Joanna S. Fowler, Ph.D. - US grants

The Program Project theme encompasses both basic and clinical research using a broad spectrum of labeled tracers in the study of normal and pathophysiological conditions which can be followed by metabolic markers, neurotransmitter activity and adaptation, and other biochemical pathways in human and non-human primate brain. An essential correlate of these studies is the test-retest paradigm for establishing the reproducibility (baseline range) of a particular PET measurement in a single subject. Thus the validity of changes brought about in somatosensory, neurophysiological or pharmacologic interventions can be established. The study of binding sites of labeled ethical drugs and their effects on metabolic and neurochemical activity in the brain will be developed. Wherever possible and appropriate, these studies will be used to develop quantitative biochemical models, either to provide data on neurochemical parameters in normal and pathological states or to establish diagnostic criteria for specific disease states. Substance abuse studies will address mechanisms of reward in the brain and adaptation of receptors to repeated stimulation, for example the role dopamine plays including metabolic correlates of the addicting properties of cocaine and alcohol. In schizophrenia, we wish to identify possible physiological trait markers and elaborate underlying malfunctions or defects which bring about the disease. These studies include the acute and chronic consequences of drug perturbation of the dopamine system on LCMRglu and the perturbation of various neurotransmitter systems on the properties of other neurotransmitters. In Alzheimer's Disease, the interrelationships between glucose metabolism, hippocampal atrophy, neuroendocrine changes and cognitive impairment, with a particular focus on cortisol disregulation will be examined. Human brain malignancy will be evaluated in terms of LCGMglu, polyamine metabolism and the imaging of growth factor receptors in tumors and correlated with therapeutic efficacy. Opiate receptor research will include investigation of PCP receptors and mu, delta and kappa sites. Clinical populations such as Alzheimer's patients and drug abusers will be assessed. The core programs are designed to provide the basic support needed to carry out a PET research program. The administration will serve to provide the cohesion necessary to be certain that projects are effectively carried out and that information developed becomes quickly available and applicable to all in the project and the scientific community at large.

For over fifty years, the application of tracer techniques has enhanced our understanding of biochemical and physiological processes. PET is a unique tool in tracer methodology because of its ability to track the distribution and kinetics of labeled compounds in the intact living human and animal body. The rate at which these special characteristics of PET can be applied to problems in biology and medicine is tightly coupled to the availability of biologically selective and sensitive radiotracers. This proposal, "Radiotracer R & D in Nuclear Medicine and Neuroscience" focusses on radiotracer chemistry with the ultimate goal of advancing and facilitating applications in the neurosciences, in clinical practice and in drug research and development. This approach is multifaceted and synergistic, covering research in three major areas: cyclotron targetry; synthetic methodology; radiotracer biology and mechanisms. Over the past 7 year award period, we have made major advances including the first synthesis of no-carrier-added (NCA)F-18 labeled catecholamines and fluoroDOPA using a novel application of the nucleophilic aromatic substitution reaction on electron-rich aromatic rings; the first use of a kinetic isotope effect with PET to characterize the molecular mechanism for the binding of the monoamine oxidase B (MAO B) tracer, [11C]L-deprenyl in brain; the use of PET in drug research and development and application to new CNS drugs; a critical study of the chemical purity of 2-deoxy-2- [18F]fluoro-D-glucose (FDG) introducing highly sensitive analytical methods; the optimization of targetry for producing iodine-123 and iodine- 124 from a medium energy cyclotron and; the application of robotics in quantitative PET studies. Major scientific thrusts in this renewal application will build on these advances and undertake new research including: (1) cyclotron targetry including the development of a cryogenic C18O2 target for fluorine-18 production in response to the current shortage of O-18 enriched water and the optimization of iodine-124 production for planning radiotherapy; (2) synthetic chemistry (for C-11, F-18 and 1-124) including the synthesis of NCA F-18 perchloryl fluoride ([18F]CIO3) for electrophilic fluorination; new C-1 alkylation methods; a diphenyleneiodonium conjugate for increased radioiodine stability in vivo and; the investigation of supercritical fluid chromatography as a new approach to radiotracer purification (3) radiotracer biology and mechanisms including a study of the NCA F-18 labeled catecholamines with a view to their use in neurocardiology and of [11C]RO 19 6327 a new reversible MAO B inhibitor drug an potential second generation MAO B tracer. This research builds on the strengths and diversity of the Brookhaven group and its history of major contributions in the PET field. Accomplishments in the past funding period have demonstrated this multifaceted approach to be both productive and synergistic supporting the hypothesis that a firm foundation in radiotracer chemistry and biology can lead to important advances in PET and nuclear medicine.

