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 that exist in high- and low-affinity states with respect to agonist binding. The two states are inter-convertible. 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 (K_d) of 7 nM for the high-affinity state (K_high) and a K_d of 1,720 nM for the low-affinity state (K_low) (5). Under physiologic conditions, dopamine binds 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 receptors, making study of extrastriatal D₂ receptors difficult (7-9). In binding studies, [¹²³I]epidepride, an analog of isoremoxipride, was found to have high potency and low nonspecific binding, and to be selective for striatal and extrastriatal D₂ 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 D_2/3 receptors (11), and in positron emission tomography (PET) in vivo studies (12-14) it identified extrastriatal D_2/3 receptors. However, none of these antagonists distinguishes between the high- and low-affinity states of the D₂ receptors. (–)-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 developed as radiolabeled dopamine agonists for the non-invasive study of the high-affinity state of the D_2/3 receptors in the brain.

Various hydroxytetralin analogs with different binding affinities for the D₂ receptors have been developed as agonist radiotracers (15). (+/-)-2-(N-Phenethyl-N-1’-[¹¹C]propyl)amino-5-hydroxytetralin ([¹¹C]PPHT) is being evaluated as a PET agent for the high-affinity state of D_2/3 receptors.