Skip to main content
SpringerLink
Log in

Evaluation of [18F]-CP18 as a PET Imaging Tracer for Apoptosis

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

We identified and validated [18F]-CP18, a DEVD (the caspase 3 substrate recognition motif) containing substrate-based compound as an imaging tracer for caspase-3 activity in apoptotic cells.

Procedures

CP18 was radiolabeled with fluorine-18 using click chemistry. The affinity and selectivity of CP18 for caspase-3 were evaluated in vitro. The biodistribution and metabolism pattern of [18F]-CP18 were assessed in vivo. [18F]-CP18 positron emission tomography (PET) scans were performed in a dexamethasone-induced thymic apoptosis mouse model. After imaging, the mice were sacrificed, and individual organs were collected, measured in a gamma counter, and tested for caspase-3 activity.

Results

In vitro enzymatic caspase-3 assay demonstrated specific cleavage of CP18. In vivo, [18F]-CP18 is predominantly cleared through the kidneys and urine, and is rapidly eliminated from the bloodstream. There was a sixfold increase in caspase activity and a fourfold increase of [18F]-CP18 retention in the dexamethasone-induced thymus of treated versus control mice.

Conclusions

We report the use [18F]-CP18 as a PET tracer for imaging apoptosis. Our data support further development of this tracer for clinical PET applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Jacobson MD, Weil M, Raff MC (1997) Programmed cell death in animal development. Cell 88:347–354

    Article  PubMed  CAS  Google Scholar 

  2. Thompson C (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  PubMed  CAS  Google Scholar 

  3. Rimon G, Bazenet CE, Philpott KL, Rubin LL (1997) Increased surface phosphatidylserine is an early marker of neuronal apoptosis. J Neurosci Res 48:563–570

    Article  PubMed  CAS  Google Scholar 

  4. Olivetti G, Abbi R, Quaini F et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141

    Article  PubMed  CAS  Google Scholar 

  5. Krams SM, Martinez OM (1998) Apoptosis as a mechanism of tissue injury in liver allograft rejection. Semin Liver Dis 18:153–167

    Article  PubMed  CAS  Google Scholar 

  6. Darzynkiewicz Z (1995) Apoptosis in antitumor strategies: modulation of cell cycle or differentiation. J Cell Biochem 58:151–159

    Article  PubMed  CAS  Google Scholar 

  7. Blankenberg FG, Katsikis PD, Tait JF et al (1998) In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci U S A 95:6349–6354

    Article  PubMed  CAS  Google Scholar 

  8. Lahorte CMM, Vanderheyden J, Steinmetz N et al (2004) Apoptosis-detecting radioligands: current state of the art and future perspectives. Eur J Nucl Med Mo Imaging 31:887–919

    Article  CAS  Google Scholar 

  9. Kemerink GJ, Liu X, Kieffer D et al (2003) Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application. J Nucl Med 44:947–952

    PubMed  CAS  Google Scholar 

  10. Grütter MG (2000) Caspases: key players in programmed cell death. Curr Opin Struct Biol 10:649–655

    Article  PubMed  Google Scholar 

  11. Shi Y (2004) Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci 13:1979–1987

    Article  PubMed  CAS  Google Scholar 

  12. Blankengerg FG, Norfray JF (2011) Multimodality molecular imaging of apoptosis in oncology. AJR Am J Roentgenol 197:308–317

    Article  Google Scholar 

  13. Kim K, Lee M, Park H et al (2006) Cell-permeable and biocompatible polymeric nanoparticles for apoptosis imaging. J Am Chem Soc 128:3490–3491

    Article  PubMed  CAS  Google Scholar 

  14. Chu W, Zhang J, Zeng C et al (2005) N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: synthesis, in vitro activity, and molecular modeling studies. J Med Chem 48:7637–7647

    Article  PubMed  CAS  Google Scholar 

  15. Zhou D, Chu W, Chen DL et al (2009) [18F]- and [11C]-labeled N-benzyl-isatin sulfonamide analogues as PET tracers for apoptosis: synthesis, radiolabeling mechanism, and in vivo imaging study of apoptosis in Fas-treated mice using [11C]WC-98. Org Biomol Chem 7:1337–1348

    Article  PubMed  CAS  Google Scholar 

  16. Zhou D, Chu W, Rothfuss J et al (2006) Synthesis, radiolabeling, and in vivo evaluation of an 18F-labeled isatin analog for imaging caspase-3 activation in apoptosis. Bioorganic & Medicinal Chemistry Letters 16:5041–5046

    Article  CAS  Google Scholar 

  17. Nguyen Q, Smith G, Glaser M et al (2009) Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide. Proc Natl Acad Sci U S A 106:16375–16380

    Article  PubMed  CAS  Google Scholar 

  18. Nguyen Q, Challapalli A, Smith G et al (2012) Imaging apoptosis with positron emission tomography: "Bench to bedside" development if the caspase 3/7 specific [18F] ICMT-11. Eur J Cancer 48:432–440

    Article  PubMed  CAS  Google Scholar 

  19. Thornberry NA, Rano TA, Peterson EP et al (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B functional relationships established for key mediators of apoptosis. J Biol Chem 272:17907–17911

    Article  PubMed  CAS  Google Scholar 

  20. Dutot L, Lécorché P, Burlina F et al (2010) Glycosylated cell-penetrating peptides and their conjugates to a proapoptotic peptide: preparation by click chemistry and cell viability studies. J Chem Biol 3:51–65

