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Targeting phosphatidylserine for radionuclide-based molecular imaging of apoptosis

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Abstract

One major characteristic of programmed cell death (apoptosis) results in the increased expression of phosphatidylserine (PS) on the outer membrane of dying cells. Consequently, PS represents an excellent target for non-invasive imaging of apoptosis by single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Annexin V is a 36 kDa protein which binds with high affinity to PS in the presence of Ca2+ ions. This makes radiolabeled annexins valuable apoptosis imaging agents for clinical and biomedical research applications for monitoring apoptosis in vivo. However, the use of radiolabeled annexin V for in vivo imaging of cell death has been met with a variety of challenges which have prevented its translation into the clinic. These difficulties include: complicated and time-consuming radiolabeling procedures, sub-optimal biodistribution, inadequate pharmacokinetics leading to poor tumour-to-blood contrast ratios, reliance upon Ca2+ concentrations in vivo, low tumor tissue penetration, and an incomplete understanding of what constitutes the best imaging protocol following induction of apoptosis. Therefore, new concepts and improved strategies for the development of PS-binding radiotracers are needed. Radiolabeled PS-binding peptides and various Zn(II) complexes as phosphate chemosensors offer an innovative strategy for radionuclide-based molecular imaging of apoptosis with PET and SPECT. Radiolabeled peptides and Zn(II) complexes provide several advantages over annexin V including better pharmacokinetics due to their smaller size, better availability, simpler synthesis and radiolabeling strategies as well as facilitated tissue penetration due to their smaller size and faster blood clearance profile allowing for optimized image contrast. In addition, peptides can be structurally modified to improve metabolic stability along with other pharmacokinetic and pharmacodynamic properties. The present review will summarize the current status of radiolabeled annexins, peptides and Zn(II) complexes developed as radiotracers for imaging apoptosis through targeting PS utilizing PET and SPECT imaging.

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(adapted from Plaunt et al. [130])

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Acknowledgements

We gratefully acknowledge the support of this research by the Dianne and Irving Kipnes Foundation, the Alberta Cancer Foundation (ACF) and the Canadian Foundation for Innovation (CFI).

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Authors and Affiliations

  1. Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada

    Melinda Wuest, Amanda Perreault, Susan Richter & Frank Wuest

  2. School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK

    James C. Knight

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  1. Melinda Wuest
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  2. Amanda Perreault
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  5. Frank Wuest
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Correspondence to Frank Wuest.

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Wuest, M., Perreault, A., Richter, S. et al. Targeting phosphatidylserine for radionuclide-based molecular imaging of apoptosis. Apoptosis 24, 221–244 (2019). https://doi.org/10.1007/s10495-019-01523-1

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