[11C](+)-4- N-Propyl-,3,4a,5,6,10b-hexahydro-2 H-naphth[1,2- b][1,4]-oxazin-9-ol

Excerpt

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 level. 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 (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 is expected to bind predominately to the high-affinity state, which is ~50% occupied by 10 nM dopamine. The high-affinity state has been 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 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 D_2/3 receptors (10), and in positron emission tomography (PET) in vivo studies (11-13), 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-Propyl-norapomorphine (NPA), an agonist of the D_2/3 receptors, was reported to have K_high and K_low values of 0.07-0.4 and 20-200 nM, respectively (5, 14, 15). This provides a >50-fold selectivity for the high-affinity over the low-affinity receptors. NPA has good affinity (K_i = 0.3 nM) for D₃ receptors but not other neurotransmitters (16). [¹¹C]NPA is being developed as a PET agent for the non-invasive study of the high-affinity state of the D_2/3 receptors in the brain.

(+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol (PHNO) is an agonist of the D₂ receptors with a reported K_d of 0.56 nM in the canine striatum and a >10,000-fold selectivity for D₂ over D₁ receptors (17). PHNO has a high affinity for human cloned D₂ (K_i = 8.5 nM) and D₃ (K_i = 0.16 nM) receptors (18). [¹¹C]PHNO showed robust specific binding in the striatum of rodents with insensitivity to displacement by D₁, norepinephrine, or serotonin ligands (19). [¹¹C]PHNO is being developed as a PET agent for the non-invasive study of the high-affinity state of the D_2/3 receptors in the brain.

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