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, D1 through D5, have been well characterized pharmacologically and biochemically (4). These five dopamine receptor subtypes are classified into two subfamilies: D1-like (D1 and D5) and D2-like (D2, D3, and D4). D1-like and D2-like receptors exert synergistic as well as opposite effects at both the biochemical and overall system levels. Most striatal D1 and D2 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. The two states are interconvertible. In the high-affinity state, dopamine receptors are coupled to G-proteins, whereas in the low-affinity state they are not. Dopamine has a dissociation constant (Kd) of 7 nM for the high-affinity state (Khigh) and a Kd of 1,720 nM for the low-affinity state (Klow) (5). Under physiologic conditions, dopamine is expected to bind predominately to receptors in the high-affinity state. The high-affinity state was suggested to be the functional form of the dopamine receptors (6).
Substituted benzamides, such as sulpiride, raclopride, and iodobenzamide, are specific ligands with only moderate affinity for the D2/3 receptors, making studies of extrastriatal D2/3 receptors difficult (7-9). In binding studies, [123I]epidepride was found to have high potency and low nonspecific binding, and to be selective for striatal and extrastriatal D2/3 receptors (10). Epidepride exhibits marginal binding to D4 receptors, with little affinity for other known neurotransmitter receptors. (S)-N-((1-Allyl-2-pyrrolidinyl)methyl)-5-(3-[18F]fluoropropyl)-2,3-dimethoxybenzamide ([18F]fallypride), an analog of epidepride, was found to be a selective, high-affinity antagonist of D2/3 receptors (11), and in positron emission tomography (PET) in vivo studies (12-15) it identified extrastriatal D2/3 receptors. However, none of these antagonists distinguishes between the high- and low-affinity states of the D2 receptors. Many effects have been pursued to develop radiolabeled agonists for the non-invasive study of the high-affinity state of the D2/3 receptors in the brain. (–)-N-[11C]Propyl-norapomorphine ([11C]NPA) and [11C](+)-4-N-propyl-,3,4a,5,6,10b-hexahydro-2H-naphth[1,2-b][1,4]oxazin-9-ol ([11C]PHNO) have been studied as radiolabeled dopamine agonists.
Various hydroxytetralin analogs with different binding affinities for the D2 receptors have been evaluated as agonist radiotracers (16). (R,S)-2-(N-Propyl-N-1'-[11C]-propyl)amino-5-hydroxytetralin ([11C]5-OH-DPAT) is being developed as a PET agent for the high-affinity state of D2/3 receptors.