DESCRIPTION (Verbatim from the Applicant's Abstract): An exciting area of human health R&D for positron emission tomography (PET) is its application to the study of drug actions in humans both centrally and peripherally. During the previous grant period, the unexpected and remarkable discovery was made that cigarette smokers have lower brain monoamine oxidase (MAO) than non-smokers and former smokers, an effect not caused by nicotine. Compelled by this discovery, the applicant has expanded studies of brain MAO in smokers and initiated the development of radiotracer methods to measure peripheral MAO. Peripheral MAO levels in smokers are of relevance because MAO is a crucial enzyme for detoxifying vasoactive amines in foods or those released by many substances including nicotine. Advances in radiotracer chemistry made over the previous 26-year history of this grant will be exploited along with the ability to merge them with the unique characteristics of human PET imaging. Cigarette smoking is a massive public health problem worldwide. Yet surprisingly little is known about the pharmacologic effects of smoke on the human body, or their relationships to smoking epidemiology and to evidence that components of tobacco smoke including nicotine may be neuroprotective. Building on novel approaches to measure brain MAO and recent progress in the synthesis of radiotracers to measure brain nicotinic acetylcholine receptors (nAChR), the study of the effects of tobacco smoke in humans on these two important molecular targets is proposed. Having shown reduced brain MAO in smokers, the effects of smoking on peripheral MAO will be studied exploiting the deuterium isotope effect with [C-11]clorgyline and [C-11]L-deprenyl and deuterium substituted derivatives as radiotracers (Specific Aim 1). In order to examine the functional significance of brain MAO B inhibition is smokers, radiotracers for studying phenethylamine (PEA), an endogenous neuromodulator of dopamine and a specific MAO B substrate will be developed using [N-13]PEA to track PEA metabolism (Specific Aim 2). Finally, a safe radiotracer for examining the effects of smoking on central nAChR (the major molecular target of nicotine) in humans (Specific Aim 3) will be developed. Hypotheses to be tested are that smokers have: 1) reduced peripheral MAO; 2) reduced metabolism of PEA; and 3) elevated nAChR. New studies in the applicant's laboratory and emerging knowledge in the neurosciences support the feasibility of the proposed studies. The overarching view is that that PET, coupled with sophisticated radiotracer methods and a commitment to translating the fruits of basic radiotracer research into scientific tools for human neuroscience, is well posed to characterize the molecular targets underlying the addictive, protective, and toxic effects of tobacco smoke.

enzyme activity; protein metabolism; amine oxidase (flavin); brain metabolism; genetic polymorphism; emotions; norepinephrine; serotonin; neurotransmitter metabolism; dopamine; behavioral genetics; clinical research; human subject;

human therapy evaluation; amine oxidase (flavin); brain metabolism; diagnosis design /evaluation; brain disorder chemotherapy; Alzheimer's disease; brain disorder diagnosis; disease /therapy duration; memory; protein metabolism; glucose metabolism; brain imaging /visualization /scanning; neuritic plaques; piperidine; clinical research; human subject; positron emission tomography;

DESCRIPTION (provided by applicant): This is a new application for K05 Senior Scientist Award. The applicant, Dr. Joanna S. Fowler, Director of the Center for Translational Neuroimaging is an organic chemist with a distinguished record of accomplishments in the development and applications of radiotracers for the neurosciences including the development of 18FDG, the development of the first radiotracers for monoamine oxidase (MAO) (and the discovery that smokers have reduced brain MAO) and the application of PET in the study of drug addiction. She is also a sought after lecturer in bringing the power of science and brain imaging to the problem of drug addiction. She is currently mentoring several junior scientists in addition to her administrative duties as Center Director. If funded, this K award will provide 60% salary support, which will provide at least 75% protected time to focus intensely on her new interests in understanding the links between genes, the environment and behavior, and on mentoring. In support of this application, the Department has agreed to use the funds released from the Program to hire an administrator to assume the administrative duties that are now performed by Dr. Fowler. There are 2 major activities: (1) Research (60%): to investigate the role of monoamine oxidase (MAO) genotype and maternal smoking on brain MAO, brain function and behavior and (2) Mentoring (15%): to mentor junior clinical scientists, graduate students and post-doctoral fellows in trans-disciplinary research related to substance abuse. The research in this application takes advantage of outstanding collaborators at Brookhaven, SUNY Stony Brook and SUNY Downstate and Kings College (London, UK) and is funded by our major Department of Energy grant which was recently peer reviewed and renewed for 5 years. These goals build on the urgent need to understand the role of gene-brain-behavior relationships and developmental stressors in substance abuse and the need to train and inspire scientists across disciplines to respond to the major public health problems created by drug addiction.

