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Abstract

The design, synthesis and evaluation of eight contrast agents for metabotropic glutamate receptors is reported. Each of the contrast agents contains a selective mGluR5 binding moiety linked to a ‘DOTA’-derived gadolinium complex. The potential of these systems was evaluated in vitro for application as responsive MR imaging probes. The targeting moieties mGluR5 antagonists based on aromatic alkyne and dipyridyl/heterobiaryl amide derivatives integrated in a modular fashion, involving linkage to the macrocyclic DOTA ligand to allow specific binding to the mGluR5 receptors. Signal intensity enhancements of up to 27 were observed by MRI in primary astrocyte suspensions and the reversibility of probe binding to the receptor sites, induced by added glutamate, was demonstrated using optical emission and the antagonistic activity of complexes was defined by calcium binding assays.