Synthesis and properties of a functionalized heterobimetallic Re(I)-Gd(III) complex as a potential dual-contrast agent for molecular imaging

Article abstract of DOI:10.1016/j.tetlet.2013.07.121

In the design of dual-imaging probes, the first functionalized and neutral heterobimetallic Re(I)-Gd(III) complex, highly soluble in aqueous solutions, has been prepared. This system exhibits interesting photophysical properties (λ_em = 578 nm, φ = 1.4%) for optical imaging and substantial higher relaxivity (r₁ = 6.6 mM^-1 s ^-1 at 0.47 T and 37 C) than the clinically used MRI contrast agents. Moreover, this system incorporates an aromatic ester functionality suitable for bioconjugation.

Full text of DOI:10.1016/j.tetlet.2013.07.121

Tetrahedron Letters 54 (2013) 5395–5398
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and properties of a functionalized heterobimetallic
Re(I)–Gd(III) complex as a potential dual-contrast agent for
molecular imaging
Alexandre Boulayca,b, Sophie Laine a,b, Nadine Leygue a,b, Eric Benoist , Sophie Laurent
a,b
c
c
a,b,
⇑
a,b,
⇑
Luce Vander Elst , Robert N. Muller , Béatrice Mestre-Voegtle
, Claude Picard
a
CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, SPCMIB, UMR-5068, 118 Route de Narbonne, F-31062 Toulouse cedex 9, France
Université de Toulouse, UPS, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, SPCMIB, 118 route de Narbonne, F-31062 Toulouse cedex 9, France
NMR and Molecular Imaging Laboratory, Department of General, Organic and Biomedical Chemistry, University of Mons, B-7000 Mons, Belgium
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
In the design of dual-imaging probes, the first functionalized and neutral heterobimetallic Re(I)–Gd(III)
complex, highly soluble in aqueous solutions, has been prepared. This system exhibits interesting photo-
Received 10 June 2013
Revised 19 July 2013
Accepted 23 July 2013
Available online 29 July 2013
1
physical properties (kem = 578 nm, / = 1.4%) for optical imaging and substantial higher relaxivity (r -
ꢀ1 ꢀ1
=
6.6 mM
s
at 0.47 T and 37 °C) than the clinically used MRI contrast agents. Moreover, this
system incorporates an aromatic ester functionality suitable for bioconjugation.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dinuclear complex
Rhenium(I)
Gadolinium(III)
Luminescent agent
MRI agent
Dual imaging probe
+
2
6
Re(I) complexes of general formula [ReX(CO)
3
(N^N)] where
copy. A wide range of such d complexes have also been shown to
be highly effective sensitizers for lanthanide(III) ions (Yb(III) and
Nd(III) in particular) which open perspectives for optical bioimag-
0
N^N indicates a chelating
a,a
’-diimine ligand (such as 2,2 -bipyri-
dine (bpy) or 2-pyridyltriazole (pyta)) and X a neutral monoden-
tate ligand (azaheterocycle such as pyridine) are currently
attracting much interest for their wide applications in bioimaging.
These complexes have found uses as biological probes because of
their kinetic inertness in many different chemical and biological
environments, as well as their rich physico-chemical behavior
and their general synthetic flexibility and modularity of the X
component.
3
ing in the NIR domain (900–1200 nm). Recently, it has been dem-
onstrated that these metal tris-carbonyl species may be used as IR
bio-imaging labels, thanks to their specific IR signal in the 1800–
2000 cm region, where biological samples are transparent. Fi-
nally, the derivatization of the coligand X opens many avenues to
bioconjugation or to the formation of hetero dinuclear complexes
ꢀ1
4
5
,6
through the introduction of another chelating unit.
These complexes are well known as triplet metal-to-ligand
On the other hand, the design of multi-imaging probes, allowing
to combine strengths of several imaging modalities was intensified
in recent years due to the emergence of molecular imaging sci-
3
charge transfer ( MLCT) luminescent systems with useful photo-
1
physical properties. They can luminesce at room temperature,
7
with excitation and emission in the visible domain (350–600 nm)
ences. In this context, heterobimetallic complexes based on rhe-
and exhibit long-lived emission (
l
s domain) which potentially
nium(I) architectures are promising dual-imaging probes,
combining both optical imaging and other imaging modalities such
as (i) magnetic resonance imaging (additional Gd(III) core),6 (ii)
can overcome the major drawback of organic fluorophores, that
is the superposition of short-lived fluorescence of biological mate-
rials. As a consequence, these complexes are exploited in in vitro
optical imaging, that is cellular imaging using fluorescence micros-
a,c
111
single photon emission computed tomography (additional
In
9
9m
6b
or
Tc core), (iii) positron emission tomography (additional
8
9Y, 64Cu or 68Ga core).
