()-3-(Pyridin-2-ylethynyl)-cyclohex-2-enone--2-(2-[F]fluoroethoxy)ethyl oxime

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). 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. 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 the 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 expression in normal physiological and pathological conditions. 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) and its methyl analog M-MPEP have been identified as potent, 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 (3, 4). 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; this agent produced strong and specific signals in rodent and human brain tissue (5-8). 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 (9). Wanger-Baumann et al. (10) have developed a new DABP688 derivative, ()-3-(pyridin-2-ylethynyl)-cyclohex-2-enone--2-(2-[F]fluoroethoxy)ethyl-oxime ([F]FDEGPECO), for use with PET imaging of mGluR5.