2. Academic Validation
  3. Development of radiolabeling 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as potential molecular probes for excitatory amino acid transporter 2

Development of radiolabeling 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as potential molecular probes for excitatory amino acid transporter 2

  • Eur J Med Chem. 2025 Jul 16:298:117981. doi: 10.1016/j.ejmech.2025.117981.
Pengfei Song 1,  Kehao Gong 2,  Liyuan Xing 1,  Jinping Kong 3,  Donglang Jiang 2,  Ze Wang 1,  Qi Huang 2,  Yihui Guan 2,  Fang Xie 2,  Junbin Han 4,  Yingfang He 5
Affiliations

Affiliations

  • 1 Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China.
  • 2 Department of Nuclear Medicine & PET center, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 3 Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550004, China.
  • 4 Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China; Department of Nuclear Medicine & PET center, Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address: jhanoa@fudan.edu.cn.
  • 5 Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China. Electronic address: yingfang_he@fudan.edu.cn.
PMID: 40712458 DOI: 10.1016/j.ejmech.2025.117981
Abstract

Excitatory Amino acid Transporter 2 (EAAT2) is an appealing target for drug development, as it plays a crucial role in synaptic glutamate transport under physiological conditions and its malfunction is implicated in neurodegenerations. In this study, we designed and synthesized a series of 2-oxo-2-(4-phenylpiperazin-1-yl)acetamide derivatives as novel EAAT2 positive allosteric modulators (PAMs). [131I]2 ([131I]SF-1) was successfully developed as a valuable tool for in vitro competitive binding assay. Structure-affinity relationship led to the identification of compound 4 with an inhibitory constant of 29 nM. In ex vivo biodistribution studies, [18F]4 ([18F]SF-2) exhibited excellent brain penetration and sufficient reversibility in the rodent brains. Pretreatment with cold reference or previously reported EAAT2 PAMs resulted in significant reductions of radioactivity accumulations in the brain and spinal cord, confirming its high specificity in vivo. These findings present a valuable molecular probe to directly measure the interactions of the novel structures with EAAT2 and open an opportunity to non-invasively monitor EAAT2 expression through PET neuroimaging.

Keywords

EAAT2; Neuroimaging; Positron emission tomography; Structure-affinity relationship.

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