Download Team CIE The CIE team comprises various disciplines, involving

Team CIE
The CIE team comprises various disciplines, involving synthetic and coordination chemistry, biology,
physics and exobiology, all linked by a common theme centred around imaging. The last decade has
seen a spectacular evolution of imaging techniques in medical, biological and other areas in which
chemistry has a pivotal role. Our team has gained international recognition in three, partially
interconnected axes: (i) lanthanide luminescence and probes for biological optical imaging, (ii) MRI
contrast agents and small animal MR imaging and (iii) exobiology, where imaging of ancient
carbonaceous biosignatures in rocks in their mineral and elemental context is of prime importance.
Our most important achievements include: creation of highly near-infrared luminescent lanthanidebased small molecules, macromolecules and nanomaterials and their successful use for cellular and
in vivo optical imaging; the design of metal-based responsive molecular MRI probes that are able to
report on specific biomarkers; the combination of multimodal and theragnostic capabilities in single
molecules or nanosized objects; novel MR imaging and spectroscopic approaches to characterize
animal models (drosophila, mice, rats) of diseases; and new insights into the environment and
formation of prebiotic building bricks leading to the first cells, characterisation of the oldest
signatures of life preserved on Earth and their recent analogues, and search for extraterrestrial life.
The team involves three thematic groups:
A. Luminescent lanthanide compounds, optical spectroscopy and bioimaging
B. Metal complexes and MRI
C. Exobiology
B. Metal complexes and MRI
This thematic group integrates expertise in probe chemistry and small animal MR imaging.
A. Probe chemistry
Our chemistry is devoted to the design, synthesis and characterization of innovative probes
based on metal, mainly lanthanide complexes for applications in magnetic resonance imaging.
We apply coordination chemistry concepts to create molecular MR imaging probes. We are also
interested in fundamental aspects, such as optimizing complex stability and understanding MRI
efficiency of paramagnetic systems. We cover various steps of probe development: (i) design and
synthesis of novel ligands, (ii) full physico-chemical characterization of the complexes, involving the
determination of individual microscopic parameters that govern relaxivity or chemical exchange
saturation transfer (CEST), (iii) assessment of stability and kinetic inertness related to in vivo
toxicity, (iv) in vitro/in vivo MRI evaluation of the agents.
Major chemistry projects involve:
Enzyme-responsive MRI agents: We work on MRI probes containing a selfimmolative linker between the Ln3+ complex and the enzyme-specific
substrate. Enzymatic cleavage initiates an electronic cascade that leads to
structural changes in the complex, with concomitant relaxivity or PARACEST
response. This platform has been extended to optical detection by
incorporating a pyridine chromophore in the ligand and constitutes the first
example where a single molecular system can be used as a responsive imaging
agent in three different independent modalities (T 1-weighted and Chemical
Exchange Saturation Transfer MRI, optical imaging). These results have been
recently published (J. Am. Chem. Soc. 2016, 138, 2913−2916) and highlighted on the cover of JACS
(collaboration with P. Durand, ICSN, and S. Petoud).
Detection of neurotransmitters (NT): has been achieved by a synthetic
molecular platform with recognition moieties for zwitterionic NTs. NT
binding occurs via ditopic interactions (i) between a positively charged Gd 3+
chelate and the carboxylate function of the NT and (ii) between a mono- or triazacrown ether and
the amine group of the NT (figure). One probe was successfully used to monitor neural activity in
acute mouse brain slices by MRI which showed for the first time that Gd 3+-based probes can provide
an alternative to monitor brain function under biologically relevant conditions (collab. G.
Angelovski, Max Planck Tübingen, ACS Chem. Neuroscience, 2015, 6, 219–225; Chem. Eur. J. 2015,
21, 11226 – 11237).
Zn2+ sensing: Gd3+ complexes are conceived using a modular design, by coupling a pyridine scaffold
for Gd3+ complexation to Zn2+ binding DPA derivatives via different linkers, which allows
optimization of each part of the molecule (Chem. Eur. J. 2014, 20, 10959 – 10969).
In an effort to visualize -amyloid plaques by multimodal imaging, various PiB derivatives have
been conjugated through different linkers to DO3A-type chelates. Affinity and interaction
mechanism with monomer and aggregated A1-40 were assessed by various techniques (SPR, STDNMR, CD, DLS, TEM). These results showed that even slight differences in chelate structure have
important consequences on peptide aggregation and shed light on the behaviour of amyloidtargeted metal complexes in general. Although ex vivo immunohistochemical data showed selective
targeting of A plaques on AD human brain tissue, in vivo biodistribution with 111In- or 68Gaanalogues pointed to moderate BBB penetration in mice, even if a 2.5-fold greater BBB permeability
was observed in transgenic APP/PS1 model as compared to control mice. (coll. C. Geraldes,
Coimbra; Chem. Eur. J. 2015, 21, 5413–5422; ACS Med Chem Lett, 2013,4, 436-440).
