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In Vivo Evaluation of Radiofluorinated Caspase-3/7 Inhibitors as Radiotracers for Apoptosis Imaging and Comparison with [18F]ML-10 in a Stroke Model in the Rat

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Abstract

Purpose

The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.

Procedures

In vivo characteristics of isatins [18F]-2 and [18F]-3 were studied and compared by μPET to previously described 1-[4-(2-[18F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([18F]-1) and to 2-(5-[18F]fluoropentyl)-2-methyl-malonic acid ([18F]ML-10) used as a reference radiotracer in a rat stroke model.

Results

[18F]-2 and [18F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [18F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [18F]-1 after 45 min. No differences were observed for [18F]ML-10.

Conclusions

Radiolabelled isatins are more promising radiotracers to image apoptosis than [18F]ML-10 in this stroke animal model without craniectomy. In particular, [18F]-1 presented significant uptake in apoptotic area 45 min after administration

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References

  1. 1.

    Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241

  2. 2.

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

  3. 3.

    Reshef A, Shirvan A, Akselrod-Ballin A et al (2010) Small-molecule biomarkers for clinical PET imaging of apoptosis. J Nucl Med 51:837–840

  4. 4.

    Vangestel C, Peeters M, Mees G et al (2011) In vivo imaging of apoptosis in oncology: an update. Mol Imaging 10:340–358

  5. 5.

    Blankenberg FG (2009) Imaging the molecular signatures of apoptosis and injury with radiolabeled annexin V. Proc Am Thorac Soc 6:469–476

  6. 6.

    Niu G, Chen X (2010) Apoptosis imaging: beyond Annexin V. J Nucl Med 51:1659–1662

  7. 7.

    Zhenodarova SM (2010) Small-molecule caspase inhibitors. Russ Chem Rev 79:119–143

  8. 8.

    Häcker HG, Sisay MT, Gütschow M (2011) Allosteric modulation of caspases. Pharmacol Ther 132:180–195

  9. 9.

    Chen DL, Engle JT, Griffin EA et al (2014) Imaging caspase-3 activation as a marker of apoptosis-targeted treatment response in cancer. Mol Imaging Biol. doi:10.1007/s11307-014-0802-8

  10. 10.

    Chen DL, Zhou D, Chu W et al (2012) Radiolabeled isatin binding to caspase-3 activation induced by anti-Fas antibody. Nucl Med Biol 39:137–144

  11. 11.

    Faust A, Wagner S, Law MP et al (2007) The nonpeptidyl caspase binding radioligand (S)-1-(4-(2-[18F]Fluoroethoxy)-benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin ([18F]CbR) as potential positron emission tomography-compatible apoptosis imaging agent. Q J Nucl Med Mol Imaging 51:67–73

  12. 12.

    Kopka K, Faust A, Keul P et al (2006) 5-Pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis. J Med Chem 49:6704–6715

  13. 13.

    Nguyen QD, 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

  14. 14.

    Nguyen QD, Lavdas I, Gubbins J et al (2013) Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging. Clin Cancer Res 19:3914–3924

  15. 15.

    Witney TH, Fortt RR, Aboagye EO (2014) Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography. PLoS One 9:e91694

  16. 16.

    Challapalli A, Kenny LM, Hallett WA et al (2013) 18F-ICMT-11, a caspase-3-specific PET tracer for apoptosis: biodistribution and radiation dosimetry. J Nucl Med 54:1551–1556

  17. 17.

    Krause-Heuer AM, Howell NR, Matesic L et al (2013) A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis. Med Chem Commun 4:347–352

  18. 18.

    Bauwens M, De Saint-Hubert M, Cleynhens J et al (2013) In vitro and in vivo comparison of 18F and 123I-labeled ML10 with 68Ga-Cys2-AnxA5 for molecular imaging of apoptosis. Q J Nucl Med Mol Imaging 57:187–200

  19. 19.

    Cohen A, Shirvan A, Levin G et al (2009) From the Gla domain to a novel small-molecule detector of apoptosis. Cell Res 19:625–637

  20. 20.

    Reshef A, Shirvan A, Waterhouse RN et al (2008) Molecular imaging of neurovascular cell death in experimental cerebral stroke by PET. J Nucl Med 49:1520–1528

  21. 21.

