(,)-2-(-Propyl--1'-[C]-propyl)amino-5-hydroxytetralin

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 (4). These five dopamine receptor subtypes are classified into two subfamilies: D-like (D and D) and D-like (D, D, and D). D-like and D-like receptors exert synergistic as well as opposite effects at both the biochemical and overall system levels. Most 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. 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 () of 7 nM for the high-affinity state () and a of 1,720 nM for the low-affinity state () (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 D receptors, making studies of extrastriatal D receptors difficult (7-9). In binding studies, [I]epidepride was found to have high potency and low nonspecific binding, and to be selective for striatal and extrastriatal D receptors (10). Epidepride exhibits marginal binding to D receptors, with little affinity for other known neurotransmitter receptors. (S)--((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 (11), and in positron emission tomography (PET) studies (12-15) it identified extrastriatal D receptors. However, none of these antagonists distinguishes between the high- and low-affinity states of the D receptors. Many effects have been pursued to develop radiolabeled agonists for the non-invasive study of the high-affinity state of the D receptors in the brain. (–)--[C]Propyl-norapomorphine ([C]NPA) and C-4--propyl-,3,4a,5,6,10b-hexahydro-2-naphth[1,2-][1,4]oxazin-9-ol ([C]PHNO) have been studied as radiolabeled dopamine agonists. Various hydroxytetralin analogs with different binding affinities for the D receptors have been evaluated as agonist radiotracers (16). (,)-2-(-Propyl--1'-[C]-propyl)amino-5-hydroxytetralin ([C]5-OH-DPAT) is being developed as a PET agent for the high-affinity state of D receptors.