2026 PhD prize to Katharina Zimmeter

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During my PhD thesis in the “Biometals and Biological Chemistry” team under the supervision of Prof. Peter Faller and Dr. Angélique Sour, I worked on the development of responsive MRI contrast agents (CAs) for the detection of copper(II) in biological media. Copper (Cu) is an essential element, whose homeostasis is tightly regulated, yet dysregulation is associated with several diseases. In particular, an increase in the CuII fraction bound to human serum albumin (HSA) in the blood has been observed in Wilson’s disease and in Alzheimer’s disease, alongside elevated extracellular brain CuII-levels and Cu accumulation in senile amyloid-β plaques. The visualization of the copper distribution by magnetic resonance imaging (MRI) using responsive CAs therefore represents a promising strategy to improve our understanding and diagnosis of these pathologies. However, the few CuII-responsive MRI sensors reported so far suffer from major limitations for in vivo use, including insufficient affinity to compete with physiological CuII-carriers such as HSA, poor selectivity over ZnII, and MRI responses too weak for reliable detection.

The aim of my PhD was to address these challenges by developing GdIII-based responsive MRI CAs containing CuII-binding sites specifically optimized for strong and selective recognition, and to characterize them under physiologically relevant conditions in the presence of competing ligands and metal ions. Beyond affinity and selectivity, CuII-binding has to trigger a significant MRI signal enhancement through an increase in longitudinal relaxivity (r₁). I explored two complementary strategies: q-based agents, where CuII binding increases the number of water molecules directly coordinated to GdIII, and τR-based agents, where CuII-mediated ternary complex formation with HSA slows molecular rotation, both leading to an enhanced MRI signal.

During this work, I synthesized and characterized four q-based and three τR-based candidates. Their originality lies in the design of optimized CuII-binding motifs: a bioinspired peptidic ligand derived from the native HSA CuII-site for q-based agents, and α-pyridyl thiosemicarbazones, known to form ternary HSA adducts, for τR-based systems. The most promising compound, GdIII–DO3A–pyrGH, contains a pyridine switching arm that coordinates GdIII in the absence of CuII and relocates upon CuII-binding, opening an additional water coordination site on GdIII which increases the relaxivity and thus the MRI signal (Figure A and B, Zimmeter et al. Inorg Chem., 2024). This design produced an exceptional ~400% relaxivity increase upon CuII-binding (Figure C1), exceeding previously reported CuII-responsive MRI agents, together with excellent selectivity for CuII, showing an MRI response only in presence of this ion (Figure C2). However, its CuII-affinity remained only micromolar, in striking contrast with the femtomolar affinity of the isolated peptide binding site (Figure C3, Zimmeter et al., Inorg. Chem., 2023). Through DFT calculations performed in collaboration with Dr. Carlos Platas-Iglesias, we showed that this loss probably originates from steric constraints and distortion of the CuII-coordination sphere induced by the neighbouring GdIII-complex.

I subsequently investigated structural modifications to improve CuII-affinity, including the introduction of spacers to reduce steric and electrostatic hindrance between the CuII-ligand and the GdIII-complex (Zimmeter et al., Dalton Trans., 2025). While affinity could indeed be enhanced, this occurred at the expense of the MRI response, highlighting the challenge of simultaneously optimizing all critical parameters of a responsive CA. In parallel, I developed three τR-based CAs showing good CuII-affinities and measurable relaxivity increases upon ternary complex formation with HSA.

Overall, my PhD work constitutes an important proof of principle for the two classes of CuII-responsive MRI contrast agents and a starting point for the development of new compounds. As MRI is no quantitative technique, the principal aim of these sensors lies in the visualisation of the copper distribution and of variations associated to diseases, contributing to a better understanding of the underlying mechanisms and potentially to diagnostic and treatment monitoring.

Figure A) Principle of q-based CuII-responsive MRI CAs, green: GdIII-complex, blue: CuII-binding site, red: switching arm. B) Structure of GdIII-DO3A-pyrGH. C) Characterisation of GdIII-DO3A-pyrGH: 1) Relaxometric titration of GdIII-DO3A-pyrGH (2 mM) by addition of CuII in HEPES buffer pH 7.4, measured at 60 MHz, 25°C. 2) T1-weighted images of phantoms of GdIII-DO3A-pyrGH in absence and presence of metal ions (0.3 mM GdIII-DO3A-pyrGH, 1 eq. CuII, 10 eq. ZnII, 10 eq. CaII, HEPES buffer pH 7.4, 9.4 T, 25°C). 3) Structures and CuII-affinities of GdIII-DO3A-pyrGH and its isolated CuII-binding site.
  • K. Zimmeter, B. Vileno, A. Pallier, C. Platas-Iglesias, P. Faller, C. S. Bonnet, A. Sour, Lanthanide complexes bearing a bioinspired CuII binding site with picomolar affinity: synthesis, structural, relaxometric and luminescence studies, Dalton Trans, 2025, 54, 15432, doi: 10.1039/D5DT01735A
  • C. Perdriau, A. Luton, K. Zimmeter, M. Neuville, C. Saragaglia, C. Peluso-Iltis, J. Osz, B. Kauffmann, G. W. Collie, N. Rochel, G. Guichard, M. Pasco, Guanidinium-Stapled Helical Peptides for Targeting Protein-Protein Interactions, Angew. Chem. Int. Ed., 2025, e202416348, doi: 10.1002/anie.202416348.
  • M. Sanadar, K. Zimmeter, H. Martin, A. Pallier, B. Vileno, P. Faller, A. Sour, C. S. Bonnet, Exploring Bioinspired Ln3+ Complexes for Cu2+ Detection: Design and Efficacy as MRI Contrast Agents, EurJIC, 2025, 28, e202500049, doi: 10.1002/ejic.202500049.
  • K. Zimmeter, A. Pallier, B. Vileno, M. Sanadar, F. Szeremeta, C. Platas-Iglesias, P. Faller, C. S. Bonnet, A. Sour, A Bioinspired Cu2+-Responsive Magnetic Resonance Imaging Contrast Agent with Unprecedented Turn-On Response and Selectivity, Inorg Chem, 2024, 63, 23067–23076, doi.org/10.1021/acs.inorgchem.4c03631.
  • K. Zimmeter, B. Vileno, C. Platas-Iglesias, B. Vinjamuri, A. Sour, P. Faller, Derivatization of the Peptidic Xxx-Zzz-His Motif toward a Ligand with Attomolar CuII Affinity under Maintaining High Selectivity and Fast Redox Silencing, Inorg Chem, 2023, 62, 9429–9439, doi: 10.1021/acs.inorgchem.3c00480

Current affiliation: Laboratoire de Chimie de Coordination (LCC), UPR 8241, CNRS, Toulouse, Equipe ALAMBIC (Dr. Christelle Hureau, Dr. Emilie Mathieu)

Past affiliations : PhD thesis and ATER : Equipe Biométaux et Chimie Biologique (Pr. Peter Faller, Dr. Angélique Sour), UMR7177, Université de Strasbourg, Master thesis : Institut Européen de Chimie et Biologie (IECB), Bordeaux (Pr. Gilles Guichard, Dr. Morgane Pasco)


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