Development of Novel PET Probes for Central 2‑Amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic Acid Receptors

We
document the development of PET probes for central AMPA receptors
and their application to in vivo animal imaging. An initial screening
of perampanel derivatives was performed to identify probe candidates.
Despite the high autoradiographic contrast yielded by several radioligands,
rat PET scans did not support their in vivo suitability. Further focused
derivatization and a second screening by ex vivo LC-MS measurements
led to the selection of 2-[1-(3-methylaminophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl]­benzonitrile, 21a, and its analogues as candidates. [11C]21a was shown by autoradiography to specifically bind to the
neocortex and hippocampus, consistent with AMPA receptor localization.
PET imaging with [11C]21a demonstrated moderate
uptake of radioactivity in rat and monkey brains, with the retention
of radiosignals being consistent with that from the autoradiogram
data, and the uptake was blocked by pretreatment with unlabeled 21a in a dose-dependent manner. The current approach has facilitated
the discovery of a PET probe potentially suitable for translational
research and development focused on AMPA receptors.