Imaging of Transmembrane AMPA Receptor Regulatory Proteins by Positron Emission Tomography

The transmembrane α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8)
constitutes an auxiliary subunit of AMPA receptors, which mediates
various brain functions including learning and memory. TARP γ-8
has emerged as a promising therapeutic target for central nervous
system disorders. Despite considerable efforts, previously reported
TARP γ-8 PET radioligands, such as [11C]­TARP-1903
and [11C]­TARP-1811 series, were plagued by limited brain
uptake and/or high nonspecific binding in vivo. Herein, we developed
two novel 11C-labeled probes, [11C]8 and [11C]15 (also named as [11C]­TARP-2105), of which the latter exhibited a reasonable brain uptake
as well as specific binding toward TARP γ-8 both in vitro and
in vivo, as confirmed by blocking experiments with the commercially
available TARP γ-8 inhibitor, JNJ-55511118 in the TARP γ-8-rich
hippocampus. Overall, [11C]15 exhibited promising
tracer characteristics and proved to be a lead positron-emission tomography
ligand for the non-invasive quantification of TARP γ-8 in the
mammalian brain.