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PET Imaging Agents for a4b2 Nicotinic Receptors

a4b2 烟碱受体 PET 显像剂

基本信息

批准号：
9264445
负责人：
Jogeshwar Mukherjee
金额：
$ 31.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2019-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264445
关键词：
A/J Mouse Adverse effects Affinity Agonist Alzheimer&apos s Disease Animal Model Animals Antibodies Applications Grants Autopsy Binding Brain Brain Diseases Brain region California Central Nervous System Diseases Cognition Comparative Study Corpus Callosum Data Development Diagnosis Disease Dose Evaluation Exhibits FDA approved Fluorine Functional disorder Funding Goals Human Image Investigation Investigational Drugs Iodine Kinetics Learning Ligands Lung Neoplasms Magnetic Resonance Imaging Malignant neoplasm of lung Measures Memory Methodology Methods Molecular Molecular Structure Nerve Degeneration Neurobiology Neurodegenerative Disorders Nicotine Nicotine Dependence Nicotinic Receptors Nodule PET/CT scan Parkinson Disease Patients Positron-Emission Tomography Principal Investigator Radiolabeled Radiometry Rattus Reproducibility Scanning Schizophrenia Slice Staining method Stains Study models System Testing Thalamic structure Time Tobacco Tobacco Dependence Translations United States National Institutes of Health Universities base brain behavior cigarette smoking cytisine design experimental study frontal lobe gray matter human imaging human subject imaging agent imaging modality imaging probe imaging study inhibitor/antagonist learned behavior lung cancer screening mouse model novel preclinical development programs public health relevance quantitative imaging receptor receptor function single photon emission computed tomography therapeutic development treatment planning uptake validation studies volunteer white matter

项目摘要

DESCRIPTION (provided by applicant): Nicotinic α4ß2 receptors have been implicated in a number of pathophysiologies and are being studied extensively. At University of California-Irvine (UCI), we have several major programs that would gain from imaging nicotinic receptors. These include: 1) Program in neurodegenerative disorders; 2) Program on studies related to nicotine dependence; 3) Program in the early detection of lung cancer, and 4) Neurobiology of learning and memory. During the previous funding period we have successfully taken a new imaging agent, 18F-Nifene to human studies. 18F-Nifene, which has high affinity for α4ß2 receptors, had no adverse effects in the healthy subjects, showed rapid brain uptake with ratios of thalamus to corpus callosum reaching 3 in 45 mins. A scan time of 45 mins is considered optimal. Both thalamic and extrathalamic receptors were clearly visualized in the human brain. The high ratios in specific brain regions and short scan time suggest 18F-Nifene to be amongst the most suitable agonist as a PET imaging agent for α4ß2 receptors in humans. Therefore, our goals in this renewal NIH application are to complete the brain human studies with 18F-Nifene. Brain distribution of 18F-Nifene will be evaluated in normal volunteers in a test-retest paradigm to establish reproducibility and imaging methodology for quantitative analysis. Human radiation dosimetry studies will be carried out using a PET/CT scanner on 6 subjects. A second goal of the study is to evaluate effects of nicotine in healthy subjects in order to assess the degree of 18F-Nifene displacement in various brain regions, including corpus callosum. Sensitivity of 18F-Nifene to cigarette smoking will also be assessed, in order to evaluate its usefulness in tobacco dependence studies. A third goal of the proposal is to complete the preclinical development of a novel PET/SPECT agent Niofene which is a putative antagonist for this receptor and can be radiolabeled with fluorine-18 for PET or iodine-123 for SPECT studies. The availability of an agonist and antagonist will allow comparative studies of this receptor system in various disorders. The fourth goal of this application is to evaluate if 18F-Nifene is able to detect changes in the receptors in postmortem brains of Alzheimer's and Parkinson's disease patients using autoradiographic methods. This will help in translation of the use of 18F- Nifene in PET studies of neurodegeneration as well as other CNS disorders.