N-[2-(3-cyanophenyl)-3-(4-(2-[18F]fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide

Excerpt

Psychoactive cannabinoids derived from the marijuana plant (Cannabis sativa) have two known types of G-protein–coupled receptors that are linked to adenylate cyclase activity. The cannabinoid-1 receptor (CB1R) is distributed primarily in different parts of the human brain (1, 2), and the cannabinoid-2 receptor (CB2R) has been detected primarily in cells of the peripheral immune system (3). The CB1R is of particular interest because its endogenous lipid ligands are involved in the regulation of energy metabolism and body weight, and in drug and substance addiction in animals and humans (4-6). The motivation to feed oneself was reported to be regulated by CB1R ligands in rats, and CB1R knockout mice were shown to be lean and resistant to dietary obesity (7, 8). Consequently, SR-141716A, a reverse agonist (i.e., it binds to the same site on the receptor as agonist, but mediates an opposite effect), is now available in the European Union for the treatment of obesity (9).

Investigators have been interested in the in vivo imaging of CB1R and have developed ligands that can be used in conjunction with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The agents developed so far to study the CB1R show high, non-specific binding (a characteristic of lipophilic compounds), have a low penetration of the brain (a characteristic of highly polar or lipophilic compounds), display a low affinity for the receptor, and produce unsatisfactory images (9-11). Although compounds labeled with radioactive carbon (¹¹C) produced satisfactory results with PET, these compounds have a short half-life (20.4 min) (9, 12). In an effort to develop a PET ligand for CB1R with a longer half-life, N-[2-(3-cyanophenyl)-3-(4-(2-[¹⁸F]fluoroethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylpropanamide ([¹⁸F]MK-9470), a compound labeled with radioactive fluoride (¹⁸F), was developed and evaluated in baboons and humans (9, 13, 14).