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.
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.
[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.
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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Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241
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
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
Vangestel C, Peeters M, Mees G et al (2011) In vivo imaging of apoptosis in oncology: an update. Mol Imaging 10:340–358
Blankenberg FG (2009) Imaging the molecular signatures of apoptosis and injury with radiolabeled annexin V. Proc Am Thorac Soc 6:469–476
Niu G, Chen X (2010) Apoptosis imaging: beyond Annexin V. J Nucl Med 51:1659–1662
Zhenodarova SM (2010) Small-molecule caspase inhibitors. Russ Chem Rev 79:119–143
Häcker HG, Sisay MT, Gütschow M (2011) Allosteric modulation of caspases. Pharmacol Ther 132:180–195
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Heiss WD (2011) The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. Cerebrovasc Dis 32:307–320
Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91
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
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
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
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
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
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
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
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
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
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
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.
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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
- Cerebral stroke
- Caspase-3 inhibitors
- In vivo evaluation