[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

Introduction: The objective of this study was to synthesize an N-methyl-D-aspartate receptor (NMDAR) radiotracer [F-18]-GE-179 in one-pot and evaluate its in vivo binding for NMDAR activation after brain ischemia reperfusion injury. Methods: [F-18]-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 NaH(2)PO(4 )as the eluent. Dynamic micro-positron emission tomography (PET)/computed tomography (CT) study of [F-18]-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 [F-18]-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: [F-18]-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: [F-18]-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 [F-18]-GE-179 is a promising PET probe for the detection of functional NMDAR alterations. (C) 2018 Elsevier Inc. All rights reserved.