High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin

Monica Piras, Andrea Testa, Ian N Fleming, Sergio Dall'Angelo, Alexandra Andriu, Sergio Menta, Mattia Mori, Gavin D. Brown, Duncan Forster, Kaye J. Williams, Matteo Zanda

Research output: Contribution to journalArticle

4 Citations (Scopus)
6 Downloads (Pure)

Abstract

Non-peptidic 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 αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Compound 12 was successfully radiofluorinated and used for in vivo PET/CT studies in U87-tumour models, which showed only modest tumour 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 αvβ3 integrin, whereas further optimization of their pharmaco-kinetic and dynamic profile would be necessary for a successful use in in vivo imaging.
Original languageEnglish
Pages (from-to)1142-1151
Number of pages10
JournalChemMedChem
Volume12
Issue number14
Early online date3 Jul 2017
DOIs
Publication statusPublished - 20 Jul 2017

Fingerprint

Peptidomimetics
Integrins
Tumors
Pharmacodynamics
Click Chemistry
Imaging techniques
Triazoles
Molecular modeling
Pharmacokinetics
Alkynes
Azides
Fluorine
Tritium
Halogenation
Chelating Agents
Prosthetics
Radio
Aspartic Acid
Arginine
Neoplasms

Keywords

  • imaging
  • positron emission tomography
  • integrin
  • tumour metastasis
  • angiogenesis

Cite this

High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin. / Piras, Monica; Testa, Andrea; Fleming, Ian N; Dall'Angelo, Sergio; Andriu, Alexandra; Menta, Sergio ; Mori, Mattia ; Brown, Gavin D. ; Forster, Duncan ; Williams, Kaye J. ; Zanda, Matteo.

In: ChemMedChem, Vol. 12, No. 14, 20.07.2017, p. 1142-1151.

Research output: Contribution to journalArticle

Piras, M, Testa, A, Fleming, IN, Dall'Angelo, S, Andriu, A, Menta, S, Mori, M, Brown, GD, Forster, D, Williams, KJ & Zanda, M 2017, 'High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin', ChemMedChem, vol. 12, no. 14, pp. 1142-1151. https://doi.org/10.1002/cmdc.201700328
Piras, Monica ; Testa, Andrea ; Fleming, Ian N ; Dall'Angelo, Sergio ; Andriu, Alexandra ; Menta, Sergio ; Mori, Mattia ; Brown, Gavin D. ; Forster, Duncan ; Williams, Kaye J. ; Zanda, Matteo. / High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin. In: ChemMedChem. 2017 ; Vol. 12, No. 14. pp. 1142-1151.
@article{f98784f76e8c4628b2b62e3b17a98f1d,
title = "High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin",
abstract = "Non-peptidic 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 αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Compound 12 was successfully radiofluorinated and used for in vivo PET/CT studies in U87-tumour models, which showed only modest tumour 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 αvβ3 integrin, whereas further optimization of their pharmaco-kinetic and dynamic profile would be necessary for a successful use in in vivo imaging.",
keywords = "imaging , positron emission tomography, integrin , tumour metastasis , angiogenesis",
author = "Monica Piras and Andrea Testa and Fleming, {Ian N} and Sergio Dall'Angelo and Alexandra Andriu and Sergio Menta and Mattia Mori and Brown, {Gavin D.} and Duncan Forster and Williams, {Kaye J.} and Matteo Zanda",
note = "We thank The Development Trust, University of Aberdeen, for financial support and a fellowship to M.P. The work was also supported by the CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester (KJW Co-I; reference 16465). We thank Dr Massimiliano Baldassarre (University of Aberdeen) for helpful discussions.",
year = "2017",
month = "7",
day = "20",
doi = "10.1002/cmdc.201700328",
language = "English",
volume = "12",
pages = "1142--1151",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "14",

}

TY - JOUR

T1 - High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin

AU - Piras, Monica

AU - Testa, Andrea

AU - Fleming, Ian N

AU - Dall'Angelo, Sergio

AU - Andriu, Alexandra

AU - Menta, Sergio

AU - Mori, Mattia

AU - Brown, Gavin D.

AU - Forster, Duncan

AU - Williams, Kaye J.

AU - Zanda, Matteo

N1 - We thank The Development Trust, University of Aberdeen, for financial support and a fellowship to M.P. The work was also supported by the CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester (KJW Co-I; reference 16465). We thank Dr Massimiliano Baldassarre (University of Aberdeen) for helpful discussions.

PY - 2017/7/20

Y1 - 2017/7/20

N2 - Non-peptidic 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 αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Compound 12 was successfully radiofluorinated and used for in vivo PET/CT studies in U87-tumour models, which showed only modest tumour 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 αvβ3 integrin, whereas further optimization of their pharmaco-kinetic and dynamic profile would be necessary for a successful use in in vivo imaging.

AB - Non-peptidic 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 αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [18F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Compound 12 was successfully radiofluorinated and used for in vivo PET/CT studies in U87-tumour models, which showed only modest tumour 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 αvβ3 integrin, whereas further optimization of their pharmaco-kinetic and dynamic profile would be necessary for a successful use in in vivo imaging.

KW - imaging

KW - positron emission tomography

KW - integrin

KW - tumour metastasis

KW - angiogenesis

U2 - 10.1002/cmdc.201700328

DO - 10.1002/cmdc.201700328

M3 - Article

VL - 12

SP - 1142

EP - 1151

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 14

ER -