[unreadable] DESCRIPTION (provided by applicant): Drug abuse is one of the world's most challenging public health problems, taking a tremendous societal toll at many levels - from its cost (more than $484 billion per year in the U.S. alone for health care expenditures, lost earnings, and costs associated with crime and accidents) to the human suffering it causes in the form of cancer, heart disease, AIDS, stress, child abuse and other violence. This enormous burden affects all of society - substance abusers, their families, the educational system, industry, social welfare and criminal justice systems, and the public at large. Fortunately, recent scientific advances have revolutionized our understanding of addiction as a chronic disease, with dramatic implications for improving prevention and treatment. Some of the greatest advances have come from cross-disciplinary teams of chemists, physicists, and medical doctors using sophisticated brain-imaging technologies to reveal the mechanisms underlying the reinforcing, addictive, and toxic properties of drugs. To present recent brain-imaging advances in the field of drug addiction, we propose to hold a symposium titled "Addiction and the Brain: Are We Hard Wired to Abuse Drugs?" as part of the official program of the 2007 annual meeting of the American Association for the Advancement of Science (AAAS), to be held in San Francisco, CA, February 15-19, 2007. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are a number of biological and pharmacological factors, which may account for methamphetamine's high addictive potential and for its toxicity. One likely candidate is its pharmacokinetics in the brain and other organs. However, methamphetamine's pharmacokinetics in the human brain and in other organs are not known. Here we propose a systematic investigation of the uptake and kinetics of d-methamphetamine (the active isomer) in the brain and in peripheral organs with PET and carbon-11 labeled d-methamphetamine in a group of normal healthy non-drug abusing volunteers. We will also pair the brain study with a measure of dopamine transporter (DAT) availability using [11C]cocaine to measure DAT levels in the same individuals.

3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; 8-Azabicyclo(3.2.1)octane-2-carboxylic acid, 3-(benzoyloxy)-8-methyl-, methyl ester, (1R-(exo,exo))-; Benzamide, 3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2-hydroxy-6-methoxy-; Binding; Binding (Molecular Function); Brain; CRISP; Cephalon brand of modafinil; Clinical; Cocaine; Computer Retrieval of Information on Scientific Projects Database; DAT; DAT dopamine transporter; Dopamine; Dopamine Receptor; Dose; Encephalon; Encephalons; Funding; Grant; Hour; Human; Human, General; Hydroxytyramine; Institution; Investigators; Man (Taxonomy); Man, Modern; Medical Imaging, Positron Emission Tomography; Modafinil; Molecular Interaction; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Oral; PBO; PET; PET Scan; PET imaging; PETSCAN; PETT; Placebos; Positron Emission Tomography Scan; Positron-Emission Tomography; Proton Magnetic Resonance Spectroscopic Imaging; Provigil; Purpose; Raclopride; Rad.-PET; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Sham Treatment; Source; Synapses; Synaptic; United States National Institutes of Health; benzhydrylsulfinylacetamide; dopamine transporter; dopamine transporter proteins; radiolabel; radiotracer; sham therapy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To use PET to assess the effects of sleep deprivation in brain dopaminergic function and to relate this to its cognitive and behavioral effects. We hypothesize that sleep deprivation will upregulate the dopamine transporter (DAT). To use fMRI to investigate the blood oxygenation level dependent (BOLD) response during verbal working memory and visuospatial attention in sleep deprived subjects. We hypothesize that during sleep deprivation, the activations in the prefrontal and parietal cortices will be significantly decreased and these abnormalities would correlate impaired task performance.