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Synaptic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is thought to cause excitotoxicity brain ischemia. However, given the current inability to quantify AMPARs density in live human brains, clinical translation has been limited. In this study, in vivo and in vitro experiments were conducted to evaluate the factors affecting omberacetam drug labeling with technetium-99m as a potential radiotracer of AMPARs in brain imaging. Healthy Swiss albino mice (adult male; n = 25; weight 25–30 g; age 10–14 weeks) underwent Shimadzu modeling, followed by a random intravenous injection of 99mTc-omberacetam (0.2 mL, 3.7 MBq), which was subsequently radiosynthesized in the brain-targeting AMPARs utilizing a single-photon emission computed tomography nuclear neuroimaging. Under optimal conditions, 99mTc-omberacetam with a highest radiochemical purity of 98.9% was obtained with an optimum binding (energy = − 82.3 kcal/mol) to brain AMPARs and was stable in human serum for > 24 h. A high brain uptake was noted within a time window of 15–60 min. At 5 min, this signal uptake was 8.9 ± 0.1% of the injected dose per gram (ID/g), crossing the blood–brain barrier and surpassing the uptake of commercially available brain perfusion imaging agents such as 125I-iododomperidone (5.6% ID/g at 5 min) in mice, 99mTc-HMPAO (2.25% ID/g at 2 min) in rats, and 99mTc-ECD (4.7% ID/g at 6 h) in humans. This study is the first to show the feasibility of 99mTc-omberacetam radiotracing for human brain imaging. This could be a novel diagnostic and therapeutic neuroprotective target for the hyperacute stage of ischemic stroke. [ABSTRACT FROM AUTHOR]