In vitro and in vivo characterization of (+)-3-[11C]cyano-dizocilpine

Summary. (+)-3-[¹¹C]Cyano-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ([¹¹C]MKC) was successfully synthesized as a potential radiotracer for PET studies on the NMDA receptor channel complex. In vitro binding properties of [¹¹C]MKC were investigated with newly developed techniques for efficient evaluation of ¹¹C-labeled compounds. The association curve of [¹¹C]MKC binding in rat forebrain membranes showed that the specific binding reached an equilibrium within 30 min. Specific binding was saturable with affinity constant K_D = 8.2 ± 0.4 nM and B_max = 1.62 ± 0.04 pmol/mg protein with glutamate and glycine included in the incubation medium. The binding of [¹¹C]MKC was decreased by extensive washing of the membrane preparation. (+)- and (−)-Dizocilpine, 3-cyano-dizocilpine, and ketamine inhibited the specific binding of [¹¹C]MKC with IC₅₀ values of 37.3, 445.0, 65.8 nM and 3.91 μM, respectively. High specific binding in in vitro autoradiography was distributed predominantly in telencephalic regions (the hippocampus, cerebral cortex, and striatum) followed by thalamus. PET studies using rhesus monkeys under anesthesia showed high uptake of [¹¹C]MKC in the temporoparietal and frontal cerebral cortices, striatum, and thalamic regions, although it is problematic to verify the specific binding in vivo by PET. Accepted January 5, 1998; received October 7, 1997