Pascal Kadjane

Development of ¹⁹F-labelled contrast agents for Ca²⁺ ion detection using MR-based techniques

Pascal Kadjane, Goran Angelovski, Gisela Hagberg, Nikos K. Logothetis

Introduction

Magnetic resonance imaging (MRI) is a non-invasive technique widely used in the biomedical science to visualize detailed internal structure. It provides 3D images without the use of ionizing radiation. To improve the image contrast, paramagnetic contrast agents (CAs) are utilized. Lately, considerable efforts are devoted to evolve ¹⁹F MRI probes for molecular imaging applications, in order to overcome the problem of background signal related to ¹H MRI [1]. The lack of background signal along with the possible quantification and specific detection of ¹⁹F labels have encouraged scientists to develop fluorinated smart CAs capable of detecting a particular biological event. Such probes could have great importance for instance, for the tracking of Ca²⁺ concentration changes, as this ion is an essential messenger intervening in diverse biological processes.

Goals

The aim of the project is to synthesize different fluorine-containing probes that enable us to visualize the changes in extracellular Ca²⁺ concentration, during neural activity in the brain by means of ¹⁹F MRI. We developed molecules which undergo a conformational change in the presence of Ca²⁺ which brings the ¹⁹F reporter closer to the paramagnetic ion and causes an alteration of its signal.

Methods

The fluorine reporter is attached to a well studied Ca²⁺ chelator and the corresponding compound is conjugated to a cyclen based complexing cage. The synthesized probes are studied by means of NMR spectroscopy in order to determine the T₁ and T₂ of ¹⁹F. Phantom images of the probes are subsequently acquired in the absence and presence of Ca²⁺ to assess the potential application.

Initial results

Two fluorinated probes with different numbers of fluorine atoms have been synthesized. The systems have been metallated with four different paramagnetic lanthanide ions (Gd³⁺, Tb³⁺, Dy³⁺, Tm³⁺) and, the corresponding complexes have been characterized. They exhibit different magnetic features resulting in a tuneable ¹⁹F signal. For all complexes, we observed that the addition of Ca²⁺ engender a change of the ¹⁹F signal which is followed by a decrease of the ¹⁹F T₁ and T₂. The observed changes are reversible as the relaxation times return to their initial values upon addition of EDTA.

Initial conclusions

The synthesis of two ¹⁹F-containing ligands has been successfully performed. The spectroscopic studies of the probes revealed that the systems are sensitive to Ca²⁺, providing a new platform for development of quantitative and dynamic MRI.

References

1. Ruiz-Cabello J, Walczak P, Kedziorek DA, Chacko VP, Schmieder AH,Wickline SA, Lanza GM,  Bulte JWM (2008) In vivo hot spot MR imaging of neural stem cells using ¹⁹F nanoparticles Magnetic Resonance in Medecine 60(6) 1506-1511.