Ti(H2O)3]5ꢀ in an aqueous solution of HSA (4%, ) at 20 MHz
*
and 310 K. The dashed line represents the data obtained in water (b).
AHCTUNGTREGeNNNU thylamine (2 g, 5.7 mmol, 2.2 equiv) in CH3CN (20 mL), and the mixture
was stirred for 24 h. The suspension was filtered and the organic layer
was separated from the water layer, dried, and evaporated. To remove
the remaining inorganic salts, the crude product was redissolved in
chloroform, filtered, and evaporated again. The yellow oil was passed
through a column of silica using a mixture of CHCl3/MeOH/NH3 150:3:1
Conclusion
We have demonstrated that a new ditopic DTPA–catechol
(H2O)]ꢀ,
ligand is able to bind lanthanideACHTUNGRTEN(NNGU III) ions, [LnAHCTUNRTGE(GNNNU H24)ACHTNGUTRENNGUN
Chem. Eur. J. 2012, 18, 293 – 302
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
299

T. N. Parac-Vogt et al.
as eluent to afford 1.2 g of benzyl-protected product. Rf =0.2 (50:1
chloroform/methanol).
room temperature, the complex was filtered off and dried in a vacuum.
The absence of free lanthanide ions was checked by using an arsenazo in-
dicator.
The product was dissolved in methanol (10 mL), then Pd/C 5% (0.14 g)
was added, and the suspension was stirred at room temperature under a
hydrogen atmosphere for 24 h. The mixture was filtered over Millipore
FH 0.45 mm. The solvent was evaporated to yield a highly viscid yellow
oil (0.98 g, 61%). 1H NMR (300 MHz, CDCl3): d=1.45 (s, 36H; tert-
butyl CH3), 3.19 (t, 4H; C(O)OHCH2NCH2CH2N), 3.48 (s, 8H;
NCH2C(O)OtBu), 3.54 (t, 4H; C(O)OHCH2NCH2CH2N), 4.34 ppm (s,
2H; NCH2C(O)OH); ESI-MS: m/z calcd for C30H55N3O10 [M]: 640.8
[M+Na]+; found: 641.0.
(H2O)]ꢀ: Yield: 78%; IR: n˜ =1616
LanthanumACTHNUGRTEN(NUNG III) complex [LaACHNUTRTGE(GNNNU H24)ACHTNGUTRENNGUN
(amide I), 1583 (COOꢀ asym. stretch), 1405 cmꢀ1 (COOꢀ sym. stretch);
ESI-MS: m/z calcd for C22H28LaN4O11 [M]: 709.4 [M+2Na]+; found:
709.2.
(H2O)]ꢀ: Yield: 84%; IR: n˜ =1607
EuropiumACTHUNGERTN(NNGU III) complex [EuACHTUNRTGEGN(NNU H24)ACHTNGUTRENNGUN
(amide I), 1582 (COOꢀ asym. stretch), 1409 cmꢀ1 (COOꢀ sym. stretch);
ESI-MS: m/z calcd for C22H28EuN4O11 [M]: 722.4 [M+2Na]+, found
723.0.
(H2O)]ꢀ: Yield: 55%; IR: n˜ =1617
GadoliniumACHTNUGTREN(NNUG III) complex [GdACHNUTRTGE(GNNNU H24)ACHTNGUTRENNGUN
Synthesis of benzyl- and tert-butyl-protected catechol derivative 3: Com-
pound 1 (618 mg, 1 mmol) was dissolved in dry DMF (20 mL). Dry tri-
ACHTUNGTRENNUNGethylamine (0.5 mL, 0.36 g, 3.6 mmol) and o-benzotriazol-1-yl-N,N,N’,N’-
(amide I), 1586 (COOꢀ asym. stretch), 1409 cmꢀ1 (COOꢀ sym. stretch);
ESI-MS: m/z calcd for C22H28GdN4O11 [M]: 727.7 [M+2Na]+; found:
728.0.
