Victor W. Pike

Bio: Victor W. Pike is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Radioligand & Translocator protein. The author has an hindex of 72, co-authored 499 publications receiving 17016 citations. Previous affiliations of Victor W. Pike include Center for Information Technology & Jiangxi Normal University.

Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers

Abstract: Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB1 (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ~4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

Mixed-Affinity Binding in Humans with 18-kDa Translocator Protein Ligands

Abstract: The 18-kDa translocator protein (TSPO) is expressed within microglia and macrophages and has been used as a target for PET ligands to study disease processes that involve microglial activation or the recruitment of macrophages, such as multiple sclerosis (MS) and Alzheimer disease (1,2). The PET radioligand 11C-PK11195 has been used most frequently for this purpose, but signal quantification is limited by poor specific signal-to-background ratio (1). 11C-PBR28 is a new high-affinity TSPO PET radioligand with a more favorable specific–to–nonspecific binding ratio than 11C-PK11195 (3). However, PET studies using 11CPBR28 have shown that approximately 10% of healthy volunteers do not show a specific binding signal in either the brain or the peripheral organs (4). Lymphocytes isolated from these subjects, compared with the rest of the population, also have a marked reduction in affinity for PBR28, suggesting a global reduction in affinity of PBR28 for the TSPO (5). This hypothesis is supported by our work using brain tissue donated predominantly from individuals with an antemortem diagnosis of MS. That study found that, compared with tissue samples from donors designated as high-affinity binders (HABs; 46%), samples from those designated as low-affinity binders (LABs; ~23%) demonstrated a reduced affinity for PBR28 (binding affinity [Ki], ~4 vs. ~200 nM) (6). We also identified a third group of donors, designated as mixed-affinity binders (MABs; 31%), who showed behavior consistent with the presence of 2 PBR28 binding sites in approximately equal number, with affinities similar to those of LABs and HABs (~4 and ~300 nM) (6). In contrast to PBR28, PK11195 binds with similar affinity in all subjects, which may explain why non-binding has not been reported with this radioligand. It has not been established whether mixed-affinity binding is a phenomenon specific to MS or whether it also occurs in nondiseased brain tissue. It is also unknown whether mixed-affinity binding is unique to brain tissue. The presence of differing affinities in the general population complicates the quantitative assessment of PET data, because differences in 11C-PBR28 signal cannot be safely interpreted as differences in target density. LABs are easily identifiable from a 11C-PBR28 PET scan because their specific signal is negligible (5) and are therefore easily eliminated from a cohort. MABs, however, cannot be distinguished from HABs in a single PET scan, although it may be possible to classify a subject’s status by testing TSPO in blood and assuming that the binding affinity measured in peripheral blood reflects that in the brain. Population corrections then could be applied to compare subjects even when their binding affinities are different. The phenomenon of low-affinity binding has not been reported with other TSPO PET ligands currently in clinical use, such as 18F-PBR111, 18F-PBR06 (7), 11C-DPA713 (8), and 11C-DAA1106 (2), possibly because these ligands do not distinguish between HABs and LABs. Alternatively, it may be that differences in affinity exist but, because a PET signal is dependent on both receptor density and affinity, the differences have not been recognized in vivo. Our study had 4 aims. First, we tested whether the phenomenon of mixed-affinity binding was restricted to MS or whether it was also found in neuropathologically normal brain tissue. Second, we examined whether the 3 binding patterns defined with PBR28 also were found with other TSPO ligands in clinical use. Third, we investigated whether it may be feasible to identify MABs from a peripheral blood assay by analysis of platelet binding. Finally, using a set of 11C-PBR28 PET brain scans acquired previously, we tested whether there was any evidence for mixed-affinity binding in humans in vivo.

Neuroinflammation in Alzheimer's disease

Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review

Abstract: The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.

Molecular imaging in living subjects: seeing fundamental biological processes in a new light

Abstract: References http://genesdev.cshlp.org/content/17/5/545.full.html#related-urls Article cited in: http://genesdev.cshlp.org/content/17/5/545.full.html#ref-list-1 This article cites 228 articles, 79 of which can be accessed free at: service Email alerting click here top right corner of the article or Receive free email alerts when new articles cite this article sign up in the box at the Collections Topic (33 articles) Molecular Physiology and Metabolism • (98 articles) Cancer and Disease Models • Articles on similar topics can be found in the following collections

Applications of Fluorine in Medicinal Chemistry

Abstract: The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...