In this Letter, we report the synthesis of a new bifunctional neu-
tral probe for bimodal imaging, based on fluorescence (Re core)
and magnetic resonance (Gd(III) core) imaging modalities (com-
⇑
Corresponding authors. Tel.: +33 5 6155 6288 (B.M.-V.); tel.: +33 5 6155 6296;
fax: +33 5 6155 6011 (C.P.).
E-mail addresses: mestre@chimie.ups-tlse.fr (B. Mestre-Voegtle), picard@
chimie.ups-tlse.fr (C. Picard).
8
pound 1, Scheme 1). On one hand, this hybrid platform uses a
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.121

5
396
A. Boulay et al. / Tetrahedron Letters 54 (2013) 5395–5398
CO H
catalyst. Under microwave irradiation, this reaction was completed
2
in 2 h and afforded the desired product in 72% yield after purifica-
tion on alumina column. The fully protected bifunctional chelating
agent 4 was synthesized in four steps from commercially available
N
2
N
HO C
CO
H
2
9
reagents as described previously (45% overall yield). After a selec-
N
CO
N
3
2
H
HO C
tive hydrolysis of the methyl ester group, the resulting carboxylic
acid function was activated with a phosphonium-HOBt peptide
coupling reagent (PyBOP). The formation of an amide bond be-
tween this in situ activated carboxylic function and the amino
group of 4-picolylamine afforded the desired product 6 in 79% iso-
lated yield.
2
-
N
2
O C
CO2-
N
G- d
-
O C
3+ 2
MeOOC
N
CO
2
N
N
N
With these building blocks in our hands, the dinuclear Re/Gd
complex 1 was prepared in a four step synthesis in an overall yield
of 18% (Scheme 3). Complexation to the tricarbonylrhenium core
was achieved by refluxing a methanolic solution of the bpyCOOMe
2
HN
O
MeOOC
ligand 2 with [Re(CO)
5
Cl]. Chloride abstraction of the resulting new
N
fac-[Re(CO) (bpyCOOMe)Cl] complex, 7, was achieved by AgOTf in
3
N
N
Re+
1
acetonitrile at 60 °C yielding the corresponding Re-bound acetoni-
trile molecule, 8. The substitution of the metal-bound acetonitrile
molecule by pyridine derivative 6 took place over 1 h under micro-
wave irradiation and led to Re(I) complex 9 in 56% isolated yield.
Cleavage of the tert-butyl ester protecting groups was then accom-
plished using trifluoroacetic acid at room temperature, and the
subsequent treatment of the tetracid compound with 1 equiv of
OC
CO
CO
Scheme 1. Structures of compounds 1–3.
0
functionalized 2,2 -bipyridine moiety (2, bpyCOOMe) which allows
both a photosensitization of the rhenium center as well as biocon-
jugation by means of the aromatic ester functionality.9 On the
3
GdCl in water yields the neutral dinuclear complex Re/Gd 1.
Due to the paramagnetic natureof the gadoliniumpart, the purity
of this dinuclear complex 1 was established on the basis of the
RP-UPLCchromatogram and its structuredeterminedby IR andmass
spectrometric analyses. Thiscomplexis solublein water(> 0.01 M)
and its fluorescence emission and paramagnetic properties in
aerated water solutions remained unchanged for several days at
room temperature, highlighting its kinetic inertness in this medium.
UV–vis and preliminary fluorescence studies of the dinuclear
complex1 wereundertakenatroomtemperatureinaeratedTrisbuf-
fer solutionat pH 7.4 (Fig. 1). The electronicabsorption spectrumof 1
0
other hand, the chelating part of Gd(III) metal uses a 2,2 -bipyri-
dine-based polyaminocarboxylate compound (3), which presents
1
2
a promising ligand for MRI and optical imaging based on Ln(III)
ions. Moreover, an 111In.3 bioconjugate was recently used with
10
success by some of us as a molecular nuclear imaging agent for
the visualization of CCK2R positive tumours in small animals.
The synthesis of starting materials, 4-functionalized 2,2 -bipyr-
idine ligands 2 and 6 is depicted in Scheme 2.