tetramethyluronium tetrafluoroborate (481.5 mg, 1.5 mmol) were added,
and the mixture was stirred for 10 min at room temperature. Compound
2 (370 mg, 1 mmol) was then added to the solution. The reaction mixture
was stirred at room temperature and followed by TLC through observa-
tion of the depletion of free 3,4-(dibenzyloxy)phenethylamine (Rf =0.4)
with the eluent CH2Cl2/CH3OH/NH4OH (9:1:0.1). DMF was then re-
moved by vacuum evaporation. The crude product was washed and
phase separated in ethyl acetate (40 mL) with a sodium hydrogen carbon-
ate and saturated sodium chloride solution. The crude yellow oil was
passed through a column of silica using CH2Cl2!CH2Cl2/MeOH 50:1 as
eluent. Evaporation of the solvent gave 3 as a yellow oil (0.697 g, 75%).
1H NMR (300 MHz, CDCl3): d=1.40 (s, 36H; tert-butyl), 2.6–2.8 (m,
4H; NCH2), 3.0 (s, 2H; NCH2CO), 3.0–3.1 (m, 4H; NCH2), 3.43 (s, 8H;
NCH2COOtBu), 3.99 (m, 4H; PhCH2CH2NH), 5.12 (s, 4H; PhCH2OPh),
6.7–7.0 (m, 3H; Ph), 7.3–7.5 ppm (m, 10H; Ph); 13C NMR (75 MHz,
CDCl3): d=28.1 (CH3), 39.4 (CH2), 40.9 (CH2), 52.2 (CH2), 53.8 (CH2),
55.4 (CH2), 55.8 (CH2), 71.3 (CH2), 71.5 (CH2), 81.0 (C), 115.4 (CH),
115.8 (CH), 121.7 (CH), 127.4 (CH), 127.7 (CH), 128.4 (CH), 133.2
(CH), 137.5 (CH), 147.4 (C), 149.0 (C), 170.56 (CO), 170.47 ppm (CO);
ESI-MS: m/z calcd for C52H76N4O11 [M]: 934.2 [M+H]+, 956.2 [M+Na]+;
found: 934.0 [M+H]+, 956.4 [M+Na]+.
Synthesis of titanium(IV)–lanthanide
(1 equiv; acac=acetylacetonate) and Na2CO3 (6 equiv) were added to a
solution of [Ln(H24)
(H2O)]ꢀ (3 equiv) in H2O, and the mixture was
(III) complexes:[38] [TiO
ACHUTGTNERNNUG ACHTUNGTRENNUNG(acac)2]
A
ACHTUNGTRENNUNG
stirred at room temperature for 24 h. The color of the mixture immedi-
ately changed to red, thereby indicating complexation of catechol to the
TiIV ion. The solution was concentrated, redissolved in a small amount of
methanol, and precipitated with acetone. Finally, the complex was fil-
tered off and dried in vacuum.
(H2O)3]5ꢀ: Yield: 68%,
Titanium(IV)–lanthanumACHTNUGTRENNUG(III) complex [(La4)3TiACHTUTGNRENNUGN
IR: n˜ =1617 (amide I), 1577 (COOꢀ asym. stretch), 1397 cmꢀ1 (COOꢀ
sym. stretch); ESI-MS: m/z calcd for C66H78La3N12O33Ti [M]: 709.3
[M+4Na+4H]+; found: 709.3; TXRF ratio (La/Ti): 2.92.
(H2O)3]5ꢀ: Yield: 71%;
Titanium(IV)–europiumACTHNUGTRNENUG(III) complex [(Eu4)3TiACHTUTGNRENNUGN
IR: n˜ =1617 (amide I), 1578 (COOꢀ asym. stretch), 1398 cmꢀ1 (COOꢀ
sym. stretch); ESI-MS: m/z calcd for C66H78Eu3N12O33Ti [M]: 297.6
[M+126H]7+; found: 297.7; TXRF ratio (Eu/Ti): 2.92.
