Preparation and evaluation of ethyl [18F]fluoroacetate as a proradiotracer of [18F]fluoroacetate for the measurement of glial metabolism by PET

Mori, Tetsuya; Sun, Li-Quan; Kobayashi, Masato; Kiyono, Yasushi; Okazawa, Hidehiko; Furukawa, Takako; Kawashima, Hidekazu; Welch, Michael J.; Fujibayashi, Yasuhisa

doi:10.1016/j.nucmedbio.2008.11.006

« Previous Next »Nuclear Medicine and Biology
Volume 36, Issue 2 , Pages 155-162, February 2009

Preparation and evaluation of ethyl [¹⁸F]fluoroacetate as a proradiotracer of [¹⁸F]fluoroacetate for the measurement of glial metabolism by PET

Tetsuya Mori
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Li-Quan Sun
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
- School of Life Science and Technology, Beijing Institute of Technology, Beijing 100081, China
Masato Kobayashi
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Yasushi Kiyono
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
- Corresponding author. Tel.: +81 776 61 8420; fax: +81 776 61 8170.
Hidehiko Okazawa
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Takako Furukawa
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan
Hidekazu Kawashima
- Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
Michael J. Welch
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yasuhisa Fujibayashi
- Biomedical Imaging Research Center, University of Fukui, Fukui 910-1193, Japan

Received 3 October 2008; received in revised form 5 November 2008; accepted 11 November 2008.

Abstract

Introduction

Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [¹⁸F]fluoroacetate ([¹⁸F]EFA), which is [¹⁸F]fluoroacetate ([¹⁸F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism.

Methods

The synthesis of [¹⁸F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood–brain barrier permeability of ethyl [1-¹⁴C]fluoroacetate ([¹⁴C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [¹⁴C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [¹⁴C]EFA was measured. Biodistribution studies of [¹⁸F]EFA in ddY mice were carried out and compared with [¹⁸F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [¹⁸F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method.

Results

The synthesis of [¹⁸F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6±3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [¹⁴C]EFA was 3.8 times higher than that of sodium [1-¹⁴C]fluoroacetate. [¹⁴C]EFA was hydrolyzed rapidly in rat brains. In stability studies using the plasma of five animal species, [¹⁴C]EFA was stable only in primate plasma. Biodistribution studies in mice showed that the uptake of [¹⁸F]EFA in selected organs was higher than that of [¹⁸F]FA. From nonprimate PET studies, [¹⁸F]EFA was initially taken into the brain after injection. Metabolites related to the tricarboxylic acid (TCA) cycle were detected in common marmoset brain.

Conclusion

[¹⁸F]EFA rapidly enters the brain and is then converted into TCA cycle metabolites in the brains of common marmosets. [¹⁸F]EFA shows promise as a proradiotracer for the measurement of glial metabolism.

Keywords: [¹⁸F]Fluoroacetate, Ethyl [¹⁸F]fluoroacetate, Proradiotracer, Glial metabolism, PET