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

• Published in: Nuclear medicine and biology Vol. 110-111; pp. 47 - 58
• Main Authors: Arisawa, Tetsu, Kimura, Kimito, Miyazaki, Tomoyuki, Takada, Yuuki, Nakajima, Waki, Ota, Wataru, Ichijo, Sadamitsu, Sano, Akane, Hirao, Yuuka, Kurita, Jun-ichi, Nishimura, Yoshifumi, Takahashi, Takuya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2022; Elsevier BV
• Subjects: 18F; Alkylation; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; AMPA receptor; AMPA-PET; Animals; Binding; Brain; Brain - diagnostic imaging; Brain - metabolism; Brain slice preparation; Drugs; Fluorine; Fluorine - metabolism; Fluorine isotopes; Fluorine Radioisotopes - metabolism; Half-life; K-2; Medical imaging; Neuroimaging; Neurotransmission; PEPA; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Radioactive half-life; Radioactive tracers; Radioisotopes; Radiopharmaceuticals - metabolism; Rats; Receptor mechanisms; Receptors; Receptors, AMPA - metabolism; Sulfonamides; Synthesis; Tomography; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; K-2; AMPA receptor; PEPA; positron emission tomography; AMPA-PET; 18F; F
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2022.04.009

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. 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. 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. [Display omitted] •We synthesized an 18F-labeled derivative of [11C] K-2, the world's first PET imaging drug for AMPA receptors.•Promising candidate compounds for the [18F]AMPA-PET drug were found from the results of small animal PET imaging.•Synthesis of these derivatives revealed the tolerance of substituents to maintain the function as an AMPA-PET drug.•In particular, it was found that alkylation of the sulfonamide moiety greatly improves transferability to the brain.