(H2O)3]5ꢀ: Yield: 66%;
Titanium(IV)–gadoliniumACHTNUGTRENNUG(III) complex [(Gd4)3TiACHTUTGNRENNUGN
IR: n˜ =1615 (amide I), 1577 (COOꢀ asym. stretch), 1396 cmꢀ1 (COOꢀ
sym. stretch); ESI-MS: m/z calcd for C66H78Gd3N12O33Ti [M]: 1098.0
[M+3Na+4H+2H2O]2+, 1129.0 [M+5Na+2H+3H2O]2+; found: 1098.0
[M+3Na+4H+2H2O]2+, 1129.6 [M+5Na+2H+3H2O]2+; TXRF ratio
(Gd/Ti): 2.78.
Synthesis of tert-butyl-protected catechol derivative: Product 3 was dis-
solved in MeOH (20 mL), and Pd/C 5% (0.5 g) was added. The suspen-
sion was stirred over 5 h under a hydrogen atmosphere at room tempera-
ture. The mixture was filtered over celite and evaporated to yield a
yellow oil (0.338 g, 60%). 1H NMR (300 MHz, CDCl3): d=1.44 (s, 36H;
tert-butyl), 2.6–2.8 (m, 4H; NCH2), 3.0–3.1 (m, 4H; NCH2), 3.34 (s, 8H;
NCH2COOtBu), 3.48 (s, 2H; NCH2CO), 3.98 (m, 4H; PhCH2CH2NH),
6.5–6.9 ppm (m, 3H; Ph); 13C NMR (75 MHz, CDCl3): d=28.1 (CH3),
38.6 (CH2), 40.9 (CH2), 47.9 (CH2) , 53.8 (CH2), 55.4 (CH2), 55.9 (CH2),
80.8 (C), 115.4 (CH), 116.5 (CH), 120.5 (CH), 131.1 (CH), 143.2 (CH),
143.9 (CH), 170.7 (CO), 170.8 ppm (CO); ESI-MS: m/z calcd for
C38H64N4O11 [M]: 753.0 [M+H]+, 776.0 [M+Na]+; found: 753.0 [M+H]+,
776 [M+Na]+.
Instruments: Elemental analysis was performed by using a CE Instru-
ments EA-1110 elemental analyzer. 1H and 13C NMR spectra were re-
corded by using a Bruker Avance 300 spectrometer (Bruker, Karlsruhe,
Germany) operating at 300 MHz for 1H and 75 MHz for 13C, or using a
Bruker Avance 400 spectrometer operating at 400 MHz for 1H and
100 MHz for 13C. IR spectra were measured using a Bruker Alpha-T
FTIR spectrometer (Bruker, Ettlingen, Germany). Mass spectra were ob-
tained by using a Thermo Finnigan LCQ Advantage mass spectrometer.