Compound 2 was prepared through a Stille cross-coupling reac-
tion between 2-(tri-n-butyl-stannyl)pyridine and methyl 2-bromo-
1
1
0
exhibits intense absorptions centred at 247 and 315 nm (e = 27,000
ꢀ
1
ꢀ1
pyridine-4-carboxylate in the presence of Pd(P(Ph
3
)
4
) as the
and 19,000 M cm
,
respectively) which are assigned to
⁄
intraligand transitions [
p
-p
(bpyCOOMe and py-bpy moieties)]
because similar absorptions are observed for the uncoordinated li-
gands. The lower-energy absorption shoulders at ca., 340–430 nm
COOMe
3
ꢀ1
ꢀ1
with extinction coefficients in the order of 2 ꢁ 10 M cm are
assigned to spin-allowed metal-to-ligand charge-transfer (MLCT)
MeOOC
N
2
N
⁄
[
dp(Re) ?
p
(bpyCOOMe ligand)] transitions. Excitation of dinucle-
CO tBu tBuO C
Br
2
ar complex at kexc >350 nm gives rise to a sizeable fluorescence
N
CO
N
N
4
3
tBu
tBuO
2
C
emission at 578 nm which is assigned to originate from a MLCT
2
⁄
[
dp
(Re) ?
p
(bpyCOOMe ligand)] excited state on the basis of pre-
+
ii
vious spectroscopic studies of [Re(py)(CO
3
)bpy] complexes.5 The
complex 1 displays a quantum yield of 1.4%, sufficiently large for
detection in fluorescence microscopy. It has to be noted that photo-
COOH
4
Bu
3
Sn
N
physical properties of Re(I) complexes in aqueous solutions are
N
2
N
13
poorly reported in the literature.
CO tBu tBuO C
i
2
N
CO tBu
N
In order to assess the potential of this Re/Gd complex to act as
MRI contrast agent, we estimated its relaxometric properties at
body temperature (310 K) with proton larmor frequencies of 20
and 60 MHz which correspond to magnetic fields operating cur-
rently in clinical imaging (0.2–3T). The proton longitudinal relaxiv-
5
2
tBuO C
2
MeOOC
N
N
iii
2
O
C
N
NH
ities r
and 6.0 mM
1
1
of compound 1 in H
2
O at physiological pH were equal to 6.6
, at 20 and 60 MHz, respectively. These values are
.7–1.9 times larger than those found in mono-aqua contrast
ꢀ1 ꢀ1
s
N
N
2ꢀ
ꢀ
2 2
agents [Gd(DTPA)(H O)] or [Gd(DOTA)(H O)] which are cur-
CO
2
tBu tBuO C
2
1
4
N
CO
N
rently used in clinical practice. They are also larger than those
found in some diaqua Gd(III) complexes such as DO3A deriva-
6
2
tBu
tBuO C
2
1
5
1
tives. Interestingly, no substantial reduction of r value was ob-
Scheme 2. Preparation of compounds 2 and 6. Reagents and conditions: (i)
Pd(PPh (0.2 equiv), CuBr (0.16 equiv), toluene, 140 °C (microwave 260 W), 2 h,
2%; (ii) K CO (1 equiv), methanol/water (2:1), rt, 24 h, 89%; (iii) 4-picolylamine
1.3 equiv), PyBOP (1.6 equiv), iPr NEt (5 equiv), CH Cl , rt, 48 h, 79%.
served when 1 was incubated in phosphate-buffered saline
solution. This behavior suggests that no significant displacement
of water molecule from the Gd(III) coordination sphere in 1 occurs
3 4
)
7
(
2
3
2
2
2

A. Boulay et al. / Tetrahedron Letters 54 (2013) 5395–5398
5397
MeOOC
MeOOC
CF SO3
N
N
3
i
ii
2
Re(CO) Cl
5
+
N
Cl
N
NC-CH
3
Re
Re
CO
OC
CO
OC
CO
7
8
CO
N
tBuO
2
2
C
CF SO3
3
CO tBu tBuO C
2
N
N
CO tBu
2
N
iii
iv
8
1
HN
O
MeOOC
N
N
OC
N
Re
9
CO
CO
Scheme 3. Synthesis of dinuclear complex 1. Reagents and conditions: (i) Re(CO)
reflux, 100%; (iii) 6 (2.5 equiv), THF, 105 °C (microwave 155 W), 1 h, 56%; (iv) (a) CF
two steps).
