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Leung K.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2010 Oct 24 [updated 2010 Dec 11].


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 subtypes are classified into two subfamilies: D1-like (D1 and D5) and D2-like (D2, D3, and D4) dopamine receptors. D1-Like and D2-like receptors exert synergistic as well as opposite effects at both the biochemical and overall system levels. A great majority of 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. The high-affinity state is coupled to G-proteins, whereas the low-affinity state is 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 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 was 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 D2-like receptors, making studies of extrastriatal D2 receptors difficult (6-8). In binding studies, 123I-labeled 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 (9). Epidepride has 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 (10) in positron emission tomography (PET) in vivo studies (11-13). [18F]fallypride identified extrastriatal D2/3 receptors. However, none of these antagonists distinguish between the high- and low-affinity states of the D2 receptors. (-)-N-Propyl-norapomorphine (NPA) was reported to have Khigh and Klow values of 0.07–0.4 and 20–200 nM, respectively (5, 14-16). This provides a >50-fold selectivity for the high-affinity over the low-affinity receptors. NPA has good affinity (Ki, 0.3 nM) for D3 receptors but not other neurotransmitters (17). [11C]NPA is being developed as a PET agent for the noninvasive study of the high-affinity state of the D2 receptors in the brain. (R)-(-)-2-Chloro-N-[1-11C-propyl]n-propylnorapomorphine (2-Cl-[11C]-(-)-NPA) has been evaluated as a D3-selective probe because 2-Cl-(-)-NPA showed a higher selectivity for D3 than for D2 (D3/D2, 3.85) than did (-)-NPA (D3/D2, 1.75) (18).

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