    Oborski MJ, Laymon CM, Qian Y et al (2014) Challenges and approaches to quantitative therapy response assessment in glioblastoma multiforme using the novel apoptosis positron emission tomography tracer F-18 ML-10. Transl Oncol 7:111–119

  22. 22.

    Oborski MJ, Laymon CM, Lieberman FS et al (2014) First use of 18F-labeled ML-10 PET to assess apoptosis change in a newly diagnosed glioblastoma multiforme patient before and early after therapy. Brain Behav 4:312–315

  23. 23.

    Allen AM, Ben-Ami M, Reshef A et al (2012) Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with 18F-ML-10. Eur J Nucl Med Mol Imaging 39:1400–1408

  24. 24.

    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

  25. 25.

    Charriaut-Marlangue C, Margaill I, Represa A et al (1996) Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–195

  26. 26.

    Cavallucci V, D’Amelio M (2011) Matter of life and death: the pharmacological approaches targeting apoptosis in brain diseases. Curr Pharm Des 17:215–229

  27. 27.

    Heiss WD (2011) The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. Cerebrovasc Dis 32:307–320

  28. 28.

    Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91

  29. 29.

    Liu G, Wang T, Wang T et al (2013) Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats. Biomed Rep 1:861–867

  30. 30.

    Xu XH, Zhang SM, Yan WM et al (2006) Development of cerebral infarction, apoptotic cell death and expression of X-chromosome-linked inhibitor of apoptosis protein following focal cerebral ischemia in rats. Life Sci 78:704–712

  31. 31.

    Sobrio F, Medoc M, Martial L et al (2013) Automated radiosynthesis of [18F]ML-10, a PET radiotracer dedicated to apoptosis imaging, on a TRACERLab FX-FN module. Mol Imaging Biol 15:12–18

  32. 32.

    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

  33. 33.

    Dewkar GK, Sundaresan G, Lamichhane N et al (2013) Microfluidic radiosynthesis and biodistribution of [18F] 2-(5-fluoro-pentyl)-2-methyl malonic acid. J Label Compd Radiopharm 56:289–294

  34. 34.

    Baumann A, Faust A, Law MP et al (2011) Metabolite identification of a radiotracer by electrochemistry coupled to liquid chromatography with mass spectrometric and radioactivity detection. Anal Chem 83:5415–5421

  35. 35.

    Durukan A, Marinkovic I, Strbian D et al (2009) Post-ischemic blood–brain barrier leakage in rats: one-week follow-up by MRI. Brain Res 1280:158–165

  36. 36.

    Belayev L, Busto R, Zhao W, Ginsberg MD (1996) Quantitative evaluation of blood–brain barrier permeability following middle cerebral artery occlusion in rats. Brain Res 739:88–96

  37. 37.

    Kuroiwa T, Ting P, Martinez H, Klatzo I (1985) The biphasic opening of the blood–brain barrier to proteins following temporary middle cerebral artery occlusion. Acta Neuropathol 68:122–129

  38. 38.

    Huang ZG, Xue D, Preston E et al (1999) Biphasic opening of the blood–brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 26:298–304

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Acknowledgments

Marie Médoc and the project were financed by the Conseil Régional de Basse-Normandie (Lower Normandy Council). The authors thank Olivier Tirel for performing the cyclotron production. The technical assistance of Fabien Fillesoye was greatly appreciated. Lidia Matesic gratefully acknowledges the Australian Academy of Science for a France-Australia Science Innovation Collaboration Early Career Fellowship.

Conflict of Interest

The authors declare that they have no conflict of interests.

Author information

Correspondence to Franck Sobrio.

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Médoc, M., Dhilly, M., Matesic, L. et al. In Vivo Evaluation of Radiofluorinated Caspase-3/7 Inhibitors as Radiotracers for Apoptosis Imaging and Comparison with [18F]ML-10 in a Stroke Model in the Rat. Mol Imaging Biol 18, 117–126 (2016). https://doi.org/10.1007/s11307-015-0865-1

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Key words

  • Fluorine-18
  • PET
  • Apoptosis
  • Cerebral stroke
  • Ischemia
  • Caspase-3 inhibitors
  • In vivo evaluation
  • Isatins