Glutamate is a major excitatory neurotransmitter at neuronal synapses in the central nervous system (CNS) (1). Glutamate produces its excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate receptors (mGluRs). Many neuronal projection pathways contain 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. There are eight mGluR subtypes. The fifth subtype, mGluR5, is usually found in postsynaptic neurons with moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, whereas the density in the cerebellum is low. The mGluR5 is positively coupled to phospholipase C in regulation of neuronal excitability (2). Dysfunction of mGluR5 is implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal (3). Positron emission tomography (PET) and single-photon emission tomography of radioligands targeting mGluR5 can visualize and analyze mGluR5 in normal physiological and pathological conditions. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) and its methyl analog M-MPEP have been identified as potent and highly selective noncompetitive antagonists for mGluR5. These mGluR5 antagonists have been successfully labeled, but their impact as targeted imaging agents has been limited by high lipophilicity, lack of mGluR subtype selectivity, and unfavorable brain accumulation kinetics (4, 5). Based on the structure of MPEP, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone--[C]-methyl-oxime ([C]ABP688) was synthesized and evaluated as a potential PET imaging agent for mGluR5, showing strong and specific signals in the rodent and human brain (6-9). Using ABP688 as a template, 3-(pyridin-2-ylethynyl)-cyclohex-2-enone--[F]fluoroethyl-oxime ([F]fluoroethyl-desmethyl-ABP688 or [F]FE-DABP688) was synthesized and evaluated as a specific PET imaging tool for mGluR5 (10).