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Leung K.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2013 Jan 18 [updated 2013 Apr 11].


Glutamate is a major excitatory neurotransmitter at neuronal synapses in the central nervous system (CNS) (1, 2). Glutamate produces its excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate receptors (mGluRs). The mGluRs are GTP-binding protein (G-protein)–coupled receptors that play important roles in regulating the activity of many synapses in the CNS, and many neuronal projection pathways contain mGluRs. There are eight mGluR subtypes, which are further subdivided into groups I, II, and III. The group I receptors include mGluR1 and mGluR5, and they are found predominantly in postsynaptic locations. mGluR1 is found in moderate to high density in the cerebellum, caudate, putamen, thalamus, cingulate cortex, and hippocampus, with low density in the pons. mGluR5 is usually found in moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, whereas the density in the cerebellum is low. mGluR1 and mGluR5 are positively coupled to phospholipase C in the regulation of neuronal excitability (3). Dysfunction of mGluR1 and mGluR5 is implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal (2, 4). Positron emission tomography (PET) radioligands targeting mGluR5 can visualize and analyze mGluR5 expression in normal physiological and pathological conditions (4-8). However, only a few mGluR1 ligands have been studied (1R, 2R). -N-(3-(4-hydroxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropane-carboxamide (LSN2606428) has been shown to inhibit both mGluR1 and mGluR5. Zanotti-Fregonara et al. (9) prepared (1R, 2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropane-carboxamide (LY2428703), the methoxy analog of LSN2606428, and labeled the analog as (1R, 2R)-N-(3-(4-[11C]methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropane-carboxamide ([11C]LY2428703) for use with in vivo PET imaging of mGluR1 distribution in rat brain. LY2428703 has been shown to be a full mGluR1 antagonist and partial mGluR5 antagonist.

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