Identification of safe and valid PET radioligands for metabotropic glutamate receptor, type 5 (mGluR5), is essential to measure changes in brain mGluR5 in neuropsychiatric disorders, to confirm central mGluR5 occupancy of drug candidates, and to guide dose selection for obtaining an optimum therapeutic window. Here we present the results of a first-inhuman study assessing the safety and effectiveness of a novel PET radiopharmaceutical, 18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ( 18 F-FPEB), for quantifying regional brain concentrations of mGluR5. Methods: Quantification of whole-body biokinetics was conducted in 6 healthy adults (3 men and 3 women). The radiation safety profile was estimated with OLINDA/EXM software. Subsequently, pairs of dynamic brain scans were obtained for 11 healthy men to identify optimal methods for derivation of regional distribution volume and binding potential and to determine the repeatability of measurement. Results: The whole-body effective radiation dose was approximately 17 mSv/MBq (62 mrem/mCi), with the gallbladder receiving the highest dose of 190 mSv/MBq. In brain studies, time-activity curves showed high accumulation in the insula/caudate nucleus, moderate uptake in the thalamus, and the lowest concentration in the cerebellum/pons. The plasma reference graphical analysis method appeared optimal for 18 F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (,10%) and identified the highest nondisplaceable binding potential values (from ;0.5 in the globus pallidus to ;3.5 in the insula) for target regions. Safety assessments revealed no clinically meaningful changes in vital signs, electrocardiogram, or laboratory values. Conclusion: 18 F-FPEB is safe and well tolerated, and its regional cerebral distribution is consistent with previous reports in the literature for metabotropic glutamate receptors. The repeatability of measurement suggests that 18 F-FPEB is suitable for quantifying mGluR5 in humans.
In the mouse, the osteoblast-derived hormone Lipocalin-2 (LCN2) suppresses food intake and acts as a satiety signal. We show here that meal challenges increase serum LCN2 levels in persons with normal or overweight, but not in individuals with obesity. Postprandial LCN2 serum levels correlate inversely with hunger sensation in challenged subjects. We further show through brain PET scans of monkeys injected with radiolabeled recombinant human LCN2 (rh-LCN2) and autoradiography in baboon, macaque, and human brain sections, that LCN2 crosses the blood-brain barrier and localizes to the hypothalamus in primates. In addition, daily treatment of lean monkeys with rh-LCN2 decreases food intake by 21%, without overt side effects. These studies demonstrate the biology of LCN2 as a satiety factor and indicator and anorexigenic signal in primates. Failure to stimulate postprandial LCN2 in individuals with obesity may contribute to metabolic dysregulation, suggesting that LCN2 may be a novel target for obesity treatment.
FDG PET/CT is a useful technique for identifying LVAD infection and determining the site and pattern of the infection. The latter has clinical management and patient outcome implications.
Genetic factors involved in neuroplasticity have been implicated in major psychiatric illnesses such as schizophrenia, depression, and substance abuse. Given its extended interactome, variants in the Disrupted-In-Schizophrenia-1 (DISC1) gene could contribute to drug addiction and psychiatric diseases. Thus, we evaluated how dominant-negative mutant DISC1 influenced the neurobehavioral and molecular effects of methamphetamine (METH). Control and mutant DISC1 mice were studied before or after treatment with non-toxic escalating dose (ED) of METH. In naïve mice, we assessed METH-induced conditioned place preference (CPP), dopamine (DA) D2 receptor density and the basal and METH-induced activity of DISC1 partners, AKT and GSK-3β in the ventral striatum. In ED treated mice, 4 weeks after METH treatment, we evaluated fear conditioning, depression-like responses in forced swim test, and the basal and METH-induced activity of AKT and GSK-3β in the ventral striatum. We found impairment in METH-induced CPP, decreased DA D2 receptor density and altered METH-induced phosphorylation of AKT and Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuropharmacology. Author manuscript; available in PMC 2013 March 1. GSK-3β in naïve DISC1 female mice. The ED regimen was not neurotoxic as evidenced by unaltered brain regional monoamine tissue content. Mutant DISC1 significantly delayed METH ED-produced sensitization and affected drug-induced phosphorylation of AKT and GSK-3β in female mice. Our results suggest that perturbations in DISC1 functions in the ventral striatum may impact the molecular mechanisms of reward and sensitization, contributing to comorbidity between drug abuse and major mental diseases.
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