(S)- N-(1-Ethyl-2-pyrrolidinyl)methyl)-5-bromo-2-[11C]methoxy-3-methoxybenzamide

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 (PD), 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. Extrastriatal dopamine receptors have also been suggested to play an important role in the pathophysiology of schizophrenia and other psychiatric disorders (5).

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 (K_i = 0.03 nM) of D_2/3 receptors (10), and in positron emission tomography (PET) in vivo studies (11-13). (S)-N-(1-Ethyl-2-pyrrolidinyl)methyl)-5-bromo-2,3-dimethoxybenzamide (FLB 457, or isoremoxipride) had very high affinity for D₂ (K_i = 0.017 nM) and D₃ (K_i = 0.022 nM) receptors but not other neurotransmitter receptors (14). [¹¹C]FLB 457 has been used as a PET agent for the non-invasive study of extrastriatal D_2/3 receptors in the human brain.

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