[18F]3-Fluoro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile

Excerpt

[¹⁸F]3-Fluoro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile ([¹⁸F]F-MTEB) is a radioligand developed for positron emission tomography (PET) imaging of metabotropic glutamate receptor subtype 5 (mGlu5) in the central nervous system (CNS) (1).

Glutamate is a major excitatory neurotransmitter at CNS synapses. Many neuroanatomical CNS projection pathways contain glutamatergic neurons (2). Glutamate produces its excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate (mGlu) receptors (3). The mGlu receptors are G-protein-coupled receptors, and the eight mGlu receptor subtypes are further subdivided into groups I, II, and III. The group I receptors include mGlu1 and mGlu5, and they are found mostly in postsynaptic locations. The mGlu5 receptors are found with high to moderate density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, hippocampus, and dorsal horn of the spinal cord, whereas the density in the cerebellum is low. These receptors are coupled to phospholipase C and up- or down-regulate neuronal excitability. They have been implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal. These receptors are also involved in the modulation of various pain states. They thus are attractive targets for therapeutic drug development.

PET and single-photon emission tomography of radioligands targeting mGlu5 receptors can visualize and study the CNS mGlu5 receptors in normal and pathologic states. Some mGlu5 antagonists have been successfully labeled, but their in vivo visualization has been hampered by high lipophilicity, unfavorable brain uptake kinetics, or a high metabolism (4, 5). 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) have been identified as potent and highly selective noncompetitive antagonists for mGlu5 receptors. Using the structure of MTEP as a template, Hamill et al. (1) and Patel et al (5). designed several MTEP analogs as PET radiotracers, and [¹⁸F]F-MTEB was one of the compounds that showed high affinity for mGlu5 receptors with moderate lipophilicity.