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

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Molecular Imaging of Apoptosis: the Case of Caspase-3 Radiotracers International Journal of Molecular Sciences Review 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 and Filipe Elvas 1,2,* 1 Molecular Imaging Center Antwerp, University of Antwerp, 2610 Wilrijk, Belgium; [email protected] (L.B.); [email protected] (T.V.d.W.); [email protected] (S.S.) 2 Department of Nuclear Medicine, Antwerp University Hospital, 2650 Edegem, Belgium 3 Laboratory of Medicinal Chemistry, University of Antwerp, 2610 Wilrijk, Belgium; [email protected] * Correspondence: fi[email protected] 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 an- ticancer 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. Citation: Beroske, L.; Van den Keywords: caspase-3; radiotracer; activity-based probe; substrate-based probe; positron emission to- Wyngaert, T.; Stroobants, S.; Van der mography; single-photon emission computed tomography Veken, P.; Elvas, F. Molecular Imaging of Apoptosis: The Case of Caspase-3 Radiotracers. Int. J. Mol. Sci. 2021, 22, 3948. https://doi.org/10.3390/ 1. Introduction ijms22083948 Apoptosis is a programmed form of cell death that plays a vital role in the erad- ication of aberrant cells that threaten development, homeostasis, and overall survival. Academic Editor: Gianfranco Pintus This immunologically silent form of cell death can be triggered by the activation of cell surface receptors (e.g., tumor necrosis factor (TNF) receptor superfamily), by release of cy- Received: 28 February 2021 tochrome c or DNA damage. Regardless of how apoptosis is initiated, a family of cysteine Accepted: 8 April 2021 aspartate-directed proteases, known as caspases, is systematically activated from inactive Published: 11 April 2021 zymogen-like states, and upon maturation, targets a host of cellular proteins for hydrolysis (Figure1). The induction of apoptosis leads to both protein substrate degradation and Publisher’s Note: MDPI stays neutral activation, and ultimately cell death [1–5]. Caspases are heavily regulated proteins due with regard to jurisdictional claims in published maps and institutional affil- to the nature of their activity, as inappropriate activation can have devastating effects. iations. Apoptotic caspases are generally divided into “initiators” and “executioners”. Apoptosis can be activated via two distinct pathways: the extrinsic and intrinsic pathways. The former is triggered via the activation of death receptors, starting a cascade of events that activates the initiator caspase-8. The intrinsic pathway can be induced when the cell is under stress, which leads to the depolarization of the mitochondrial membrane and the Copyright: © 2021 by the authors. subsequent release of pro-apoptotic molecules at the origin of initiator caspase-9 activa- Licensee MDPI, Basel, Switzerland. tion (Figure1 ). These activated initiator caspases initiate the executioner caspases-3, -6 This article is an open access article and -7, with caspases-3 and -7 having redundant roles, and caspase-6 is not essential for distributed under the terms and conditions of the Creative Commons apoptosis [1,6]. Attribution (CC BY) license (https:// The dysregulation of apoptosis can lead to various conditions. For example, neurode- creativecommons.org/licenses/by/ generative diseases, such as Alzheimer’s disease or Parkinson’s disease, are characterized 4.0/). by the loss of neurons, often via excessive apoptosis [7]. Additionally, apoptosis is among Int. J. Mol. Sci. 2021, 22, 3948. https://doi.org/10.3390/ijms22083948 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 3948 2 of 19 the main drivers of diseases such as ischemic heart disease [8]. On the contrary, among the hallmarks of cancer is the ability of cancerous cells to evade apoptosis [9]. For this reason, Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEWa common treatment strategy is the induction of apoptosis in tumors, via the activation2 of 19 of the caspase cascade [10,11]. FigureFigure 1. 