Samples for the mass spectrometry were prepared by dissolving the prod-
uct (2 mg) in methanol (1 mL), then adding this solution (200 mL) to a
water/methanol mixture (50:50, 800 mL). The resulting solution was in-
jected at a flow rate of 5 mLminꢀ1. Total X-ray reflection fluorescence
(TXRF) measurements were using an S2 Picofox (Bruker, Berlin, Ger-
many) with a molybdenum source. Samples for TXRF were prepared by
dissolving the complex (1 mg) in milli-Q H2O (1 mL). This solution was
diluted 10 times, and then this stock solution (500 mL) was mixed with a
Synthesis of catechol derivative H64: The tert-butyl-protected catechol
derivative was dissolved in 6n HCl (10 mL). The mixture was stirred at
room temperature for 1 h and then washed with CH2Cl2 (2ꢁ10 mL). The
aqueous solution was concentrated in vacuo and the final compound was
obtained as a white solid (223 mg, 91%). 1H NMR (300 MHz, D2O): d=
2.63 (t, 2H; PhCH2CH2CONH), 2.96 (t, 4H; NCH2), 3.26 (t, 2H;
CONHCH2CH2Ph), 3.39 (t, 4H; NCH2), 3.46 (s, 2H; NCH2CO), 3.81 (s,
8H; NCH2COOH), 6.63 (d, 1H; Ph), 6.76 (s, 1H; Ph), 6.81 ppm (d, 1H;
Ph); 13C NMR (100 MHz, D2O): d=33.69, 40.36, 50.26, 52.08, 55.47,
55.64, 116.28, 116.80, 121.30, 132.03, 142.37, 143.85, 169.66, 170.31 ppm;
calculated volume of gallium
lanthanide(III) concentration was similar to the gallium
this mixture (10 mL) was placed on a Bruker AXS quartz glass sample
plate for measurement. Absorption spectra were measured using
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
a
IR: n˜ =1733 (CO free acid), 1670 (CO amide), 1194 cmꢀ1 (Ar CO
ꢀ
Varian Cary 5000 spectrophotometer on freshly prepared aqua solutions
in quartz Suprasil cells (115F-QS) with an optical path length of 0.2 cm.
Photophysical data (excitation, emission spectra and lifetimes) were re-
corded using an Edinburgh Instruments FS920 steady state spectro-
fluorimeter. This instrument was equipped with a 450 W xenon arc lamp,
a high-energy microsecond flashlamp mF900H, and an extended red-sen-
sitive photomultiplier (185–1010 nm, Hamamatsu R 2658P). All spectra
are corrected for the instrumental functions. Luminescence lifetimes
under ligand excitation for EuIII complexes were measured by monitoring
stretch); elemental analysis calcd (%) for C22H28O11N4Na
4A
C
38.38, H 5.27, N 8.14; found: C 38.66, H 5.56, N 8.36; ESI-MS: m/z calcd
for C22H32N4O11 [M]: 528.5 [M+H]+; found: 529.1.
Synthesis of lanthanideACHTUNGTRENNUNG(III) complexes: The lanthanideACHTUNTGREN(NUGN III) complexes of
ligand H64 were synthesized according to a general procedure. A solution
of hydrated LnCl3 salt (1.05 equiv) in H2O was added to ligand H64
(1 equiv) dissolved in pyridine, and the mixture was heated at 708C for
3 h. The solvents were evaporated under reduced pressure and the crude
product was then heated to reflux in ethanol for 1 h. After cooling to
7
7
either 5D0! F2 (614 nm) or 5D0! F4 (695 nm) transitions. They are the
300
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Chem. Eur. J. 2012, 18, 293 – 302

Titanium(IV) Catecholate Core
FULL PAPER
average of at least three independent measurements. Quantum yields
were determined by comparative method using a solution of quinine sul-
fate (Fluka) in 1n H2SO4 (Q=54.6%) as standard; estimated error
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Acknowledgements
This work was financially supported by the ARC (research contract
AUWB-2010-10/15 UMONS-5), FNRS and ENCITE. Programs for Re-
search of the French Community of Belgium, and it was performed in
the framework of COST D38 (Metal-Based Systems for Molecular Imag-
ing Applications) and the European Network of Excellence EMIL (Eu-
ropean Molecular Imaging Laboratories) program LSCH-2004-503569.
The authors thank the Center for Microscopy and Molecular Imaging
(CMMI, supported by the European Regional Development Fund and
the Walloon Region). G.D., T.N.P.V., and K.B. acknowledge the I.W.T.
Flanders (Belgium) and the FWO-Flanders (project G.0412.09) for finan-
cial support. S.V.E. is a visiting postdoctoral fellow of the FWO-Flanders
(project G.0412.09). CHN microanalysis was performed by Mr. Dirk
Henot. ESI-MS measurements were made by Mr. Dirk Henot and Mr.
Bert Demarsin, and ICP-MS measurements were performed by Ms. Sol-
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