Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Apr 11;22(8):3948.
doi: 10.3390/ijms22083948.

Molecular Imaging of Apoptosis: The Case of Caspase-3 Radiotracers

Lucas Beroske  1   2   3 , Tim Van den Wyngaert  1   2 , Sigrid Stroobants  1   2 , Pieter Van der Veken  3 , Filipe Elvas  1   2
Affiliations
Review

Molecular Imaging of Apoptosis: The Case of Caspase-3 Radiotracers

Lucas Beroske et al. Int J Mol Sci. .

Abstract

The molecular imaging of apoptosis remains an important method for the diagnosis and monitoring of the progression of certain diseases and the evaluation of the efficacy of anticancer apoptosis-inducing therapies. Among the multiple biomarkers involved in apoptosis, activated caspase-3 is an attractive target, as it is the most abundant of the executioner caspases. Nuclear imaging is a good candidate, as it combines a high depth of tissue penetration and high sensitivity, features necessary to detect small changes in levels of apoptosis. However, designing a caspase-3 radiotracer comes with challenges, such as selectivity, cell permeability and transient caspase-3 activation. In this review, we discuss the different caspase-3 radiotracers for the imaging of apoptosis together with the challenges of the translation of various apoptosis-imaging strategies in clinical trials.

Keywords: activity-based probe; caspase-3; positron emission tomography; radiotracer; single-photon emission computed tomography; substrate-based probe.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of apoptosis. In the extrinsic pathway, death receptors are activated, leading to the activation of the initiator caspase-8 and -10. In the intrinsic pathway, cellular stress leads to the activation of Bcl-2 homology 3 (BH3)-only proteins, which disable the antiapoptotic proteins Bcl-2 and Bcl-2-like-1 that normally inhibit Bax and Bak proteins. This results in the permeabilization of the mitochondrial membrane, causing mitochondrial membrane depolarization and the release of cytochrome c and Smac proteins. Cytochrome c induces the formation of the apoptosome, followed by the activation of the initiator caspase-9. In both pathways, initiator caspases activate effector caspases, starting the degradation of intracellular material and the death of the cell.
Figure 2
Figure 2
The isatin sulfonamide scaffold. Reprinted with permission from ref. [26]. Copyright 2020 MDPI.
Figure 3
Figure 3
Timeline of the development of the main isatin sulfonamide radiotracers. The core isatin sulfonamide structure is represented in red.
Figure 4
Figure 4
Biodistribution profile of series of [18F]ICMT-11. The images correspond to whole-body maximum-intensity projection of representative subjects showing biodistribution of 18F activity after tracer injection up to 219 min after injection of [18F]ICMT-11. (A) A subject who had a meal 2–3 h before tracer injection; (B) a subject who had a meal just before tracer injection (due to delays in tracer production). Reprinted with permission from ref. [34]. Copyright 2013 SNMMI.
Figure 5
Figure 5
[18F]ICMT-11 uptake in primary breast tumors. Axial CT and fused [18F]ICMT-11 PET/CT images of primary breast tumors in two patients, 1 and 2, at baseline (pre-) and post-chemotherapy. Low-level uptake is noted. Reprinted with permission from ref. [35]. Copyright 2018 Springer Nature.
Figure 6
Figure 6
Decay-corrected anterior maximum-intensity projections of PET at 7, 46, 77, 144 and 179 min (from left to right) after injection of [18F]CP-18 in male volunteer. There was rapid clearance of activity in all organs. Reprinted with permission from ref. [53]. Copyright 2013 SNMMI.
Figure 7
Figure 7
Molecular structure of DEVD-based radiotracers: [18F]MICA-302 ABP, [18F]CP-18 SBP and [18F]C-SNAT SBP.
See this image and copyright information in PMC

References

    1. Riedl S.J., Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell Biol. 2004;5:897–907. doi: 10.1038/nrm1496. - DOI - PubMed
    1. Rybczynska A.A., Boersma H.H., De Jong S., Gietema J.A., Noordzij W., Dierckx R.A.J.O., Elsinga P.H., Van Waarde A. Avenues to molecular imaging of dying cells: Focus on cancer. Med. Res. Rev. 2018;38:1713–1768. doi: 10.1002/med.21495. - DOI - PMC - PubMed
    1. Creagh E.M. Caspase crosstalk: Integration of apoptotic and innate immune signalling pathways. Trends Immunol. 2014;35:631–640. doi: 10.1016/j.it.2014.10.004. - DOI - PubMed
    1. Elmore S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007;35:495–516. doi: 10.1080/01926230701320337. - DOI - PMC - PubMed
    1. Galluzzi L., Vitale I., Aaronson S.A., Abrams J.M., Adam D., Agostinis P., Alnemri E.S., Altucci L., Amelio I., Andrews D.W., et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25:486–541. doi: 10.1038/s41418-017-0012-4. - DOI - PMC - PubMed

LinkOut - more resources