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The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Methods: Using PET and a novel high-affinity and selective radioligand 11 C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. Results: The mean effective dose for 11 C-MK-8278 was 5.4 6 1.1 mSv/MBq. Human brain kinetics showed rapid high uptake and fast washout. Binding potential values can be assessed using the pons as a reference region, with a test-retest repeatability of 7%. Drug RO data showed low interindividual variability per dose (mean RO SD, 2.1%), and a targeted 90% RO can be reached for both IAs at clinically feasible doses. Conclusion: 11 C-MK-8278 is a useful novel PET radioligand for determination of human cerebral H3 receptor binding and allows highly reproducible in vivo brain occupancy of H3-targeting drugs, hereby enabling the evaluation of novel compounds in early development to select doses and schedules. Hi stamine is an aminergic neurotransmitter that is localized in the central nervous system (CNS) and in peripheral tissues such as the gut, skin, and immune system. In the brain, histaminergic neurons originate in the tuberomammillary nucleus of the hypothalamus and project throughout the CNS, including the thalamus, hypothalamus, cerebral cortex, striatum, medulla oblongata, and spinal cord. There are 4 known G-protein-coupled histamine receptor subtypes (H1-H4). These serve multiple functions in the brain, particularly control of excitability and plasticity. Type 1 and 2 histamine receptor-mediated actions are mostly excitatory. The H3 receptor was discovered in 1983 and cloned at the end of the twentieth century (1) and is mainly expressed in the CNS. H3 receptors predominate in the basal ganglia, with the highest densities in the globus pallidus (2). The H3 receptor is a presynaptic inhibitory autoreceptor that regulates the synthesis and release of histamine and also modulates the release of several other neurotransmitters such as acetylcholine, norepinephrine, serotonin, dopamine, and g aminobutyric acid. Like other G-protein-coupled receptors, H3 receptors signal constitutively, serving to tonically suppress histamine production at baseline. Agonist-induced signaling, such as that which occurs in the presence of elevated histamine levels, further suppresses histamine...

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Introduction Neurofibrillary tau pathology and amyloid beta (Aβ) plaques, characteristic lesions of Alzheimer's disease (AD), show different neocortical laminar distributions. NFT-tau pathology tends to be located closer to the gray-white-matter boundary (G-WB) whereas Aβ is dispersed throughout the width of the cortical ribbon. Methods Using PET radiotracers for tau and Aβ lesions, we developed an image analysis tool to measure the distance of tracer-positive voxels to the G-WB. We studied 5 AD and 5 healthy subjects with both 18F-THK5117 (tau) and 11C-PiB (Aβ) PET. Results We observed that on average tau positive-voxels were closer to the white matter than the Aβ positive voxels. This effect was found for all AD subjects and for all regions, both before and after regionally adjusting for the non-specific white matter binding of both tracers. The differential laminar pattern was validated at post mortem. Conclusion Within cortical lamina distance measures may be of value in testing PET tracers for their anatomical selectivity.

The findings indicate that images of the brain, but not the kidneys, are an effective way to diagnose extrapulmonary right to left shunts in patients with end-stage pulmonary disease. The problem of a right to left shunt is uncommon in patients with emphysematous lung disease and relatively common in patients with primary pulmonary hypertension.

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