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PET Detection of Cerebral Necrosis Using an Infarct-Avid Agent 2-Deoxy-2-[18F]Fluoro-d-Glucaric Acid (FGA) in a Mouse Model of the Brain Stroke

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Abstract

Purpose

Ischemic stroke is a leading cause of disability worldwide. The volume of necrotic core in affected tissue plays a major role in selecting stroke patients for thrombolytic therapy or endovascular thrombectomy. In this study, we investigated a recently reported positron emission tomography (PET) agent 2-deoxy-2-[18F]fluoro-d-glucaric acid (FGA) to determine necrotic core in a model of transient middle cerebral artery occlusion (t-MCAO) in mice.

Procedures

The radiopharmaceutical, FGA, was synthesized by controlled, rapid, and quantitative oxidation of clinical doses of 2-deoxy-2-[18F]fluoro-d-glucose (FDG) in a one-step reaction using a premade kit. Brain stroke was induced in the left cerebral hemisphere of CD-1 mice by occluding the middle cerebral artery for 1 h, and then allowing reperfusion by removing the occlusion. One day post-ictus, perfusion single-photon emission tomography (SPECT) was performed with 99mTc-lableled hexamethylpropyleneamine oxime (HMPAO), followed by PET acquisition with FGA. Plasma and brain tissue homogenates were assayed for markers of inflammation and neurotrophins.

Results

The kit-based synthesis was able to convert up to 2.2 GBq of FDG into FGA within 5 min. PET images showed 375 % more accumulation of FGA in the ipsilateral hemisphere than in the contralateral hemisphere. SPECT images showed that the ipsilateral HMPAO accumulation was reduced to 55 % of normal levels; there was a significant negative correlation between the ipsilateral accumulation of FGA and HMAPO (p < 0.05). FGA accumulation in stroke also correlated with IL-6 levels in the ipsilateral hemisphere. There was no change in IL-6 or TNFα in the plasma of stroke mice.

Conclusions

Accumulation of FGA correlated well with the perfusion defect and inflammatory injury. As a PET agent, FGA has potential to image infarcted core in the brain stroke injury with high sensitivity, resolution, and specificity.

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Acknowledgments

Technical assistance from Ms. Andria Hedrick is acknowledged.

Funding

This study was partly funded by 1R41HL140919-01A1 STTR grant to Hexakit, Inc.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, 1110 N. Stonewall Ave, Oklahoma City, OK, 73117, USA

    Hailey Houson, Alexander Mdzinarishvili, Hariprasad Gali & Vibhudutta Awasthi

  2. Department of Neurology, College of Medicine, The University of Oklahoma Health Sciences Center, 920 Stanton L. Young Blvd, Suite 2040, Oklahoma City, OK, 73104, USA

    Evgeny Sidorov

  3. Hexakit, Inc., 2401 Cheval Pointe Dr, Edmond, OK, 73034, USA

    Vibhudutta Awasthi

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  1. Hailey Houson
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  2. Alexander Mdzinarishvili
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Correspondence to Vibhudutta Awasthi.

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VA is partly employed by Hexakit, Inc. and is its owner.

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Houson, H., Mdzinarishvili, A., Gali, H. et al. PET Detection of Cerebral Necrosis Using an Infarct-Avid Agent 2-Deoxy-2-[18F]Fluoro-d-Glucaric Acid (FGA) in a Mouse Model of the Brain Stroke. Mol Imaging Biol 22, 1353–1361 (2020). https://doi.org/10.1007/s11307-020-01513-9

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