Radiosynthesis and micro-SPECT analysis of triazole-based RGD integrin ligands as non-peptide molecular imaging probes for angiogenesis

Bianchini, Francesca; Fabbrizzi, Pierangelo; Menchi, Gloria; Raspanti, Silvia; Bottoncetti, Anna; Passeri, Alessandro; Andreucci, Elena; Guarna, Antonio; Calorini, Lido; Pupi, Alberto; Trabocchi, Andrea

doi:10.1016/j.bmc.2014.12.065

Cited by 12 publications

(6 citation statements)

References 33 publications

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“…The triazole-based RGD ligand was achieved using the click chemistry by combining azide and alkyne in the Cu-catalyzed azide–alkyne cycloaddition, followed by acid-mediated hydrolysis of the protecting groups of side chain isosteres [16, 31, 47]. Three bioactive compounds were selected starting from a group of αvβ3 integrin ligands.…”

Section: Methodsmentioning

confidence: 99%

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Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

et al. 2016

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Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.

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Section: Methodsmentioning

confidence: 99%

“…The inhibition of 125 I-echistatin-specific binding to αvβ3 integrins by RGD antagonists was evaluated as previously reported [47]. Briefly, 125 I-echistatin with a specific activity of 2000 Ci/mmol was purchased from Perkin Elmer, and integrin αvβ3 from human placenta was purchased from Millipore.…”

Section: Methodsmentioning

confidence: 99%

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

et al. 2016

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“…RGD mimetic integrin inhibitors, like Cilengitide and Cilengitide-like RGD peptidomimetics, have also been investigated as chemical probes for the molecular imaging of angiogenesis in the literature [133, 140, 141]. In the near future, other strategies like sulfonation of tyrosine moieties in RGD peptides, which can modify the hydrophilicity of RGD peptides to increase renal clearance and to improve overall biodistribution [142], can also be applied to design novel probes for mapping α v β 3 expression in melanoma.…”

Section: Peptide-based Imaging Probesmentioning

confidence: 99%

PET and SPECT imaging of melanoma: the state of the art

Wei

Ehlerding

Lan

et al. 2017

Eur J Nucl Med Mol Imaging

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Melanoma represents the most aggressive form of skin cancer, and its incidence continues to rise worldwide. F-FDG PET imaging has transformed diagnostic nuclear medicine and has become an essential component in the management of melanoma, but still has its drawbacks. With the rapid growth in the field of nuclear medicine and molecular imaging, a variety of promising probes that enable early diagnosis and detection of melanoma have been developed. The substantial preclinical success of melanin- and peptide-based probes has recently resulted in the translation of several radiotracers to clinical settings for noninvasive imaging and treatment of melanoma in humans. In this review, we focus on the latest developments in radiolabeled molecular imaging probes for melanoma in preclinical and clinical settings, and discuss the challenges and opportunities for future development.

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“…[21] More recently, the direct radioiodination of non-peptide integrin ligands has been reported and the resulting tracers assessed as SPECT imaging agents. [22] In this study we designed small-molecule RGD-mimics that combine excellent biological properties (high affinity, selectivity, suitable logP value) with a variety of radiolabeling options not requiring the use of chelators or prosthetic groups. To this end, a small library of RGD peptidomimetics was synthesized and biologically screened to identify the chemical modifications that confer the highest αvβ3 affinity and selectivity against integrin αIIbβ3, which mediates platelet aggregation.…”

Section: Introductionmentioning

confidence: 99%

“…Kessler and co‐workers assessed the potential of nonpeptidic RGD mimics as PET imaging agents by equipping the integrin antagonists with a bifunctional chelator (NODAGA) and labeling with 68 Ga 3+ . More recently, the direct radioiodination of nonpeptide integrin ligands has been reported and the resulting tracers assessed as SPECT imaging agents …”

Section: Introductionmentioning

confidence: 99%

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin

et al. 2017

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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 [ 18 F]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.

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Radiosynthesis and micro-SPECT analysis of triazole-based RGD integrin ligands as non-peptide molecular imaging probes for angiogenesis

Cited by 12 publications

References 33 publications

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

PET and SPECT imaging of melanoma: the state of the art

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin

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Radiosynthesis and micro-SPECT analysis of triazole-based RGD integrin ligands as non-peptide molecular imaging probes for angiogenesis

Cited by 12 publications

References 33 publications

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

PET and SPECT imaging of melanoma: the state of the art

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

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Product

Resources

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High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin