Synthesis, radiolabelling and initial biological characterisation of <sup>18</sup>F-labelled xanthine derivatives for PET imaging of Eph receptors

Pretze, Marc; Neuber, Christin; Kinski, Elisa; Belter, Birgit; Köckerling, Martin; Caflisch, Amedeo; Steinbach, Jörg; Pietzsch, Jens; Mamat, Constantin

doi:10.1039/d0ob00391c

Cited by 13 publications

(9 citation statements)

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“…Alternatively, in a recent publication, Affinito et al introduced a RNA aptamer targeting EphA2 receptors at human glioblastoma cells for therapeutic purpose-s [ 39 ]. In another recent study, Pretze et al reported two novel xanthine derivatives as potential tracers for imaging of EphA2 and EphB4 overexpressing human A375 melanoma cells [ 40 ]. Although the suitability of those probes still needs to be evaluated in clinical trials, these studies globally underscore the potency of EphB4 as a target for tumor imaging…”

Section: Discussionmentioning

confidence: 99%

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

et al. 2020

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Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. Methods: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. Results: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. Conclusion: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases.

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Section: Discussionmentioning

confidence: 99%

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

et al. 2020

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“…Other EphR targeting peptides, including SWL and SNEW, have been radiolabeled ( Table S1 ) [ 351 , 361 ]. Finally, the recently developed [ 18 F]-labeled xanthine derivatives have potential for PET imaging of Eph receptors but lack studies in GB to date [ 362 ].…”

Section: Receptor Tyrosine Kinase Inhibitors (Rtkis) For Gb Therapymentioning

confidence: 99%

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

et al. 2021

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Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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“…A third 18 F-radiolabeling approach using xanthine derivatives was published in 2020. 27 Lafleur et al published the lead compound 18 (compound 66 of the citation, IC 50 = 2.3 (EphA2), 1.6 (EphB4)) in 2009. 26 Again, the question of the best labeling position to introduce fluorine-18 was solved by performing docking studies with the EphA3 receptor, representing the similar ATP-binding pocket as EphB4, using crystal structure data and possible fluorine-containing molecules.…”

Section: Eph/ephrin System As a Diagnostic Target In Cancermentioning

confidence: 99%

“… 26 Again, the question of the best labeling position to introduce fluorine-18 was solved by performing docking studies with the EphA3 receptor, representing the similar ATP-binding pocket as EphB4, using crystal structure data and possible fluorine-containing molecules. 27 Based on this result, the two fluorine-containing reference compounds 21a,b were synthesized from 19a,b using Deoxofluor. With this procedure, only the aliphatic OH group of 19a,b is displaced by fluoride under mild conditions ( Scheme 6 ).…”

Section: Eph/ephrin System As a Diagnostic Target In Cancermentioning

confidence: 99%

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Radiopharmacologist’s and Radiochemist’s View on Targeting the Eph/Ephrin Receptor Tyrosine Kinase System

et al. 2020

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In the past decade, there have been extensive efforts to open up the Eph/ephrin subfamily of the receptor tyrosine kinase family for diagnostic and therapeutic applications. Besides classical pharmaceutical developments, which focus either on drugs targeting the extracellular ligand binding domains or on the intracellular tyrosine kinase domains of these receptors, there also have been first radiopharmaceutical approaches. Here the focus is on the development of specific and selective probes for molecular imaging, particularly by means of positron emission tomography, and the functional characterization of the Eph/ephrin subfamily in certain target tissues. The aim of this mini-review is to summarize the different approaches toward Eph-targeting radiotracers by using antibodies, peptides, and small molecules and to discuss their radiopharmacological characterization. With regard to the small molecules, further considerations will focus on the design and synthesis of nonradioactive reference compounds and precursors as well as on radiolabeling strategies.

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Synthesis, radiolabelling and initial biological characterisation of ¹⁸F-labelled xanthine derivatives for PET imaging of Eph receptors

Abstract: Two new fluorine-18-labelled xanthine derivatives with high binding affinity were synthesised as PET-radioligand candidates for Eph receptors.

Cited by 13 publications

References 40 publications

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Radiopharmacologist’s and Radiochemist’s View on Targeting the Eph/Ephrin Receptor Tyrosine Kinase System

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Synthesis, radiolabelling and initial biological characterisation of 18F-labelled xanthine derivatives for PET imaging of Eph receptors

Abstract: Two new fluorine-18-labelled xanthine derivatives with high binding affinity were synthesised as PET-radioligand candidates for Eph receptors.

Cited by 13 publications

References 40 publications

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

Radiopharmacologist’s and Radiochemist’s View on Targeting the Eph/Ephrin Receptor Tyrosine Kinase System

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Product

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Synthesis, radiolabelling and initial biological characterisation of ¹⁸F-labelled xanthine derivatives for PET imaging of Eph receptors