(11)C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists.

UNLABELLED: 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 ± 1.1 µSv/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.

Experimental performance assessment of SPM for SPECT neuroactivation studies using a subresolution sandwich phantom design.

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.

Analysis of clinical brain SPECT data based on anatomic standardization and reference to normal data: an ROC-based comparison of visual, semiquantitative, and voxel-based methods.

UNLABELLED: The technique of anatomic standardization and comparison with normal templates is increasingly used in clinical brain SPECT practice and allows automated, operator-independent volume-of-interest (VOI) or voxel-based analysis of whole-brain data. In 2 distinct clinical populations with severe traumatic brain injury and cognitive impairment, this study compared 3 widely available approaches that use normal templates to evaluate SPECT brain perfusion deficits. METHODS: In total, 74 subjects were studied. These included 14 patients with severe, traumatic brain injury (group 1; 10 males, 4 females; mean age +/- SD, 27.6 +/- 8.2 y) and 15 patients with cognitive impairment (group 2; 7 males, 8 females; mean age, 75.8 +/- 8.6 y). These data were compared with those from, respectively, 25 and 20 age- and sex-adjusted healthy volunteers. All data were analyzed in 4 ways. Three semiquantitative statistical algorithms were used: statistical parametric mapping (SPM) using SPM99, brain registration and analysis of SPECT studies (BRASS) using a voxelwise region-growing technique, and a predefined VOI approach. These results were compared with visual analysis based on consensus reading by 3 experienced nuclear medicine physicians. Receiver operating characteristic (ROC) analysis was performed at various statistical cutoffs. Moreover, as a measure of regional agreement, relative regional agreement between methods was assessed. RESULTS: In both study groups, BRASS voxel-based analysis was most accurate, as defined by the area under the ROC curve (0.97 for group 1 and 0.96 for group 2). VOI assessment was slightly more accurate than visual consensus analysis, whereas SPM showed, overall, a lower area under the ROC curve. SPM analysis was also significantly less sensitive at thresholds corresponding to low false-positive fractions. Regional analysis showed 83%-92% agreement between all methods. CONCLUSION: Under clinical conditions, classification of brain SPECT studies can greatly be aided by anatomic standardization techniques and reference to normal data. Under the investigated circumstances, SPM was found to have a lower sensitivity than VOI or voxelwise region-growing techniques, especially at low false-positive fractions.