Synthesis and evaluation of hydroxypyridinone-based smart contrast agents responsive to calcium ions
Karolina Jankowska, Martin E. Maier, Nikos K. Logothetis, Goran Angelovski
Calcium ions (Ca2+) play an important role in signal transduction pathways as a secondary messenger and a trigger of neurotransmitter release. Therefore its concentration can be used as an indicator of neural activity within brain tissue measured by magnetic resonance imaging (MRI). To enhance the MR signal, contrast agents (CAs) are used. Most available CAs responsive to Ca2+ show certain limitations in vivo, such as reduced stability, low selectivity and interactions with anions.
We seek for the development of the hydroxypyridinone (HOPO)-based gadolinium (Gd3+) complexes which may overcome limitations of existing CAs. Over 30 HOPO-based complexes are reported by Raymond and co-workers since 1995, and despite the great potential HOPO agents show, currently there is no smart probe based on this system. Therefore, the aim of the project is to synthesize a library of HOPO-based CAs responsive to Ca2+ and evaluate their performance by means of NMR and MRI.
Due to lack of specialized equipment the synthesis of the two first ligands had to be fully established. The synthesis of ligands involves a series of general organic chemistry procedures (alkylation, protection-deprotection, carboxylation etc.). Synthesized compounds are characterized by NMR and mass spectroscopy. The loading with Gd3+ is performed and the CAs are examined for response to Ca2+ concentration changes by NMR spectroscopy.
Longitudinal relaxation times (T1) have been measured. Initial relaxometric measurements of HOPO CAs in absence of Ca2+ show values in the range of DOTA/DO3A systems.
First two ligands have been synthesized. Their fully established synthesis opens access to a whole library of responsive and targeted HOPO-based CAs. Although for the projects purpose the ligands contain a calcium chelator, the responsive part can be varied according to targeted metabolite or ion.
1. Werner, E.J., et al., (2008) High-Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging. Angewandte Chemie-International Edition, 47 p. 8568-8580.
Figure1. General structure of modified HOPO-based CAs.