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Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy

(2019) ORGANIC & BIOMOLECULAR CHEMISTRY. 17(19). p.4801-4824
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Abstract
Apoptosis is a highly regulated process involved in the normal organism development and homeostasis. In the context of anticancer therapy, apoptosis is also studied intensively in an attempt to induce cell death in cancer cells. Caspase activation is a known key event in the apoptotic process. In particular, active caspase-3 and -7 are the common effectors in several apoptotic pathways, therefore effector caspase activation may be a promising biomarker for response evaluation to anticancer therapy. Quantitative imaging of apoptosis in vivo could provide early assessment of therapeutic effectiveness and could also be used in drug development to evaluate the efficacy as well as potential toxicity of novel treatments. Positron Emission Tomography (PET) is a highly sensitive molecular imaging modality that allows non-invasive in vivo imaging of biological processes such as apoptosis by using radiolabeled probes. Here we describe the development and evaluation of fluorine-18-labeled caspase-3 activitybased probes (ABPs) for PET imaging of apoptosis. ABPs were selected by screening of a small library of fluorine-19-labeled DEVD peptides containing different electrophilic warhead groups. An acyloxymethyl ketone was identified with low nanomolar affinity for caspase-3 and was radiolabeled with fluorine-18. The resulting radiotracer, [18F] MICA-302, showed good labeling of active caspase-3 in vitro and favorable pharmacokinetic properties. A mu PET imaging experiment in colorectal tumor xenografts demonstrated an increased tumor accumulation of [18F] MICA-302 in drug-treated versus control animals. Therefore, our data suggest this radiotracer may be useful for clinical PET imaging of response to anticancer therapy.
Keywords
PEPTIDE MICHAEL ACCEPTORS, SOLID-PHASE SYNTHESIS, CELL-DEATH, IN-VITRO, SELECTIVE DETECTION, EPITHELIAL-CELLS, BREAST-CANCER, AMINO-ACIDS, INHIBITORS, ACTIVATION

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Chicago
Elvas, Filipe, Tom Vanden Berghe, Yves Adriaenssens, Peter Vandenabeele, Koen Augustyns, Steven Staelens, Sigrid Stroobants, Pieter Van der Veken, and Leonie Wyffels. 2019. “Caspase-3 Probes for PET Imaging of Apoptotic Tumor Response to Anticancer Therapy.” Organic & Biomolecular Chemistry 17 (19): 4801–4824.
APA
Elvas, F., Vanden Berghe, T., Adriaenssens, Y., Vandenabeele, P., Augustyns, K., Staelens, S., Stroobants, S., et al. (2019). Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy. ORGANIC & BIOMOLECULAR CHEMISTRY, 17(19), 4801–4824.
Vancouver
1.
Elvas F, Vanden Berghe T, Adriaenssens Y, Vandenabeele P, Augustyns K, Staelens S, et al. Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy. ORGANIC & BIOMOLECULAR CHEMISTRY. 2019;17(19):4801–24.
MLA
Elvas, Filipe et al. “Caspase-3 Probes for PET Imaging of Apoptotic Tumor Response to Anticancer Therapy.” ORGANIC & BIOMOLECULAR CHEMISTRY 17.19 (2019): 4801–4824. Print.
@article{8617546,
  abstract     = {Apoptosis is a highly regulated process involved in the normal organism development and homeostasis. In the context of anticancer therapy, apoptosis is also studied intensively in an attempt to induce cell death in cancer cells. Caspase activation is a known key event in the apoptotic process. In particular, active caspase-3 and -7 are the common effectors in several apoptotic pathways, therefore effector caspase activation may be a promising biomarker for response evaluation to anticancer therapy. Quantitative imaging of apoptosis in vivo could provide early assessment of therapeutic effectiveness and could also be used in drug development to evaluate the efficacy as well as potential toxicity of novel treatments. Positron Emission Tomography (PET) is a highly sensitive molecular imaging modality that allows non-invasive in vivo imaging of biological processes such as apoptosis by using radiolabeled probes. Here we describe the development and evaluation of fluorine-18-labeled caspase-3 activitybased probes (ABPs) for PET imaging of apoptosis. ABPs were selected by screening of a small library of fluorine-19-labeled DEVD peptides containing different electrophilic warhead groups. An acyloxymethyl ketone was identified with low nanomolar affinity for caspase-3 and was radiolabeled with fluorine-18. The resulting radiotracer, [18F] MICA-302, showed good labeling of active caspase-3 in vitro and favorable pharmacokinetic properties. A mu PET imaging experiment in colorectal tumor xenografts demonstrated an increased tumor accumulation of [18F] MICA-302 in drug-treated versus control animals. Therefore, our data suggest this radiotracer may be useful for clinical PET imaging of response to anticancer therapy.},
  author       = {Elvas, Filipe and Vanden Berghe, Tom and Adriaenssens, Yves and Vandenabeele, Peter and Augustyns, Koen and Staelens, Steven and Stroobants, Sigrid and Van der Veken, Pieter and Wyffels, Leonie},
  issn         = {1477-0520},
  journal      = {ORGANIC & BIOMOLECULAR CHEMISTRY},
  keywords     = {PEPTIDE MICHAEL ACCEPTORS,SOLID-PHASE SYNTHESIS,CELL-DEATH,IN-VITRO,SELECTIVE DETECTION,EPITHELIAL-CELLS,BREAST-CANCER,AMINO-ACIDS,INHIBITORS,ACTIVATION},
  language     = {eng},
  number       = {19},
  pages        = {4801--4824},
  title        = {Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy},
  url          = {http://dx.doi.org/10.1039/c9ob00657e},
  volume       = {17},
  year         = {2019},
}

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