5
Cl (1.2 equiv), MeOH, 65 °C; overnight, 91%; (ii) AgOTf (1.2 equiv), THF-CH
3
CN, overnight,
3
COOH (300 equiv), CH Cl , rt, 24 h; then, (b) GdCl 6H O, H O (pH 5-6), rt, overnight, 36%
2
2
3
2
2
(
10
3
2
2
1
1
0000
5000
0000
5000
0000
8
6
4
2
0
5
00
600 700 800
Wavelength (nm)
5
000
0
.01
0.1
1
10
100
2
20
280
340
400
460
520
580
Proton Larmor frequency (MHz)
Wavelength (nm)
Figure 2. 1H NMRD relaxivity profile of dinuclear complex 1 (closed circles), Gd 3
open circles) and Gd-DTPA (closed triangles) in water at 310 K. The lines are drawn
Figure 1. Absorption and emission (inset, kexc = 365 nm) of dinuclear complex 1 in
0 mM tris buffer (pH 7.4) at 298 K.
(
5
to guide the eyes.
in the presence of phosphate anion.16 We have also investigated
the relaxometric properties of 1 on a larger range of magnetic fields
group suitable for a subsequent bioconjugation has been conve-
niently prepared. This system is highly soluble in water and aque-
ous buffer solutions, retains exploitable MLCT emission
characteristics of the Re(I) moiety for fluorescence imaging and
displays a high relaxivity of the Gd(III) component promising for
MRI. This hybrid system once bioconjugated with a given targeting
vector will exhibit a unique biodistribution profile for two imaging
probes. It should be useful for in vivo detection of pathologies via
MRI and for supporting surgical guidance via intraoperative fluo-
rescence imaging.
(
(
0.01–60 MHz). The resulting NMRD relaxivity profile of 1 at 310 K
Fig. 2) revealed a high relaxivity at all magnetic fields and has the
3
typical shape for a low-molecular-weight Gd complex. These val-
ues are larger over the whole magnetic field range than those of
the parent complex Gd.3. This is probably the result of the increase
in the molecular weight of 1 with a concomitant slower tumbling
in solution, that is an increase in the rotational correlation time
(s
R
).
Finally, no significant binding of the dinuclear complex 1 with
Human Serum Albumin (HSA) was detected. In the presence of
References and notes
ꢀ1 ꢀ1
4
2
% HSA, relaxivity value r
0 MHz and 310 K. Such weak increase (<15%) of the r
1
of 7.4 mM
s
was observed at
value does
1
1. Coleman, A.; Brennan, C.; Vos, J. G.; Pryce, M. T. Coord. Chem. Rev. 2008, 252,
1
7
not indicate a significant interaction of the complex with HSA.
2585–2595.
2.
(a) Balasingham, R. G.; Thorp-Greenwood, F. L.; Williams, C. F.; Coogan, M. P.;
Pope, S. J. A. Inorg. Chem. 2012, 51, 1419–1426; (b) Lo, K. K.-W.; Zhang, K. Y.; Li,
S. P.-Y. Eur. J. Inorg. Chem. 2011, 3551–3568; (c) Lloyd, D.; Coogan, M. P.; Pope,
S. J. A. Rev. Fluoresc. 2010, 7, 15–44; (d) Lo, K. K.-W.; Louie, M.-W.; Zhang, K. Y.
Coord. Chem. Rev. 2010, 254, 2603–2622.
This result is promising, since a molecular imaging agent must spe-
cifically bind to its target while avoiding non-specific interferences
with blood macromolecules such HSA.
In conclusion, a trifunctional system combining a tridentate do-
3.
(a) Perry, W. S.; Pope, S. J. A.; Allain, C.; Coe, B. J.; Kenwright, A. M.; Faulkner, S.
Dalton Trans. 2010, 39, 10974–10983; (b) Kennedy, F.; Shavaleev, N. M.;
Koullourou, T.; Bell, Z. R.; Jeffery, J. C.; Faulkner, S.; Ward, M. D. Dalton Trans.
nor set for complexation of a {Re(CO)
3
} moiety, an octadentate do-
nor set for complexation of a Gd(III) ion and an aromatic ester

5
398
A. Boulay et al. / Tetrahedron Letters 54 (2013) 5395–5398
ꢀ
2
007, 1492–1499; (c) Pope, S. J. A.; Coe, B. J.; Faulkner, S.; Laye, R. H. Dalton
IR (
m
max, cm 1) 2039 and 1924 (br) (CBO), 1734 (C@O); HRMS (DCI, CH4)+
+
Trans. 2005, 1482–1490.