Mn-based MRI probes. Some years ago we were among the first to “rediscover” Mn 2+ complexes as
potential MRI agents. Several macrocyclic structures have been explored in order to find a balance
between MRI efficiency and complex stability and inertness. Our dissociation kinetic studies on
MnDOTA provided the first experimental proof that not all Mn2+ complexes are kinetically labile
(Dalton Trans. 2011, 40, 1945-1951). Recently, we have started to investigate Mn3+ complexes, for
which the relaxation mechanism is poorly understood (J. Inorg. Biochemistry, 2016, 154, 50–59).
Theragnostic probes. We are combining MRI and photodynamic therapy via molecular or
nanoparticle approaches. Gd3+ chelates were conjugated to
porphyrin-photosenzitizers, some for two-photon excitation. We
showed that their chemical association can be beneficial for both
the relaxation properties and the photosensitizer (collab. V. Heitz,
Strasbourg; Chem. Eur. J. 2016, 22, 2775–2786, Inorg. Chem. 2016,
55, 4545–4554). In a proof of concept X-ray induced PDT study, we
took advantage of the X-ray excited luminescence of lanthanides to
locally generate light in a micellar system comprising amphiphilic
Ln-chelates and integrating hypericin as photosensitizer in its
hydrophobic core (figure). This circumvents intrinsic depth
limitations of PDT and could be synergistically combined with classical radiotherapy and MRI
tracking of the probe (collab. M. Réfrégiers, SOLEIL; Nano Research, 2015, 8, 2373-2379).
B. Small animal MR imaging
The MRI activities focus on preclinical research at high field (7, 9.4T) including morphological,
perfusion, diffusion studies, angiography, susceptibility weighted and CEST imaging. A major force is
our specific expertise in in-house design and construction of dedicated RF coils,
conception/optimisation of pulse sequences and image analysis (texture analysis). Our MRI studies
aim on characterizing cerebral, pulmonary, muscular and hepatic tissues in small animal models of
inflammation, trisomy 21, malaria or cancer and on assessment of chronic brain exposure to
environmental xenobiotics (pesticides, bisphenol A). For in vivo spectroscopy, we develop 1H or 1H
observed-13C edited sequences to monitor brain or liver metabolism.
1.The effect of perinatal exposure to Bisphenol A (BPA) and its chlorinated derivatives have
been assessed in mouse brain and liver. BPA is an environmental xenoestrogen to which humans are
regularly exposed. Chlorinated BPA products, generated by hypochlorite disinfection of tap water,
show higher affinity to oestrogen receptors but their effects remain unknown. As they can be
detected in human embryos, we assessed the effect of perinatal exposure to dichloro-BPA on mouse
brain and liver by in vivo 1H MRS and MRI. We showed that gestational and lactational exposure even
at very low dose, (20μg/kg/day) induces precocious disturbances in hippocampal metabolism and
microstructure and alters lipid composition in offspring mice. These results raise questions about
the risk
tCr
NAA
Cho
Tau
tC
r Glx
Glx
Ins
Glx
NAA, N-acetylaspartate; Glx, glutamate and glutamine
pool, tCr, total creatine; Cho, choline; Ins, myo-Inositol
2. We have evaluated bimodal targeted nanoprobes, consisting of a superparamagnetic iron oxide
core covalently grafted with the NIR fluorochrome NHS-cyanine 5-5, for early stage tumour diagnosis
in an orthotopic model of mammary cancer. MRI findings confirmed efficient in vivo
immunotargeting of the probe to the HER2 tumor in addition to its accumulation in main clearance
organs (spleen, liver and kidneys). In vivo whole body fluorescence imaging was correlated with the
MRI results (collab. I. Chourpa, Tours).
3. MR diffusion and perfusion to study mice intrauterine growth restriction
The animal model of IUGR considered IS a
model of placental hypoperfusion by ligation
of the uterine artery in rats previously
described by Wigglesworth et al. The
parameters defined in perfusion MRI showed a
downward flow (11%) and plasma volume (32%)
in the placentas of fetus affected by IUGR.
They also revealed an increase in the
permeability of placental capillaries. The DWI
(diffusion weighted images) has revealed a
significant alteration in plasma diffusion
(collab. C. Arthuis, Tours).
4. Lung MRI with hyperpolarized Xe
Xenon inside biosensors (made
of an optically active
cryptophane scaffold. This cryptophane will show a high
affinity for xenon) takes a specific spectral signature that enables
localization of the target via spectroscopic imaging. As sensitivity of
the method is still a concern, we plan to increase the contrast by
conceiving a smart biosensor, for which the resonance frequency of
caged xenon is different whether the biological target has been
reached or not. Therefore the grafting on the xenon host of a short
peptide cleavable by an enzyme will ensure that the local
environment of the caged xenon atom is drastically changed, which
will be translated into a consequent chemical shift variation. As the
lungs are organs for which the introduction of xenon is easy, the
enzyme that we will target is Caspase-1, which is activated by
pulmonary inflammation (Collab. P. Berthault, Saclay, T. Brotin,
Lyon,I. Couillin, Orléans).
