Lanthanide–tetrazine probes for bio-imaging and click chemistry†

Abstract

The blood–brain-barrier prevents many imaging agents and therapeutics from being delivered to the brain that could fight central nervous system diseases such as Alzheimer's disease and strokes. However, techniques such as the use of stapled peptides or peptide shuttles may allow payloads through, with bioconjugation achieved via bio-orthogonal tetrazine/norbornene click chemistry. A series of lanthanide–tetrazine probes have been synthesised herein which could be utilised in bio-orthogonal click chemistry with peptide-based delivery systems to deliver MRI agents through the blood–brain-barrier. The Gd complexes show higher relaxivities than the clinical standard of Gd(DOTA) at 1.4 T and phosphorescence is observed from the Eu and Tb complexes via tetrazine sensitization, with supporting in vitro cytotoxicity and cell imaging. A bio-orthogonal click reaction between a Gd-tetrazine complex and a cyclic-RGD-norbornene conjugate was successful and the resulting clicked probe demonstrated enhanced relaxivity and could potentially act as a peptide shuttle for the Gd MRI agent.