PET imaging of ischemic brain stroke necrosis with novel agent ¹⁸F-Fluoroglucaric Acid

Objectives: Brain stroke is the second most common cause of death worldwide, with considerable disability among survivors. Greater than 80% of brain strokes are due to cerebrovascular occlusion, particularly middle cerebral artery occlusion. Current management of stroke patients is aimed at preventing the progression of at-risk cerebral tissue towards infarction by restoring blood supply to ischemic but viable tissue (a.k.a. penumbra). The timing of treatment with respect to the type and stage of evolution of stroke critically determines the treatment success. By providing valuable information about the presence, size, and growth of infarct (umbra) and surrounding ischemia (penumbra), imaging contributes greatly to clinical decision making. While the gold standard for determining the penumbra is F-18-FMISO/PET, the agent is unavailable in most medical centers. The objective of this research was to investigate the utility of a new PET agent F-18-Fluoroglucaric acid (FGA) to delineate infarct in a mouse brain stroke model of middle cerebral artery occlusion (MCAO).

Methods: Radiopharmaceutical FGA was synthesized in one-pot by a 5 min controlled oxidation of commercially available F-18-Fluorodeoxyglucose. Quality control of FGA was performed by radio-TLC. Brain stroke was induced in the left cerebral hemisphere of male CD-1 mice (20-25 g) by occluding middle cerebral artery and allowing reperfusion after 1 h of occlusion. After 24 h of reperfusion, mice were subjected to imaging with Tc-99m-HMPAO (92.5 MBq) and F-18-FGA (92.5 MBq) for perfusion and infarct assessment, respectively. Helical SPECT was acquired after 1 h of Tc-99m-HMPAO injection, whereas PET was acquired after 1-2 h of F-18-FGA injection. PET was also acquired ex vivo after separating skull from whole body. In addition, radioactivity associated with left (ipsilateral) and right (contralateral) cerebral hemispheres was determined in a well counter. The brains were sectioned for TTC staining. Results: Gamma counting of the brain hemispheres showed an almost three-fold increase in FGA accumulation in the ipsilateral hemisphere as compared to the contralateral hemisphere. Ex vivo PET of intact skull clearly demonstrated differential FGA accumulation in the stroke area. However, in vivo resolution of stroke was noticeably affected by normal nasal accumulation of FGA. Corresponding HMPAO/SPECT also showed a perfusion defect in the ipsilateral hemisphere, which was corroborated with TTC staining. Conclusions: Results show that FGA has a potential to enable extremely sensitive and high resolution neuroimaging of brain infarcts. F-18-labeled FGA can be rapidly synthesized from ubiquitously available F-18-FDG in a simple reaction.

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