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

• 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
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700328

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.