Effect of peptide-chelate architecture on the metabolic stability of peptide-based MRI contrast agents (original) (raw)

2010, New Journal of Chemistry

A strategy for preparing high relaxivity, metabolically stable peptide-based MR contrast agents is described. The chemical and topological diversity of peptides offer tremendous possibilities to identify new diagnostic imaging compounds. Peptides have been widely used to target an imaging probe to a specific protein or receptor and thereby provide greater specificity. Typically an imaging reporting moiety (e.g. positron emitter, gamma emitter, paramagnetic ion, near infrared fluorophore) is conjugated to the peptide. The site of conjugation, the linker, and the type of imaging reporter all play a role in determining biological activity and pharmacokinetics. 1, 2 For peptide-based magnetic resonance imaging (MRI) contrast agents, an additional factor is detection sensitivity of the imaging probe. 3 Multiple copies of the MR active reporter, typically a gadolinium complex, are required to provide robust image contrast. An additional major challenge to creating new drugs from peptides is peptide degradation by endogenous peptidases. There are numerous medicinal chemistry approaches to improve peptide stability, biological activity, and/or bioavailability that increase in complexity from modified peptides to pseudopeptides to small molecule peptidomimetics. 4, 5 In this report, we explore the potential of using the imaging reporter to block peptidase activity. We, 6-9 and others, 10-14 have been interested in developing gadolinium-based peptide-targeted MR imaging agents. Compared to other modalities, MRI provides a favorable combination of high spatial resolution, depth penetration, and lack of ionizing radiation. Unlike nanoparticles, these relatively small molecules can rapidly reach targets in extravascular spaces and can be readily excreted through the kidneys to reduce/avoid long-term gadolinium retention and toxicity. On the other hand, extravasation into the kidneys and liver exposes these compounds to a range of peptidases. There is some flexibility as to where and how the gadolinium chelates are conjugated to the peptide. Conjugation is possible at the Nor C-terminus and/or within the peptide structure. 6 We recently reported some fibrin-specific peptides conjugated with one or four [Gd (DTPA)] 2− moieties. 8 The construct with highest affinity had two peptides linked via their Nterminus to a GdDTPA tetramer, i.e. Pep N-Gd 4-N Pep, termed EP-1084