IMAGING THE BRAIN MARIJUANA RECEPTOR - DEVELOPMENT OF A RADIOLIGAND THAT BINDS TO CANNABINOID CB1 RECEPTORS IN-VIVO

The major active ingredient of marijuana, (-)-Delta(9)-tetrahydrocanna binol, exerts its psychoactive effects via binding to cannabinoid CB1 receptors, which are widely distributed in the brain. Radionuclide ima ging of CB1 receptors in living human subjects would help explore the presently unknown physiological roles of this receptor system, as well as the neurochemical consequences of marijuana dependence. Currently available cannabinoid receptor radioligands are exceedingly lipophilic and unsuitable for in vivo use. We report the development of a novel radioligand, chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide}, that i s structurally related to the CB1-selective antagonist SR141716A hloro phenyl)-4-methyl-1-H-pyrazole-3-carboxamide]. Baboon single photon emi ssion computed tomography studies, mouse brain dissection studies, and ex vivo autoradiography in rat brain demonstrated rapid passage of [I -123]AM281 into the brain after intravenous injection, appropriate reg ional brain specificity of binding, and reduction of binding after tre atment with SR141716A. AM281 has an affinity in the low nanomolar rang e for cerebellar binding sites labeled with [H-3]SR141716A in vitro, a nd binding of [I-123]AM281 is inhibited by several structurally distin ct cannabinoid receptor ligands. We conclude that [I-123]AM281 has app ropriate properties for in vivo studies of cannabinoid CB1 receptors a nd is suitable for imaging these receptors in the living human brain.