Heteroditopic Binding of MR Contrast Agents for Increased Relaxivity

Zhaoda Zhang¹, Matthew Greenfield², Andrew Kolodziej², Peter Caravan¹

Fibrin-specific peptides conjugated to multiple Gd-chelates, e.g. EP-2104R and EP-1242, have shown efficacy in MR detection of thrombus. We hypothesized that a second small binding group at the N-terminus may provide additional fibrin affinity, while at the same time would restrict internal motion at the N-terminus upon fibrin binding and this would result in higher relaxivity. We demonstrate that a minor perturbation (addition of a thymine moiety at the N-terminus) in probe structure can result in a 50% increase in relaxivity at the target, but does not increase off-target relaxivity. This heteroditopic binding approach is generalizable to other protein-targeted probes.