Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers

Ebert, Kristin; Wiemer, Jens; Caballero, Julio; Köckerling, Martin; Steinbach, Jörg; Pietzsch, Jens; Mamat, Constantin

doi:10.1016/j.bmc.2015.06.040

Cited by 11 publications

(11 citation statements)

References 39 publications

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“…However, under the used labeling conditions, 12 converted into 13 ; no differences between 12 and 13 were found. Previously published conditions were used: K[ 18 F]F, K 2 CO 3 , K 222 , anhydrous acetonitrile to give [ 18 F] 10 ( t R = 30.7 minutes) . For the removal of the EOE group, [ 18 F] 10 was treated with 2 M HCl to yield [ 18 F] 14 ( t R = 11.9 minutes) (Scheme /Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…For this purpose, we have chosen compound III as basis published by Bardelle et al in 2010 . Previous in silico studies were accomplished to find the best labeling positions (structures IV , V , and VI in Figure ) . Based on these findings, we tried to prepare an 18 F‐labeled compound V by replacing the methyl group of the original compound III , but without success.…”

Section: Introductionmentioning

confidence: 99%

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Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor

Wiemer

Steinbach

Pietzsch

et al. 2017

Labelled Comp Radiopharmac

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The visualization of Eph receptors, which are overexpressed in various tumor entities, using selective small molecule Eph inhibitors by means of positron emission tomography is a promising approach for tumor imaging. N-(Pyrimidinyl)indazolamines represent a class of compounds, which are known to have high affinity especially for the EphB4 receptor. Radiofluorination of these compounds could provide a highly specific imaging agent and was investigated using a classical nucleophilic introduction of [ F]fluoride as well as a less common nucleophilic ring-opening reaction of azetidinium salts. In the past, radiofluorinations using azetidinium precursors were demonstrated to result in high radiochemical yields in short periods. For this purpose, an azetidinium precursor based on the N-(pyrimidinyl)indazolamine lead compound was developed, and radiofluorination was successfully accomplished. The respective [ F]radiotracer was quickly prepared with high radiochemical purity >97% and in a radiochemical yield of 34%.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor

Wiemer

Steinbach

Pietzsch

et al. 2017

Labelled Comp Radiopharmac

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“…Due to its potential influence on, particularly, tumor vascularization and hypoxia, functional expression of EphB4 should be considered as potential differentiating characteristics or biomarker of malignant melanoma, which preferentially should be determined by non-invasive imaging. The latter would gain impetus from development of specific and selective radioligands for quantitation of EphB4’s functional expression by means of PET [ 58 , 94 , 95 ]. Considering the impact of tumor vascularization and hypoxia, eg, on chemo- and radioresistance of tumors, targeted theranostics of functional EphB4 is suspected to contribute to early detection of high risk groups and to personally improve patients’ prognosis and therapy outcome, which are the major principles of melanoma control [ 96 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments

et al. 2018

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Experimental evidence has associated receptor tyrosine kinase EphB4 with tumor angiogenesis also in malignant melanoma. Considering the limited in vivo data available, we have conducted a systematic multitracer and multimodal imaging investigation in EphB4-overexpressing and mock-transfected A375 melanoma xenografts. Tumor growth, perfusion, and hypoxia were investigated by positron emission tomography. Vascularization was investigated by fluorescence imaging in vivo and ex vivo. The approach was completed by magnetic resonance imaging, radioluminography ex vivo, and immunohistochemical staining for blood and lymph vessel markers. Results revealed EphB4 to be a positive regulator of A375 melanoma growth, but a negative regulator of tumor vascularization. Resulting in increased hypoxia, this physiological characteristic is considered as highly unfavorable for melanoma prognosis and therapy outcome. Lymphangiogenesis, by contrast, was not influenced by EphB4 overexpression. In order to distinguish between EphB4 forward and EphrinB2, the natural EphB4 ligand, reverse signaling a specific EphB4 kinase inhibitor was applied. Blocking experiments show EphrinB2 reverse signaling rather than EphB4 forward signaling to be responsible for the observed effects. In conclusion, functional expression of EphB4 is considered a promising differentiating characteristic, preferentially determined by non-invasive in vivo imaging, which may improve personalized theranostics of malignant melanoma.

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“…Mamat and co‐workers developed a new class of indazolylpyrimidine derivatives as EphB4 ligands and potential radiotracers . These ligands can be used for the noninvasive imaging of the EphB4 receptor.…”

Section: Recent Advances In Small‐molecule Antiangiogenic Agentsmentioning

confidence: 99%

“…148 Mamat and co-workers developed a new class of indazolylpyrimidine derivatives as EphB4 ligands and potential radiotracers. 149 These ligands can be used for the noninvasive imaging of the EphB4 receptor. Médard and co-workers designed hybrid molecules of dasatinib and EphB4 inhibitor in order to exploit both the ATP pocket entrance in the kinase EphA2.…”

Section: Recent Progress In the Development Of Ephb4 Inhibitorsmentioning

confidence: 99%

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Shan

Wang

Zhang

2018

Medicinal Research Reviews

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Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.

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Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers

Cited by 11 publications

References 39 publications

Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor

Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor

Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

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