Michael R. Kilbourn

Bio: Michael R. Kilbourn is an academic researcher from University of Michigan. The author has contributed to research in topics: Dihydrotetrabenazine & Vesicular monoamine transporter. The author has an hindex of 63, co-authored 299 publications receiving 14034 citations. Previous affiliations of Michael R. Kilbourn include University of Pennsylvania & University of Illinois at Urbana–Champaign.

A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.

Abstract: We propose an in vivo method for use with positron emission tomography (PET) that results in a quantitative characterization of neuroleptic binding sites using radiolabeled spiperone. The data are analyzed using a mathematical model that describes transport, nonspecific binding, and specific binding in the brain. The model demonstrates that the receptor quantities Bmax (i.e., the number of binding sites) and KD-1 (i.e., the binding affinity) are not separably ascertainable with tracer methodology in human subjects. We have, therefore, introduced a new term, the binding potential, equivalent to the product BmaxKD-1, which reflects the capacity of a given tissue, or region of a tissue, for ligand-binding site interaction. The procedure for obtaining these measurements is illustrated with data from sequential PET scans of baboons after intravenous injection of carrier-added (18F)spiperone. From these data we estimate the brain tissue nonspecific binding of spiperone to be in the range of 94.2 to 95.3%, and the regional brain spiperone permeability (measured as the permeability-surface area product) to be in the range of 0.025 to 0.036 cm3/(s X ml). The binding potential of the striatum ranged from 17.4 to 21.6; these in vivo estimates compare favorably to in vitro values in the literature. To ourmore » knowledge this represents the first direct evidence that PET can be used to characterize quantitatively, locally and in vivo, drug binding sites in brain. The ability to make such measurements with PET should permit the detailed investigation of diseases thought to result from disorders of receptor function.« less

Regional mu opioid receptor regulation of sensory and affective dimensions of pain.

Abstract: The endogenous opioid system is involved in stress responses, in the regulation of the experience of pain, and in the action of analgesic opiate drugs. We examined the function of the opioid system and μ-opioid receptors in the brains of healthy human subjects undergoing sustained pain. Sustained pain induced the regional release of endogenous opioids interacting with μ-opioid receptors in a number of cortical and subcortical brain regions. The activation of the μ-opioid receptor system was associated with reductions in the sensory and affective ratings of the pain experience, with distinct neuroanatomical involvements. These data demonstrate the central role of the μ-opioid receptors and their endogenous ligands in the regulation of sensory and affective components of the pain experience.

Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain

Abstract: β-amyloid plaques (Aβ plaques) in the brain, containing predominantly fibrillary Aβ peptide aggregates, represent a defining pathologic feature of Alzheimer disease (AD). Imaging agents targeting the Aβ plaques in the living human brain are potentially valuable as biomarkers of pathogenesis processes in AD. (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45) is such as an agent currently in phase III clinical studies for PET of Aβ plaques in the brain. Methods: In vitro binding of 18F-AV-45 to Aβ plaques in the postmortem AD brain tissue was evaluated by in vitro binding assay and autoradiography. In vivo biodistribution of 18F-AV-45 in mice and ex vivo autoradiography of AD transgenic mice (APPswe/PSEN1) with Aβ aggregates in the brain were performed. Small-animal PET of a monkey brain after an intravenous injection of 18F-AV-45 was evaluated. Results:18F-AV-45 displayed a high binding affinity and specificity to Aβ plaques (Kd, 3.72 ± 0.30 nM). In vitro autoradiography of postmortem human brain sections showed substantial plaque labeling in AD brains and not in the control brains. Initial high brain uptake and rapid washout from the brain of healthy mice and monkey were observed. Metabolites produced in the blood of healthy mice after an intravenous injection were identified. 18F-AV-45 displayed excellent binding affinity to Aβ plaques in the AD brain by ex vivo autoradiography in transgenic AD model mice. The results lend support that 18F-AV-45 may be a useful PET agent for detecting Aβ plaques in the living human brain.

Regulation of Human Affective Responses by Anterior Cingulate and Limbic µ-Opioid Neurotransmission

Abstract: Background Human affective responses appear to be regulated by limbic and paralimbic circuits. However, much less is known about the neurochemical systems engaged in this regulation. The µ-opioid neurotransmitter system is distributed in, and thought to regulate the function of, brain regions centrally implicated in affective processing. Objective To examine the involvement of µ-opioid neurotransmission in the regulation of affective states in healthy human volunteers. Design Measures of µ-opioid receptor availability in vivo were obtained with positron emission tomography and the µ-opioid receptor selective radiotracer [ 11 C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis. Setting Imaging center at a university medical center. Participants Fourteen healthy female volunteers. Intervention Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion. Main Outcome Measures Changes in µ-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively. Results The sustained sadness condition was associated with a statistically significant deactivation in µ-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in µ-opioid receptor availability in vivo. The deactivation of µ-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, and amygdala was correlated with the increases in negative affect ratings and the reductions in positive affect ratings during the sustained sadness state. Conclusions These data demonstrate dynamic changes in µ-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the µ-opioid receptor system in the physiological regulation of affective experiences in humans.

Compartmental Analysis of [11C]Flumazenil Kinetics for the Estimation of Ligand Transport Rate and Receptor Distribution Using Positron Emission Tomography

Abstract: The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.

Principles of Neural Science

Abstract: I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.

Abstract: We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.