Lanthanoid complexes as enzyme-activated responsive MRI contrast agents

• Applicant: Dr. Stephan David Köster
• Subject Area: Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 214078570

The proposal is centered around the further development of Gd-HOPO-based MRI contrast agents by introducing peptide sequences for the delivery into specific cells and tissues. As outlined in the first proposal, an interesting enzymatic target would be ß-secretases (e.g. BACE1), that are involved in the onset and progression of neurodegenerative diseases, e.g. Alzheimers. The blood-brain-barrier (BBB) constitutes an important obstacle in the therapy and diagnosis of these diseases. For this reason, ways to cross the BBB for diagnostic and therapeutic agents are pivotal for the treatment of these diseases. In particular, the use of a 12 amino acid peptide G 23, that has been identified to bind to gangliosides (phospholipids of the central nervous system) shall be investigated. The Gd-HOPO-based contrast agent shall be linked to the G23 transport peptide by a short amino acid sequence, which incorporates the cleavage site for the ß-secretase BACE1. The usefulness of the new HOPO-peptide to cross the BBB shall be probed by an in vitro transwell assay. This setup was employed to determine the transcytosis capability of fluorescently tagged polymeric vesicles modified with the G23 peptide. The recently developed immortalized human brain endothelial cell line hCMEC/D3 has already proven to be a promising tool in a number of BBB model studies and shall be used in this study, too.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Kenneth N. Raymond