m/z Calcd for [C18
Calcd for C18
3.02; N, 5.44. Compound 9. UPLC (Acquity BEH C18 column, 1.7
50 ꢁ 2.1 mm, gradient: HCOONH 10 mM pH 4/CH CN + 10% HCOONH
mM pH 4 80/20 to 0/100 in 7 min; flow: 0.6 mL/min): t
= 5.07 min. 1H NMR
(300 MHz, CDCl ) d (ppm) = 9.23 (d, J = 5.4 Hz, 1H), 9.11 (dd, J = 0.8, 5.4 Hz, 1H),
H
N
13 3
O
8
F
3
SRe–CH
3
CN] = 631.9640. Found 631.9697. Anal.
4
.
.
Clède, S.; Lambert, F.; Sandt, C.; Gueroui, Z.; Réfrégiers, M.; Plamont, M.-A.;
Dumas, P.; Vessières, A.; Policar, C. Chem. Commun. 2012, 7729–7731.
(a) Lo, K. K.-W.; Louie, M.-W.; Sze, K.-S.; Lau, J. S.-Y. Inorg. Chem. 2008, 47, 602–
H
13
F
N
3 3
O
8
ReSꢂOEt
2
: C, 35.29; H, 3.10; N, 5.61. Found: C, 35.03; H0 ,
M, 100 ÅA ,
100
l
5
4
3
4
6
11; (b) Amoroso, A. J.; Arthur, R. J.; Coogan, M. P.; Court, J. B.; Fernandez-
Moreira, V.; Hayes, A. J.; Lloyd, D.; Millet, C.; Pope, S. J. A. New J. Chem. 2008, 32,
097–1102; (c) Lo, K. K.-W.; Ng, D. C.-M.; Hui, W.-K.; Cheung, K.-K. J. Chem. Soc.,
R
3
1
8.94 (d, J = 0.7 Hz, 1H), 8.69 (d, J = 1.3 Hz, 1H), 8.63 (d, J = 8.1 Hz, 1H), 8.32 (d,
J = 7.8 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.22 (dd, J = 1.5, 5.7 Hz, 1H), 8.05–7.99
(m, 3H), 7.83–7.73 (m, 2H), 7.58 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 6.3 Hz, 2H), 4.58
(br s, 2H), 4.13(s, 2H), 4.08 (s, 2H), 4.04 (s, 3H), 3.52 (s, 4H), 3.50
Dalton Trans. 2001, 2634–2640.
6
.
.
(a) Tropiano, M.; Record, C. J.; Morris, E.; Rai, H. S.; Allain, C.; Faulkner, S.
Organometallics 2012, 31, 5673–5676; (b) Boulay, A.; Artigau, M.; Coulais, Y.;
Picard, C.; Mestre-Voegtlé, B.; Benoist, E. Dalton Trans. 2011, 40, 6206–6209; (c)
Koullourou, T.; Natrajan, L. S.; Bhavsar, H.; Pope, S. J. A.; Feng, J.; Narvainen, J.;
Shaw, R.; Scales, E.; Kauppinen, R.; Kenwright, A. M.; Faulkner, S. J. Am. Chem.
Soc. 2008, 130, 2178–2179.
1
9
(s, 4H), 1.44 (s, 18H), 1.43 (s, 18H); F NMR (300 MHz, CDCl
3
) d (ppm) =
+
ꢀ
+
ꢀ78.3; HRMS (ESI ) m/z Calcd for [C59
70 8 17 3 3
3
H N O F SRe–CF SO ] 1287.4541.
Found 1287.4591.Dinuclear complex 1: UPLC (Acquity BEH C18 column,
0
1.7
HCOONH
= 1.59 min; HRMS (ESI) Calcd for [C42
Found 1220.1099;
l
M, 100 ÅA , 50 ꢁ 2.1 mm, gradient: HCOONH
100 mM pH 4 80/20 to 0/100 in 7 min; flow:+ 0.6 mL/min):
+
4 3
10 mM pH 4/CH CN + 10%
7
(a) Kobayashi, H.; Longmire, M. R.; Ogawa, M.; Choyke, P. L. Chem. Soc. Rev.
4
2
011, 40, 4626–4648; (b) Cassidy, P. J.; Radda, G. K. J. R. Soc., Interface 2005, 2,
t
R
H
34
8
N O
14ReGd + H] = 1220.1071.
1
33–144.
ꢀ
1
ꢀ
8
9
.
.
A complex with a neutral overall charge may be advantageous for getting lower
proteins or other biological species interactions.
