[¹¹C]K-2 image with positron emission tomography represents cell surface AMPA receptors

The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) is an important molecule in neurotransmission. We have recently developed the first positron emission tomography (PET) tracer [¹¹C]K-2 to visualize and quantify AMPARs in the living human brain. After injection, [¹¹C]K-2 is hydrolyzed at the terminal amide (and is thus metabolized to a major metabolite, [¹¹C]K-2_OH) within 10 min, representing the PET image in rodents and humans. Here, we found that K-2_OH did not penetrate the cell membrane but slowly passed through the blood brain barrier (BBB) with paracellular transport. Furthermore, major efflux transporters in the BBB did not carry K-2_OH. Logan graphical analysis exhibited reversible binding kinetics of this radiotracer in healthy individuals; these results demonstrated that the PET image of this tracer represents cell surface AMPARs with passive penetration of [¹¹C]K-2_OH through the BBB, resulting in reversible binding kinetics. Thus, PET images with this tracer depict the physiologically crucial fraction of AMPARs.