Responsive Probes for the quantitative detection of Zn(II) and Cu(II) by MRI and PET/SPECT – ZiCoRes

We will design, synthetise and characterise responsive MRI probes for zinc and copper detection. The probes will be designed in a modular approach consisting of three building blocks :
(1) the Ln3+ chelate, which should be thermodynamically stable, kinetically inert, and should not interact with physiological anions
(2) the unit complexing Zn2+ or Cu2+, which should be selective for the chosen cation
(3) a linker between the two previous units
Each building block can be optimized separately. Potentiometry will be used to assess the thermodynamic stability of the complexes formed. Relaxometry and 17O NMR will be used to determine the parameters influencing the efficacy of the complex as an MRI probe. Complementary techniques (such as UV, fluoresence) can also be used if needed.

We have successfully synthetised a first ligand. the synthesis haas been otimised to obtain sufficient quantities to perform physico-chemical studies. The results are promissing as Zn2+ detection by relaxometry is possible with the corresponding GdL complex in the presence of BSA (Bovine Serum Albumin).
Two other ligands for Zn2+ detection are currently synthetised and should be obtained soon.
From the point of view of the production of radioactive Ln3+, we have focused on the production of 165Er from 165Ho. The results obtained are very encouraging, and studies to separate remaining Ho for Er are currently on-going.

We plan a thorough physico-chemical study of the complexes corresponding to the two ligands being synthetised: stability, selectivity for Ln3+ over physiological cations, relaxometric response to Zn2+, selectivity for Zn2+ over other physiological cations. Depending on the results obtained, we will design and study new probes with optimized parameters, especially concerning the thermodynamic stability and kinetic inertness of the Ln complexes.

Publication: Bonnet C.S., Caillé F., Pallier A., Morfin J.-F., Petoud S., Suzenet F., Tóth E., Chem. Eur. J., 2014, 20, 10959-10969. “Mechanistic studies of Gd3+-based MRI contrast agents for Zn2+ detection: towards a rational design”

Communications at international conferences: Dalton discussion – Metal ions in Medical imaging: optical, radiopharmaceutical and MRI contrast. Sept. 2014, York (Royaume-Uni) « Mechanistic studies of Gd3+-based MRI contrast agents for Zn2+ detection: Towards a rational design »

Communications at national conferences: 1. Groupe d’étude en chimie des Polyamines cycliques et linéaires (GPOL 2014).Juin 2014, Obernai.
2. Journées de la division de Chimie de Coordination. Janvier 2014, Rennes.
“Novel MRI contrast agents for zinc detection”,

Molecular imaging aims at visualizing the expression and function of bioactive molecules which often represent specific molecular signatures of diseases. Metal ions, which are involved in many fundamental biological processes, are highly regulated, and their misregulation is connected to long term and acute diseases. The assessment and understanding of metal distribution in living systems by non-invasive imaging is crucial to give more insight into metal homeostasis as well as into diseases and could ultimately contribute to their proper treatment.

The objective of the present project is to design, synthetize and validate efficient imaging probes for quantitative Zn2+ and Cu2+ detection. Our approach will be based on combining two imaging modalities: Magnetic Resonance Imaging (MRI), and PET (Positron Emission Tomographie) or SPECT (Single Photon Emission Tomography). MRI will be the “responsive” technique, and PET/SPECT will be the “quantitative” technique. We propose to design a chelate that can complex Gd3+ for MRI or a radioactive Ln3+ active in PET or SPECT. The two complexes will be mixed in ratio accounting for the differences of sensitivity of the two techniques. The similar chemical behavior of the two Ln3+ complexes will allow for an identical biodistribution, and for the superimposition of the images obtained with the two techniques. This approach offers several advantages including: (i) a single ligand synthesis, (ii) a minimal handling of the radioactive elements, (iii) a versatile design.
The ligands will be designed in a modular approach consisting of three building blocks :
(1) the Ln3+ chelate, which should be thermodynamically stable, kinetically inert, and should not interact with physiological anions
(2) the unit complexing Zn2+ or Cu2+, which should be selective for the chosen cation
(3) a linker between the two previous units
The MRI response of the Gd3+ complex will be based on a change of the hydration number upon Zn2+ or Cu2+ coordination. The modular approach will allow us to separately optimize the various building blocks of the agents thus to rapidly design the most efficient molecules for Zn2+ and Cu2+ detection. The design process will also strongly rely on a comprehensive physical-chemical study and understanding of the microscopic parameters influencing the MRI response.
The in vitro and in vivo toxicity, as well as the biodistribution of the compounds will also be evaluated and taken into account to identify the most promising compounds.
This proposal is a first step towards the in vivo imaging of Cu2+ and Zn2+ which will require further development in terms of targeting and blood brain barrier crossing. The present project will bring new competences to the laboratory, particularly through the collaboration with the CEMHTI and regarding nuclear imaging. This project is part of the current developments to create an imaging pole in “Région Centre” and more particularly in Orléans.