The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.

Recent genetic and pharmacological studies have suggested that the metabotropic glutamate receptor subtype 5 (mGluR5) may represent a druggable target in identifying new therapeutics for the treatment of various central nervous system disorders including drug abuse. In particular, considerable attention in the mGluR5 field has been devoted to identifying ligands that bind to the allosteric modulatory site, distinct from the site for the primary agonist glutamate. Both 2-methyl-6-(phenylethynyl)pyridine (MPEP) and its analogue 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have been shown to be selective and potent noncompetitive antagonists of mGluR5. Because of results presented in this study showing that MTEP prevents the reinstatement of cocaine self-administration caused by the presentation of environmental cues previously associated with cocaine availability, we have prepared a series of analogues of MTEP with the aim of gaining a better understanding of the structural features relevant to its antagonist potency and with the ultimate aim of investigating the effects of such compounds in blunting the self-administration of cocaine. These efforts have led to the identification of compounds showing higher potency as mGluR5 antagonists than either MPEP or MTEP. Two compounds 19 and 59 exhibited functional activity as mGluR5 antagonists that are 490 and 230 times, respectively, better than that of MTEP.

We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the α4β2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a heterogeneous family of pentameric ligand-gated ion channels which are differently expressed in many regions of the central nervous system (CNS) and peripheral nervous system. 1,2 In the CNS, nAChRs regulate transmitter release, cell excitability, and neuronal integration. Neuronal nicotinic receptors constitute therapeutically relevant targets for the treatment of neurodegenerative disorders and other CNS disorders including inter alia, Alzheimer's and Parkinson's disease, Tourette's syndrome, schizophrenia, attention deficit disorder, anxiety, and pain. Moreover, as the addictive properties of tobacco products are due to the nicotine contained therein, nAChRs also become important targets for the discovery of medications for use in smoking cessation. 3The nAChRs are comprised of various combinations of different subunits, of which seventeen (α1-α10, β1-β4, γ, δ and ε) are known at present. Different subunit combinations define the various nAChR subtypes, and different receptor subtypes have characteristic pharmacological and biophysical properties, as well as different locations within the nervous system. 4 Therefore, subtype selectivity is an important issue for the effectiveness and safety of nicotinic therapeutics.While a host of nAChR ligands have been identified, there is still a substantial need to discover subtype-selective ligands that can be used to establish the physiological and pathophysiological significance of each of the receptor subtypes. As is now apparent from clinical results obtained with a variety of drugs, both the safety and efficacy of therapeutic agents often depend upon their subtype selectivity. While, as noted, a large number of nicotinic agonists and noncompetitive antagonists exist, very few of these are subtype-selective. 1,6 Exquisite subtype selectivity is difficult to achieve because of the large number of possible subtypes together with their relatively subtle structural differences, but is of great societal value in terms of possible disease treatment.The α4β2 nAChR is the most abundant subtype in the brain. 7 Several findings suggest that α4β2 receptors are involved in behavioral activity such as nicotine dependence, avoidance learning, and antinociception. 8 Nicotine (1) and epibatidine (2) are both naturally occurring nAChR agonists that have attracted interest as lead candidates for analog synthesis aimed at identifying structures with improved pharmacological properties. 1,9,10 For example, we recently reported that introduction of a hydrophobic or hydrogen-bonding alkynyl group into the C-5 position of the pyridine ring of epibatidine and A-84543 (3) significantly increased the s...