Objective-Clinical and preclinical evidence suggest a hyperactive glutamatergic system in clinical depression. Recently, the metabotropic glutamate receptor 5 (mGluR5) has been proposed as an attractive target for discovery of novel therapeutic approaches against depression. The goal of this study was to compare mGluR5 binding (PET study) and mGluR5 protein expression (postmortem study) between subjects with major depressive disorder and healthy controls.Method-Images of mGluR5 receptor binding were acquired using PET and [ 11 C]ABP688 that binds to an allosteric site with high specificity in 11 unmedicated subjects with major depression and 11 matched healthy controls; the amount of mGluR5 protein was investigated using Western blot method in brain samples of 15 depressed subjects and 15 matched controls (postmortem study).Results-The PET study revealed decreased regional mGluR5 binding in the prefrontal cortex, the cingulate cortex, the insula, the thalamus and the hippocampus of the depressed individuals (uncorrected p<0.001). Severity of depression correlated negatively with mGluR5 binding in the hippocampus (cluster-level corrected p=0.029). The postmortem study showed reduced mGluR5 protein expression in the prefrontal cortex (Brodmann's area 10) in depression (p<0.014), while prefrontal mGluR1 protein expression was unchanged.Conclusions-The reductions in mGluR5 binding found in the depressed sample are compatible with reduced protein expression in postmortem tissue. Thus, both studies suggest that basal or

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Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with [ 11 C]ABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system. substance use disorders | thalamus | caudate | relapse

(S,S)-2-(alpha-(2-Fluoromethoxyphenoxy)benzyl)morpholine ((S,S)-FMeNER) was found to be a selective high-affinity ligand for the norepinephrine transporter (NET). (S,S)-FMeNER) was labeled with fluorine-18 (t1/2 = 109.8 min) by O-fluoromethylation of desfluoromethoxy-(S,S)-FMeNER with [18F]bromofluoromethane. An analog, di-deuterated in the fluoromethoxy group ((S,S)-FMeNER-D2), was similarly labeled with di-deutero-[18F]bromofluoromethane. These two new radioligands were obtained in radiochemical purities greater than 98% and with specific radioactivities ranging from 111-185 GBq/micromol at the end of synthesis (75 min). After intravenous injection of (S,S)-[18F]FMeNER into cynomolgus monkey, PET examination with the head in the field of view revealed skull-bound radioactivity, contaminating images of the brain, and indicated fast defluorination of the radioligand. Defluorination was much reduced in similar PET experiments with (S,S)-[18F]FMeNER-D2. Ratios of radioactivity in the lower brainstem, mesencephalon, thalamus, and temporal cortex to striatum obtained with (S,S)-[18F]FMeNER-D2 at 160 min after i.v. injection were 1.5, 1.6, 1.3, and 1.5, respectively. In another PET experiment, pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the radioactivity ratios in all examined regions to near unity (e.g., to a ratio of 1.03 in mesencephalon). Labeled metabolites of (S,S)-[18F]FMeNER-D2 or (S,S)-[18F]FMeNER found in plasma were all more polar than the parent radioligand. In vitro autoradiography of (S,S)-[18F]FMeNER-D2 on post-mortem human brain cryosections furthermore showed specific binding to NET in the locus coeruleus and thalamus. (S,S)-[18F]FMeNER-D2 is the first useful radiofluorinated ligand for imaging brain NET in monkey in vivo and is superior to (S,S)-[11C]MeNER because a specific binding peak equilibrium is obtained during the PET experiment at a lower noise level.