Major recent publications (2013-2016):
Probe chemistry:
 S. Lacerda, C. S. Bonnet, A. Pallier, S. Villette, F. Foucher, F. Westall, F. Buron, F.
Suzenet, C. Pichon, S. Petoud and É. Tóth, Lanthanide-based, near-infrared luminescent
and magnetic lipoparticles: monitoring particle integrity, Small, 2013, 9, 2662-2666.
 A. F. Martins, J.-F. Morfin, A. Kubíčková, V. Kubíček, F. Buron, F. Suzenet, M. Salerno, A. N.
Lazar, C. Duyckaerts, N. Arlicot, D. Guilloteau, C. F.G.C. Geraldes, É. Tóth, PiB-conjugated,
metal-based imaging probes: multimodal approaches for the visualization of-amyloid
plaques ACS Med Chem Lett, 2013,4, 436-440.
 A. Carné-Sánchez, C. S. Bonnet, I. Imaz, J. Lorenzo, É. Tóth, D. Maspoch, Relaxometry
Studies of a Highly Stable Nanoscale Metal-Organic Framework made of Cu(II), Gd(III) and
the Macrocyclic DOTP, J. Am. Chem. Soc. 2013, 135, 17711-17714.
 C. S. Bonnet, F. Caillé, A. Pallier, J.-F. Morfin, S. Petoud, F. Suzenet, and É. Tóth,
Mechanistic studies of Gd3+-based MRI contrast agents for Zn2+ detection: towards a
rational design, Chem. Eur. J. 2014, 20, 10959 – 10969.
 F. Oukhatar, H. Meudal, C. Landon, C. Platas-Iglesias, N. K. Logothetis, G. Angelovski, and
É. Tóth, Macrocyclic Gd3+ complexes with pendant crown ethers designed for binding
zwitter-ionic neurotransmitters, Chem. Eur. J. 2015, 21, 11226 – 11237
 J. He, C. S. Bonnet, S. V. Eliseeva, S. Lacerda, T. Chauvin, P. Retailleau, F. Szeremeta, B.
Badet, S. Petoud, É. Tóth and P. Durand, Prototypes of Lanthanide(III) Agents Responsive to
Enzymatic Activities in Three Complementary Imaging Modalities: Visible/Near-Infrared
Luminescence, PARACEST- and T1-MRI, J. Am. Chem. Soc. 2016, 138, 2913−2916.


Small animal MRI
Même S., Joudiou N., Szeremeta F., Mispelter J., Louat F., Decoville M., Locker D. and
Beloeil J. C. In vivo magnetic resonance microscopy of drosophila at 9.4T. (2013) Magnetic
resonance imaging, 31, 109-19.
Même S., Joudiou N., Yousfi N., Szeremeta F., Lopes-Pereira P., Beloeil J. C., Herault Y.
and Même W. In Vivo 9.4T MRI and 1H MRS for Evaluation of Brain Structural and Metabolic
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

Changes in the Ts65Dn Mouse Model for Down Syndrome. (2014) World Journal of
Neuroscience, 4, 152-63.
Mouton-Liger F., Sahún I., Collin T., Lopes Pereira P., Masini D., Thomas S., Paly E., Luilier
S., Même S., Jouhault Q., Bennaï S., Beloeil J.-C., Bizot J.-C., Hérault Y., Dierssen M. and
Créau N. Developmental molecular and functional cerebellar alterations induced by
PCP4/PEP19 overexpression: Implications for Down syndrome. (2014) Neurobiology of
Disease, 63, 92-106.
Carrouee A., Allard-Vannier E., Même S., Szeremeta F., Beloeil J. C. and Chourpa I.
Sensitive Trimodal Magnetic Resonance Imaging-Surface-Enhanced Resonance Raman
Scattering-Fluorescence Detection of Cancer Cells with Stable Magneto-Plasmonic
Nanoprobes. (2015) Analytical Chemistry, 87, 11233-41
Sarou-Kanian V., Joudiou N., Louat F., Yon M., Szeremeta F., Même S., Massiot D., Decoville
M., Fayon F. and Beloeil J. C. Metabolite localization in living drosophila using High
Resolution Magic Angle Spinning NMR. (2015) Scientific Reports, 5, 9872.
Book edition:
"The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging" edited by A. E. Merbach,
L. Helm and É. Tóth, John Wiley & Sons, 2nd edition 2013