-(4-(4-(2-(2-[F]Fluoroethoxy)phenyl)piperazine-1-yl)butyl)-4-(3-thienyl)benzamide

Dopamine, a neurotransmitter, plays an important role in the mediation of movement, cognition, and emotion (1, 2). Dopamine receptors are involved in the pathophysiology of neuropsychiatric diseases, such as Parkinson’s disease, Alzheimer's disease, Huntington’s disease, and schizophrenia (3). Five subtypes of dopamine receptors, D through D, have been well characterized pharmacologically and biochemically . These five subtypes are classified into two subfamilies: D-like (D and D) and D-like (D, D, and D) dopamine receptors. D-Like and D-like receptors exert synergistic as well as opposite effects at both the biochemical and overall system levels. A great majority of striatal D and D receptors are localized postsynaptically on caudate-putamen neurons and to a lesser extent presynaptically on nigrostriatal axons. Dopamine receptors are G-protein–coupled receptors and exist in high- and low-affinity states with respect to agonist binding (4). The two states are interconvertible. The high-affinity state is coupled to G-proteins, whereas the low-affinity state is not. Dopamine has a dissociation constant () of 7 nM for the high-affinity state () and a of 1,720 nM for the low-affinity state () (5). Under physiological conditions, dopamine is expected to bind predominantly to the high-affinity state, which is ~50% occupied by 10 nM dopamine. The high-affinity state is suggested to be the functional form of the dopamine receptors. Substituted benzamides, such as sulpiride, raclopride, and iodobenzamide, are specific ligands with only moderate affinity for the D receptors, making studies of extrastriatal D receptors difficult (6-8). In binding studies, I-labeled epidepride, an analog of isoremoxipride, was found to have high potency and low nonspecific binding and to be selective for striatal and extrastriatal D receptors (9). Epidepride has marginal binding to D receptors, with little affinity for other known neurotransmitter receptors. ()--((1-Allyl-2-pyrrolidinyl)methyl)-5-(3-[F]fluoropropyl)-2,3-dimethoxybenzamide ([F]fallypride), an analog of epidepride, was found to be a selective, high-affinity antagonist of D receptors in positron emission tomography (PET) studies (10-13). [F]Fallypride identified extrastriatal D receptors. However, none of these antagonists distinguish between the high- and low-affinity states of the D receptors. (-)--Propyl-norapomorphine (NPA) is reported to have and values of 0.07–0.4 and 20–200 nM, respectively (3, 4, 14, 15). This provides a >50-fold selectivity for the high-affinity over the low-affinity receptors. NPA has good affinity (, 0.3 nM) for D receptors but not for other neurotransmitters (16). [C]NPA is being developed as a PET agent for the noninvasive study of the high-affinity state of the D receptors in the brain. Because of high D receptor expression in the limbic structures of the brain and possible involvement of striatal D receptors in the pathophysiology of dystonia, there is a need for D-selective probes. ()-(-)-2-Chloro--[1-C-propyl]-propylnorapomorphine (2-Cl-[C]-(-)-NPA) has been evaluated as a D-selective probe because 2-Cl-(-)-NPA showed a higher selectivity for D than for D (D D, 3.85) than did (-)-NPA (D D, 1.75) (17). However, 2-Cl-[C]-(-)-NPA is less likely to be a useful PET agent for D receptors because of its slow brain uptake and low striatum/cerebellum ratio. Mach et al. (18) have reported the development of -(4-(4-(2-(2-[F]fluoroethoxy)phenyl)piperazine-1-yl)butyl)-4-(3-thienyl)benzamide ([F]5), a D partial agonist, for PET imaging of D receptors. Compound 5 showed ~162-fold selectivity for D over D.