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Age-related perfusion changes are paralleled by similar more symmetric changes in gray matter concentration, which are more prominent than the perfusion changes in some regions. No sex-based differences between perfusion and gray matter concentration were found.

The validity domain of voxel-based statistical analysis of SPECT neuroactivation studies with statistical parametric mapping (SPM) has been investigated by a limited number of theoretical and simulation studies. In this work, an experimental setup is described with an assessment of its activation detection performance together with the influence of acquisition and processing parameters. A subresolution sandwich phantom was constructed using a printed high-resolution digital Hoffman phantom with a (99m)TcO(4)-ink mixture. Activations of 8, 16, and 24 mm diameter, with an intensity ranging from 5 to 60%, were constructed in the right frontal cortex, anterior and posterior cingulate, and left striatum. Triple-headed SPECT acquisitions were carried out using both fan-beam and parallel beam geometry. The impact of activation characteristics (size, intensity and location), study size, physical degradation factors, and reconstruction technique were studied using SPM99 in a group comparison design with correction for multiple comparisons. For a 15 x 15 design, all 24-mm activations of 5% intensity were detected for the fan-beam data. Decreased focus or study size, lower SPECT resolution, absence of scatter, and attenuation correction resulted in an increase in minimally detectable activation. For a single study referred to 15 control studies, only 24-mm activation foci with a minimal intensity of 10% were detected in the optimal configuration. This approach allows experimental parameter optimization of SPM-based group or single-subject SPECT activation studies compared to normal data, as used in clinical applications. In principle, these findings can be extended to SPECT receptor studies or PET data.

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...