High-Affinity "Click" RGD Peptidomimetics as Radiolabeled Probes for Imaging [alpha]v[beta]3 Integrin

Nonpeptidic Arg-Gly-Asp (RGD)-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent invitro properties (high [alpha]v[beta]3 affinity, selectivity, drug-like logD, high metabolic sta...

Full description

Saved in:
Bibliographic Details
Published in:ChemMedChem 2017-07, Vol.12 (14), p.1142
Main Authors: Piras, Monica, Testa, Andrea, Fleming, Ian N, Dall'Angelo, Sergio, Andriu, Alexandra, Menta, Sergio, Mori, Mattia, Brown, Gavin D, ster, Duncan, Williams, Kaye J, Zanda, Matteo
Format: Article
Language:English
Subjects:
Affinity
Alkynes
Arginine
Aspartic acid
Chelating agents
Chemical synthesis
Computed tomography
Computer simulation
Emission analysis
Excretion
Fluorine
Iodination
Ligands
Medical imaging
Molecular modelling
Optimization
Peptidomimetics
Pharmacology
Positron emission
Positron emission tomography
Probes
Prostheses
Prosthetic groups
Radio
Receptors
Selectivity
Tomography
Tritium
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Nonpeptidic Arg-Gly-Asp (RGD)-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent invitro properties (high [alpha]v[beta]3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g., tritium and fluorine-18, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD mimics to [alpha]v[beta]3 or [alpha]IIb[beta]3 receptors was investigated by molecular modeling simulations. Lead compound 12 was successfully radiofluorinated and used for invivo positron emission tomography/computed tomography (PET/CT) studies in U87 tumor models, which showed only modest tumor uptake and retention, owing to rapid excretion. These results demonstrate that the novel click RGD mimics are excellent radiolabeled probes for invitro and cell-based studies on [alpha]v[beta]3 integrin, whereas further optimization of their pharmacokinetic and dynamic profiles is necessary for successful use in invivo imaging.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700328