Publications Repository - Helmholtz-Zentrum Dresden-Rossendorf
[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.
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).
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.
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.
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  are encouraging.
 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)
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