[18F]-GE-179 positron emission tomography (PET) tracer for N-methyl-d-aspartate receptors: One-pot synthesis and preliminary micro-PET study in a rat model of MCAO

Weiyan Zhou; Weiqi Bao; Donglang Jiang; Yanyan Kong; Fengchun Hua; Xiuhong Lu; Yihui Guan

doi:10.1016/j.nucmedbio.2018.04.002

[¹⁸F]-GE-179 positron emission tomography (PET) tracer for N-methyl-d-aspartate receptors: One-pot synthesis and preliminary micro-PET study in a rat model of MCAO

Nucl Med Biol. 2018 Jun:61:45-55. doi: 10.1016/j.nucmedbio.2018.04.002. Epub 2018 Apr 25.

Authors

Weiyan Zhou¹, Weiqi Bao¹, Donglang Jiang¹, Yanyan Kong¹, Fengchun Hua¹, Xiuhong Lu², Yihui Guan³

Affiliations

¹ PET Center, Huashan Hospital, Fudan University, No. 518, East Wuzhong Road, Xuhui District, Shanghai 200235, China.
² PET Center, Huashan Hospital, Fudan University, No. 518, East Wuzhong Road, Xuhui District, Shanghai 200235, China. Electronic address: xiuhonglu@fudan.edu.cn.
³ PET Center, Huashan Hospital, Fudan University, No. 518, East Wuzhong Road, Xuhui District, Shanghai 200235, China; Institute of Integrative Medicine, Fudan University, No. 12, Middle Urumqi Road, Jing'an District, Shanghai 200040, China. Electronic address: guanyihui@hotmail.com.

PMID: 29747036
DOI: 10.1016/j.nucmedbio.2018.04.002

Abstract

Introduction: The objective of this study was to synthesize an N-methyl-d-aspartate receptor (NMDAR) radiotracer [¹⁸F]-GE-179 in one-pot and evaluate its in vivo binding for NMDAR activation after brain ischemia reperfusion injury.

Methods: [¹⁸F]-GE-179 was auto-synthesized using a quick one-pot method from a stable disulfide precursor and purified using semi-preparative high-performance liquid chromatography (HPLC) with ethanol/aqueous NaH₂PO₄ as the eluent. Dynamic micro-positron emission tomography (PET)/computed tomography (CT) study of [¹⁸F]-GE-179 was successfully performed using a rat model of middle cerebral artery occlusion (MCAO, induced by transient occlusion into the left MCA). A simplified reference tissue model method was used to calculate the [¹⁸F]-GE-179 non-displaceable binding potential (BPND) for intracranial NMDAR activation assessment. Immunofluorescence staining of NMDAR NR1 subunit in brain slices containing lesion was also performed.

Results: [¹⁸F]-GE-179 was successfully prepared in a yield of 23-30% in a formulation that could be injected directly after dilution. Localized radioactivity accumulation was observed in the animal model of MCAO. Significantly higher (p = 0.0003-0.0404) BPND relative to equivalent contralateral was found in the ipsilateral caudate putamen, Acb core/shell, cortex cingulate, amygdala, hypothalamus, and superior colliculus. Immunofluorescence staining showed elevated NMDAR expression in the affected hemisphere.

Conclusions: [¹⁸F]-GE-179 was synthesized using a one-pot process with a markedly improved yield. Preliminary in vivo micro-PET study visualized excessive NMDAR stimulation successfully in a rodent model of MCAO, which was consistent with results of in vitro immunofluorescence staining. The study demonstrates that [¹⁸F]-GE-179 is a promising PET probe for the detection of functional NMDAR alterations.

Keywords: Ischemia reperfusion; Middle cerebral artery occlusion (MCAO); N-methyl-d-aspartate receptor (NMDAR); Positron emission tomography (PET).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / diagnostic imaging
Brain / metabolism
Chemistry Techniques, Synthetic
Disease Models, Animal
Fluorine Radioisotopes / chemistry*
Infarction, Middle Cerebral Artery / diagnostic imaging*
Infarction, Middle Cerebral Artery / metabolism*
Magnetic Resonance Imaging
Male
Positron Emission Tomography Computed Tomography / methods*
Radiopharmaceuticals / chemical synthesis*
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / metabolism*

Substances

Fluorine Radioisotopes
Radiopharmaceuticals
Receptors, N-Methyl-D-Aspartate