[18F]FETA PET - A new method for hot spot imaging of the ischemic penumbra in acute stroke


[18F]FETA PET - A new method for hot spot imaging of the ischemic penumbra in acute stroke

Barthel, H.; Großmann, U.; Zeisig, V.; Patt, M.; Wagner, D.; Patt, J.; Kluge, M.; Franke, H.; Sorger, D.; Luthardt, J.; Nitzsche, B.; Dreyer, A.; Brust, P.; Steinbach, J.; Boltze, J.; Emmrich, F.; Sabri, O.

Objectives:

In acute ischemic stroke, an imaging method to directly visualize the ischemic penumbra - the salvageable part of the affected brain - in positive image contrast would potentially improve therapy stratification and monitoring. This study aimed to test [18F] fluoroetanidazole ([18F]FETA), a second-generation radiolabeled 2-nitroimidazole, for the first time with respect to its suitability to image brain hypoxia with positron emission tomography (PET).

Methods:

Primary embryonal corticoencephalic cells (Wistar rats) and necortical brain slices (Sprague Dawley rats) were ex vivo exposed to nitrogen or air. The cells and brain slices were incubated with 5MBq [18F]FETA up to 120min, respectively. The activities of three nitroreductases - enzymes which mediate the intracellular [18F]FETA accumulation - were determined in the corticoencephalic cells. Further, organ distribution was determined in Sprague
Dawley rats up to 2h after i.v. injection of 20MBq [18F]FETA, and ex vivo brain autoradiography was performed up to 24h after permanent middle cerebral artery occlusion (pMCAO). Target-to background image contrast of [18F]FETA autoradiograms at 3h after pMCAO was compared with that of corresponding [18F]fluoromisonidazole ([18F]FMISO) autoradiograms. At 24h after pMCAO, animals were additionally i.v. injected with 1MBq [14C]iodoantipyrine to determine the local cerebral blood flow (lCBF). Nissl staining of brain slices as well as stroke-specific MRI were carried out at 24h after pMCAO to confirm the existence and localization of ischemic brain tissue damage.

Results:

In vitro, the oxygen concentration in the cell suspension was < 1 mm Hg and ~70 mm Hg under nitrogen and air, respectively. The normoxic [18F]FETA uptake by the cells and the brain slices was low and constant over time (0.3±0.08 %ID.mio cells-1 and 0.04±0.01 %ID.g tissue-1). In contrast, under hypoxia a time-dependent linear increase of the [18F]FETA uptake was found which was 2.0- and 2.5-fold by the cells and 2.0- and 2.4-fold by the brain slices at 60min and 120min (p< 0.05), respectively. The analyses of nitroreductases activities showed that cell oxygenation does not affect the enzyme activities. The biodistribution studies revealed fast blood clearance, a rapid urinary excretion and a constantly low uptake in unaffected brain tissue (0.1±0.02 %ID.g-1). Ex vivo brain autoradiography in the pMCAO rats showed a relevant time-dependent [18F]FETA uptake in ipsilateral brain regions which reached maximum target-to background ratios of 3.3±0.2 at 3h. The corresponding [18F]FMISO uptake ratios were only 1.5±0.3 (p< 0.05). Furthermore, at 24h after pMCAO the lCBF was reduced in the infarction core (as determined by Nissl staining and MRI) and surrounding brain areas by 25% and 10%, respectively.

Conclusions:

These results demonstrate that [18F]FETA has a better potential than [18F]FMIS to serve as a brain hypoxia marker. Further testing of this promising new stroke PET marker is warranted. First results employing a new sheep stroke model developed recently by our group [1] are encouraging.

References:

[1] Boltze et al., J Cereb Blood F Metab 2008

First and second author contributed equally to this study

This research was supported by the Translational Centre for Regenerative Medicine Leipzig/BMBF (PtJ-Bio 0313909)

  • Lecture (Conference)
    XXIVth International Symposium on Cerebral Blood Flow, Metabolism and Function and the IXth International Conference on Quantification of Brain Function with PET, 29.06.-03.07.2009, Chicago, USA
  • Abstract in refereed journal
    Journal of Cerebral Blood Flow and Metabolism 29(2009)Suppl. 1, S42-S43
    ISSN: 0271-678X

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Publ.-Id: 12178