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ChemMedChem. 2017 Jul 20;12(14):1142-1151. doi: 10.1002/cmdc.201700328. Epub 2017 Jul 3.

High-Affinity "Click" RGD Peptidomimetics as Radiolabeled Probes for Imaging αv β3 Integrin.

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Institute of Medical Sciences and Kosterlitz Centre for Therapeutics, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, UK.
Dipartimento di Chimica e Tecnologie del Farmaco, "Sapienza" Università di Roma, P.le A. Moro 5, 00185, Rome, Italy.
Current affiliation: IRBM Science Park SpA, Via Pontina km 30 600, 00071, Pomezia, RM, Italy.
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Roma, RM, Italy.
Manchester Cancer Research Centre and Wolfson Molecular Imaging Centre, The University of Manchester, Palatine Road, Manchester, M20 3JJ, UK.
CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester, Manchester Cancer Research Centre, Division of Pharmacy and Optometry, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
C.N.R.-I.C.R.M., via Mancinelli 7, 20131, Milan, Italy.


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 in vitro properties (high αv β3 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 αv β3 or αIIb β3 receptors was investigated by molecular modeling simulations. Lead compound 12 was successfully radiofluorinated and used for in vivo 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 in vitro and cell-based studies on αv β3 integrin, whereas further optimization of their pharmacokinetic and dynamic profiles is necessary for successful use in in vivo imaging.


PET imaging; RGD; angiogenesis; click chemistry; peptidomimetics

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