A robust strategy for the preparation of libraries of metallopeptides. A new paradigm for the discovery of targeted molecular imaging and therapy agents

Abstract

A robust method for synthesizing structurally diverse metallopeptide libraries using a Re(i) complex of a non-natural amino acid was developed as a way to accelerate the discovery of novel molecular imaging probes.

A Novel Organometallic ReI Complex with Favourable Properties for Bioimaging and Applicability in Solid‐Phase Peptide Synthesis

“…Most luminescent rhenium complexes with potential imaging applications contain the fac-Re(CO) 3 core and are based on bisimine ligands such as bipyridine or phenanthroline [26][27][28][29][30] or on tridentate chelates such as bis(pyridylmethyl)amine or bis(quinolinylmethyl)amine. [31][32][33][34][35][36] Here we report on the synthesis, characterization and photophysical behaviour of a novel chelating tridentate ligand based on bis(phenanthridinylmethyl)amine (bpm), its rhenium complexes and peptide conjugates. The complexes described below have more favourable photophysical properties than the above ligand systems.…”

Synthesis, characterisation and bioimaging of a fluorescent rhenium-containing PNA bioconjugate

“…5 Herein, we present the preparation and in-depth characterization, including X-ray crystallography, of Tc congeners, were already used for the (radio-)labeling of biomolecules by Zubieta, Valliant, Babich and our groups for both in vitro and in vivo imaging purposes. [18][19][20][21][22][23][24][25][26][27][28][29][30] We then report on 31 with triphenyl phosphine, diisopropyl azodicarboxylate and diphenylphosphoryl azide in THF following a similar procedure described by our groups (Scheme 1). 32 The presence of L-N 3 Figure S2 in the SI).…”

The development of organometallic OBOC peptide libraries and sequencing of N-terminal rhenium(I) tricarbonyl-containing peptides utilizing MALDI tandem mass spectrometry

“…The negatively charged Re(CO) 3 -NTA organometallic peptide, therefore, is not suitable for OBOC screening. (10). Inset: b 4 and b 5 fragments showing the characteristic rhenium isotopic ratio (m/z of rhenium-187 isotopic mass shown).…”

“…9 However, because imaging agents require the addition of a radionuclide to provide visualization and traditional peptide libraries do not take into account the presence of an imaging entity, the potential of peptide libraries in imaging agent development is not fully realized. 10 The current process is inherently inefficient because peptides that have been identified as having promising properties are subsequently modified by the addition of nonpeptidic imaging entities that are usually large and bulky, such as radiometal chelates or prosthetic groups. 11 The addition of the radionuclide-containing group can have a large impact on the binding properties of the peptide as demonstrated by peptides with high in vitro affinity and selectivity that, after radiolabeling, perform poorly in vivo and vice versa.…”

“…Previous work has shown that it is possible to identify organometallic peptides with rhenium-containing amino acid side chains by using on-bead Edman degradation. 10 We have decided to investigate the effects of MALDI (matrixassisted laser desorption/ionization) fragmentation patterns and the ability to use mass spectrometry to identify individual peptides through an OBOC peptide library containing N-terminal Re(CO) 3 chelates as imaging entity surrogates. Rhenium is used as a nonradioactive mimic for technetium-99m and is desirable because it forms relatively small chelates that are generally chemically inert.…”