1. MechanismsMechanisms of of apoptosis. apoptosis. In Inthe the extrinsic extrinsic pathway, pathway, death death receptors receptors are are activated, activated, leading leading to the to theactivation activation of the of initiatorthe initiator caspase-8 caspase-8 and and-10. In -10. the In intrin the intrinsicsic pathway, pathway, cellular cellular stress stress leads leads to the to activation the activation of Bcl-2 of Bcl-2homology homology 3 (BH3)-only 3 (BH3)- proteins,only proteins, which which disable disable the antiapoptotic the antiapoptotic proteins proteins Bcl-2 and Bcl-2 Bcl-2-like-1 and Bcl-2-like-1 that norm thatally normally inhibit inhibit Bax and Bax Bak and proteins. Bak proteins. This results in the permeabilization of the mitochondrial membrane, causing mitochondrial membrane depolarization and the This results in the permeabilization of the mitochondrial membrane, causing mitochondrial membrane depolarization and release of cytochrome c and Smac proteins. Cytochrome c induces the formation of the apoptosome, followed by the acti- the release of cytochrome c and Smac proteins. Cytochrome c induces the formation of the apoptosome, followed by the vation of the initiator caspase-9. In both pathways, initiator caspases activate effector caspases, starting the degradation of intracellularactivation of material the initiator and caspase-9.the death of In the both cell. pathways, initiator caspases activate effector caspases, starting the degradation of intracellular material and the death of the cell. The dysregulation of apoptosis can lead to various conditions. For example, neuro- The availability of clinical tools to non-invasively measure apoptosis would represent degenerative diseases, such as Alzheimer’s disease or Parkinson’s disease, are character- an important asset in the development of personalized medicine, enabling early disease ized by the loss of neurons, often via excessive apoptosis [7]. Additionally, apoptosis is diagnosis, management, and treatment-response evaluation. Specifically, imaging cell among the main drivers of diseases such as ischemic heart disease [8]. On the contrary, death can have a tremendous impact in the clinic and patients, in particular, in detecting among the hallmarks of cancer is the ability of cancerous cells to evade apoptosis [9]. For degenerative disorders and predicting treatment failure, such as for certain pro-apoptotic this reason, a common treatment strategy is the induction of apoptosis in tumors, via the anticancer drugs. Current methods of monitoring therapy response rely on the monitoring activationof morphological of the caspase changes cascade using anatomical[10,11]. imaging techniques, such as computed tomog- raphyThe (CT) availability or magnetic of clinical resonance tools imaging to non-invasively (MRI). The gold measure standard apoptosis for the would evaluation repre- of senttumor an responseimportant to asset therapy in the is the development Response Evaluation of personalized Criteria medicine, in Solid Tumorsenabling (RECIST) early dis- or easeimmune-related diagnosis, management, response criteria and (irRC)treatment- for immunotherapy.response evaluation. However, Specifically, it can take imaging weeks cellto monthsdeath can before have morphologicala tremendous impact changes in the become clinic apparent.and patients, Early in particular, treatment-response in detect- ingevaluation degenerative would disorders save precious and predicting time and trea potentialtment failure, treatment-related such as for toxicity,certain pro-apop- as well as totichealthcare anticancer resources. drugs. Furthermore,Current methods it would of monitoring limit the need therapy for invasiveresponsebiopsies rely on the that mon- may itoringbe associated of morphological with pain andchanges stress using for patients. anatomical imaging techniques, such as computed tomographyWhile a (CT) number or magnetic of functional resonance imaging imag techniquesing (MRI). exist, The positron gold standard emission for tomography the eval- uation(PET) andof tumor single-photon response emission to therapy computed is the Re tomographysponse Evaluation (SPECT) Criteria can be usedin Solid to detect Tumors the (RECIST)spatial and or temporalimmune-related distribution response of radioactive criteria (irRC) probes forin immunotherapy. vivo accumulating However, at a target it can site. takePET weeks and SPECT to months have before an extremely morphologica high sensitivity,l changes enablingbecome apparent. the quantification Early treatment- of small responsechanges inevaluation tracer uptake, would with save multiple precious radioisotopes time and potential with excellent treatment-related
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