IR (m
max, cm ) 2027 and 1914 (br) (CBO), 1686 (C@O), 1614 (COO ); UV–vis
ꢀ
1
ꢀ1
(Tris buffer pH 7.4 50 mM): kmax
(e, M cm ) = 247 (27,000), 315 (19,000),
Havas, F.; Leygue, N.; Danel, M.; Mestre, B.; Galaup, C.; Picard, C. Tetrahedron
367 (2400). The absence of free Gd(III) ion in 1 was verified using a classic test
with an arsenazo indicator solution.
2
009, 65, 7673–7686.
1
0. In aqueous solutions, monoaqua Gd.3 complex displays a r
1
relaxivity of
.4 s mM at 20 MHz and 310 K, while monoaqua Eu.3 complex emits in the
visible region with an emission quantum yield of 9% and an emission lifetime
of 600 s.
13. See for example: Kirgan, R. A.; Sullivan, B. P.; Rillema, D. P. Photochemistry and
Photophysics of Coordination Compounds II In Topics in Current Chemistry;
Balzani, V., Campagna, S., Eds.; Springer, 2007; Vol. 281, pp 45–100.
ꢀ
1
ꢀ1
4
ꢀ
1
ꢀ1
for [Gd(DTPA)(H
2
O)]2- or
l
14. At 20 MHz and 310 K, r
1
= 3.8 and 3.5 s mM
O)] , respectively. Laurent, S.; Vander Elst, L.; Muller, R. N.
Contrast Media Mol. Imaging 2006, 1, 128–137.
-
1
1
1. Brillouet, S.; Dorbes, S.; Courbon, F.; Picard, C.; Delord, J. P.; Benoist, E.; Poirot,
[Gd(DOTA)(H
2
M.; Mestre-Voegtlé, B.; Silvente-Poirot, S. Bioorg. Med. Chem. 2010, 18, 5400–
ꢀ
1
ꢀ1
5
412.
1 2 2
15. At 20 MHz and 298 K, r = 7.6 and 6.0 s mM for 1 and [Gd(DO3A)(H O) ],
2. Selected characterization data for compounds 6, 8, 9 and 1. Compound 6. 1H NMR
respectively. Baranyai, Z.; Tei, L.; Giovenzana, G. B.; Kalman, F. K.; Botta, M.
Inorg. Chem. 2012, 51, 2597–2607.
(
3
300 MHz, CDCl ) d (ppm) = 8.71 (d, J = 1.4 Hz, 1H), 8.43 (d, J = 6.0 Hz, 2H), 8.24
(
dd, J = 0.5, 7.8 Hz, 1H), 8.13 (t, J = 5.9 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.71 (t,
16. This result is in contrast to what has been previously reported for a dinuclear
Re/Gd complex based on a bpy and DO3A cores (Re(I) and Gd(III) chelating
J = 7.8 Hz, 1H), 7.47 (dd, J = 0.5, 7.8 Hz, 1H), 7.21 (d, J = 6.0 Hz, 2H), 4.62 (d,
J = 5.9 Hz, 2H), 4.10 (s, 2H), 4.00 (s, 2H), 3.44 (s, 8H), 1.36 (s, 36H). MS (ESI) m/
z: 805.5 (100%) [M+H] . Anal. Calcd for C43
Found: C, 63.91; H, 7.47; N, 10.12. Compound 8. H NMR (300 MHz, CDCl
(
5
5
+
6c
units, respectively).
+
H
60
N
6
O
9
: C, 64.16; H, 7.51; N, 10.44.
17. As reported in the literature, a significant interaction between Gd(III) complex
and HSA is characterized by an increase in the relaxation rate larger than 60%.
Laurent, S.; Parac-Vogt, T. N.; Kimpe, K.; Thirifays, C.; Binnemans, K.; Muller, R.
N.; Vander Elst, L. Eur. J. Inorg. Chem. 2007, 2061–2067.
1
3
) d
ppm) = 9.08 (dd, J = 0.5, 5.7 Hz, 1H), 8.99 (d J = 0.9 Hz, 1H), 8.96 (dd, J = 0.8,
.5 Hz, 1H), 8.66 (d, J = 8.2 Hz, 1H), 8.30 (td, J = 8, 1.5 Hz, 1H), 8.15 (dd, J = 1.6,
.7, 1H), 7.71 (ddd, J = 1.1, 5.5, 7.6 Hz, 1H), 4.06 (s, 3H), 2.25 (s, 3H);