Synthesis of [18F] fluorine-labeled K-2 derivatives as radiotracers for AMPA receptors

Abstract

Introduction: AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) receptors play a central role in neurotransmission and neuronal function. A positron emission tomography (PET) tracer for AMPA receptors, [¹¹C]K-2, was recently developed by us to visualize AMPA receptors in the living human brain. [¹¹C]K-2 is a derivative of 4-[2-(phenylsulphonylamino)ethylthio]-2,6-difuluoro-phenoxyacetamide (PEPA), and is labeled with the radioactive isotope ¹¹C, which has a short half-life. PET drugs are usually labeled with ¹⁸F because of its long half-life. Therefore, we screened and identified potential ¹⁸F-labeled PET drugs for AMPA receptors (AMPA-PET drugs), which could provide an image equivalent to that of [¹¹C]K-2.

Methods: Derivatives of K-2 labeled with ¹⁸F were synthesized and administered to rats and PET imaging was performed. The transferability of each compound to the brain and its correlation with the PET image of [¹¹C]K-2 were evaluated from the obtained PET images. Furthermore, the specific binding ability of promising compounds to the AMPA receptor was evaluated by the PET imaging of rats, which we specifically knocked down the expression of AMPA by the lentivirus-mediated introduction of short hairpin RNA (shRNA) targeted to subunits of the AMPA receptor (GluA1-A3). The specific binding ability was also evaluated through electrophysiological experiments with acute brain slices.

Results: Some of the synthesized ¹⁸F-labeled candidate compounds showed a distribution similar to that of K-2, with reasonable transferability to the brain. In addition, from the evaluation of the specific binding ability to the AMPA receptor, a promising structure of an ¹⁸F-labeled AMPA PET drug was identified. This study also revealed that the alkylation of the sulfonamide group of PEPA enhances brain transferability.

Keywords: (18)F; AMPA receptor; AMPA-PET; K-2; PEPA; positron emission tomography.