    Article  Google Scholar 

  21. Nguyen J, Xie X, Neu M et al (2008) Effects of cell-penetrating peptides and pegylation on transfection efficiency of polyethylenimine in mouse lungs. J Gene Med 10:1236–1246

    Article  PubMed  CAS  Google Scholar 

  22. Kolb HC, Finn MG, Sharpless KB (2001) Click chemistry: diverse chemical function from a few good reactions. Angew Chem Int Ed 40:2004–2021

    Article  CAS  Google Scholar 

  23. Rostovtsev VV, Green LG, Fokin VV et al (2002) A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew Chem Int Ed 41:2596–2599

    Article  CAS  Google Scholar 

  24. Tornoe CW, Christensen C, Meldal M (2002) Peptidotriazoles on solid phase: [1–3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J Org Chem 67:3057–3064

    Article  PubMed  CAS  Google Scholar 

  25. Cifone MG, Migliorati G, Parroni R et al (1999) Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 93:2282–2296

    PubMed  CAS  Google Scholar 

  26. Chmielewski V, Drupt F, Morfin R (2000) Dexamethasone-induced apoptosis of mouse thymocytes: prevention by native 7alpha-hydroxysteroids. Immunol Cell Biol 78:238–246

    Article  PubMed  CAS  Google Scholar 

  27. Faust A, Hermann S, Wagner S et al (2009) Molecular imaging of apoptosis in vivo with scintigraphic and optical biomarkers—a status report. Anti-Cancer Agents in Med Chemistry 9:968–985

    Article  CAS  Google Scholar 

  28. Zhao M, Zhu X, Ji S et al (2006) 99mTc-labeled C2A domain of synaptotagmin I as a target-specific molecular probe for noninvasive imaging of acute myocardial infarction. J Nuc Med 47:1367–1374

    CAS  Google Scholar 

  29. Zhao M, Li Z, Bugenhagen (2008) 99m Tc-Labeled duramycin as a novel phosphatidylethanolamine-binding molecular probe. J Nuc Med 49:1345–1352

    Article  CAS  Google Scholar 

  30. Damianovich M, Ziv I, Heyman SN et al (2006) ApoSense: a novel technology for functional molecular imaging of cell death in models of acute renal tubular necrosis. Eur J Nucl Med Mol Imaging 33:281–291

    Article  PubMed  Google Scholar 

  31. Hoglund J, Shirvan A, Antoni G et al (2011) 18F -ML-10, a PET tracer for apoptosis: first human study. J Nucl Med 52:720–725

    Article  PubMed  Google Scholar 

  32. Edginton LE, Berger AB, Blum G et al (2009) Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes. Nat Med 15:967–973

    Article  Google Scholar 

  33. Niers JM, Kerami M, Pike L et al (2011) Multimodal in vivo imaging and blood monitoring of intrinsic and extrinsic apoptosis. Mol Ther 19:1090–1096

    Article  PubMed  CAS  Google Scholar 

  34. Scabini M, Stellari F, Cappella P et al (2011) In vivo imaging of early stage apoptosis by measuring real-time caspase-3/7 activation. Apoptosis 16:198–207

    Article  PubMed  CAS  Google Scholar 

  35. Hickson J, Ackler S, Klaubert D et al (2010) Noninvasive molecular imaging of apoptosis in vivo using a modified firefly luciferase substrate. Z-DEVD-aminoluciferin Cell Death Differ 17:1003–1010

    Article  CAS  Google Scholar 

  36. Maxwell D, Chang Q, Zhang X et al (2009) An improved cell-penetrating, caspase-activatable, near-infrared fluorescent peptide for apoptosis imaging. Bioconjug Chem 20:702–709

    Article  PubMed  CAS  Google Scholar 

  37. Xiong C, Yang Z, Zhang R et al (2009) 99mTc-labeled Ac-DEVD peptides as a substrate for measuring caspase activity. Adv Exp Med Biol 611:455–456

    Article  PubMed  CAS  Google Scholar 

  38. Bauer C, Bauder-Wuest U, Mier W et al (2005) 131I-labeled peptides as caspase substrates for apoptosis imaging. J Nucl Med 46:1066–1074

    PubMed  CAS  Google Scholar 

  39. Walsh J, Kolb H (2010) Applications of click chemistry in radiopharmaceutical development. Chimia 64:29–33

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Kai Chen for contributing to the design of CP18. We thank James Secrest and Janna Arteaga for facilitating the animal experiments.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Molecular Imaging Biomarker Research, Siemens Medical Solutions USA, Inc, 6100 Bristol Parkway, Culver City, CA, 90230, USA

    Helen Su, Gang Chen, Umesh Gangadharmath, Luis F. Gomez, Qianwa Liang, Fanrong Mu, Vani P. Mocharla, A Katrin Szardenings, Joseph C. Walsh, Chun-Fang Xia, Chul Yu & Hartmuth C. Kolb

Authors
  1. Helen Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Umesh Gangadharmath
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis F. Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qianwa Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fanrong Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vani P. Mocharla
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Katrin Szardenings
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joseph C. Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chun-Fang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chul Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hartmuth C. Kolb
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hartmuth C. Kolb.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 710 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Su, H., Chen, G., Gangadharmath, U. et al. Evaluation of [18F]-CP18 as a PET Imaging Tracer for Apoptosis. Mol Imaging Biol 15, 739–747 (2013). https://doi.org/10.1007/s11307-013-0644-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-013-0644-9

Key words

Search

Navigation