Published Online
on March 11, 2004

A more recent version of this article appeared on April 1, 2004

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Submitted on October 8, 2003
Revised on December 10, 2003
Accepted on January 8, 2004

Imaging the Ischemic Penumbra with ¹⁸F-Fluoromisonidazole in a Rat Model of Ischemic Stroke

Kazuko Saita MD, PhD; Michelle Chen BSc (Hon); Neil J. Spratt FRACP, B.Med.Sci; Michelle J. Porritt PhD; Gabriel T. Liberatore PhD; Stephen J. Read PhD, FRACP; Christopher R. Levi MBBS, FRACP; Geoffrey A. Donnan MD, FRACP; Uwe Ackermann PhD; Henri J. Tochon-Danguy PhD; John I. Sachinidis PhD; and David W. Howells PhD^*

From the Department of Medicine, University of Melbourne (K.S., M.C., G.T.L., N.J.S., G.A.D., D.W.H.), National Stroke Research Institute (N.J.S., G.A.D., D.W.H.), and Centre for Positron Emission Tomography (U.A., H.J.T.-D., J.I.S.), Austin Health, Melbourne, Victoria, Australia; Department of Neurology, John Hunter Hospital (C.R.L.) Newcastle, New South Wales, Australia; Stroke Unit, Royal Brisbane Hospital (S.J.R.), Queensland, Australia.

^* To whom correspondence should be addressed. E-mail: david.howells{at}unimelb.edu.au.

Background and Purpose--The ischemic penumbra is a major focus of stroke research. ¹⁸F-fluoromisonidazole (¹⁸F-FMISO), a positron emission tomography (PET) marker of hypoxic cells, has shown promise as a technique to image the penumbra in humans. Our aim was to delineate the pattern of ¹⁸F-FMISO binding in a rat middle cerebral artery transient thread-occlusion model, and correlate this with tissue outcome at 24 hours. We hypothesized that the pattern of ¹⁸F-FMISO binding would mimic that seen in humans.

Methods--Thirty-eight rats underwent 2 hours transient middle cerebral artery (MCA) occlusion, and then received ¹⁸F-FMISO at time points from 0.5 to 22 hours post-MCA occlusion and were killed 2 hours later. Autoradiographic assessment of ¹⁸F-FMISO binding and assessment (triphenyltetrazolium chloride) of the area of infarction were performed on tissue slices.

Results--Until 1 hour after MCA occlusion, ¹⁸F-FMISO binding was increased in the entire MCA territory, with little or no infarction visible. Over the next 5 hours, the pattern of binding evolved to a small rim of intensely binding tissue surrounding the infarct core, which itself showed reduced binding compared with the contralateral hemisphere. By 24 hours, there was minimal accumulation of ¹⁸F-FMISO binding and a large area of infarction.

Conclusions--The pattern of ¹⁸F-FMISO binding rats reproduced the pattern seen in humans, consistent with this tracer being a marker of the ischemic penumbra in both species. This technique may have application in studying the ischemic penumbra in animal models, and correlating this with similar studies in humans.

Key words: stroke • imaging • animal models of human disease • nitroimidazoles • autoradiography

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