PET Imaging Agents for a4b2 Nicotinic Receptors

a4b2 烟碱受体 PET 显像剂

• 批准号: 8332263
• 负责人: Jogeshwar Mukherjee
• 金额: $ 31.48万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332263
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Address; Affinity; Aging; Agonist; Alzheimer' s Disease; Animals; Applications Grants; Area; Binding; Bladder; Brain; Brain Diseases; Brain imaging; Brain region; California; Cerebellum; Cholinergic Agents; Cognition; Cognitive; Comparative Study; Development; Diagnosis; Disease; Dose; Evaluation; Exhibits; Focus Groups; Funding; Goals; Guidelines; Human; Human Development; Human Volunteers; Image; Imaging Techniques; Impairment; Injection of therapeutic agent; Institutes; Investigation; Investigational Drugs; Investigational New Drug Application; Kidney; Kinetics; Lateral Geniculate Body; Learning; Liver; Magnetic Resonance Imaging; Malignant neoplasm of lung; Measurement; Measures; Memory; Memory impairment; Methodology; Methods; Molecular; Nerve Degeneration; Neurobiology; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Organ; Outcome; PET/CT scan; Parkinson Disease; Pharmaceutical Preparations; Plasma; Positron-Emission Tomography; Principal Investigator; Property; Psyche structure; Radiation; Radiometry; Rattus; Reproducibility; Research; Scanning; Schizophrenia; Specificity; Synapses; System; Testing; Thalamic structure; Time; Tobacco Dependence; Toxic effect; Toxicity Tests; United States National Institutes of Health; Universities; Validation; Work; base; design; dosimetry; human subject; imaging modality; imaging probe; improved; in vivo; inhibitor/antagonist; interdisciplinary approach; lung cancer screening; nervous system disorder; novel; patient population; pre-clinical; preclinical evaluation; programs; radiotracer; receptor; receptor function; residence; therapeutic development; tool; treatment planning; validation studies; volunteer

DESCRIPTION (provided by applicant): Nicotinic a4¿2 receptors have been implicated in neurodegeneration 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) Alzheimer's Disease Research Center (ADRC) at the institute for Mental Impairments and Neurological Disorders (MIND); 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 completed preclinical evaluation of a new imaging agent, 18F-Nifene which has high affinity for a4¿2 receptors and requires an imaging time of less than 60 minutes. In animal PET studies selective binding of 18F-Nifene in thalamus, lateral geniculate, cortex and other brain regions was observed with limited binding in the cerebellum, resulting in specific binding ratios of ~3. Plasma analysis indicated the presence of 18F-Nifene and no observed defluorination. The high ratios in specific brain regions and short scan time suggest that 18F-Nifene to be amongst the most suitable agonist that has good potential as a PET imaging agent for a4¿2 receptors in humans. Our toxicity results of Nifene suggest that a radiotracer injection of 18F-Nifene is suitable for human use. Therefore, one goal in this NIH application is to carry out first human studies with 18F-Nifene. Human radiation dosimetry studies will be carried out using a PET/CT scanner on 6 subjects. 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. A second goal of the proposal is to complete the preclinical development of 18F-Nifrolene which is a putative antagonist for this receptor. Animal studies show high binding in receptor-rich brain areas with a scan time of approx. 90 mins, with specific binding ratios ~4. We propose to complete animal imaging, toxicity testing and radiation dosimetry of 18F-Nifrolene during this funding period. The availability of an agonist and antagonist will allow comparative studies of this receptor system in various disorders. The third goal of this application is to evaluate if 18F-Nifene is able to detect changes in the level of the neurotransmitter, acetylcholine in PET studies. This will be of great value to evaluate efficacy of acetylcholinesterase inhibitors used in AD. The overall proposed research in this application will also support investigations in other disorders such as Parkinson's disease and schizophrenia.

描述（由申请人提供）：烟碱α4¿2受体与神经变性有关并且正在被广泛研究。在加州大学欧文分校 (UCI)，我们有几个主要项目可以从烟碱受体成像中获益。其中包括： 1) 精神障碍和神经疾病研究所 (MIND) 的阿尔茨海默病研究中心 (ADRC)； 2) 尼古丁依赖相关研究计划； 3) 肺癌早期检测项目，以及 4) 学习和记忆神经生物学。在上一资助期间，我们成功完成了新型显像剂 18F-Nifene 的临床前评估，该显像剂对 a4¿2 受体具有高亲和力，并且需要不到 60 分钟的成像时间。在动物 PET 研究中，观察到 18F-Nifene 在丘脑、外侧膝状体、皮质和其他大脑区域中选择性结合，而在小脑中的结合有限，导致特异性结合比率约为 3。等离子体分析表明存在 18F-Nifene，并且没有观察到脱氟。特定大脑区域的高比率和短扫描时间表明 18F-Nifene 是最合适的激动剂之一，具有作为人类 a4¿2 受体的 PET 成像剂的良好潜力。我们的 Nifene 毒性结果表明 18F-Nifene 放射性示踪剂注射剂适合人类使用。因此，该 NIH 申请的一个目标是利用 18F-Nifene 进行首次人体研究。将使用 PET/CT 扫描仪对 6 名受试者进行人体辐射剂量测定研究。将在重测范式中评估正常志愿者中 18F-Nifene 的脑分布，以建立定量分析的再现性和成像方法。该提案的第二个目标是完成 18F-Nifrolene 的临床前开发，它是该受体的假定拮抗剂。动物研究表明，扫描时间约为 10 分钟，在富含受体的大脑区域中具有高结合力。 90 分钟，特异性结合比约为 4。我们建议在此资助期间完成18F-Nifrolene的动物成像、毒性测试和辐射剂量测定。激动剂和拮抗剂的出现将允许在各种疾病中对该受体系统进行比较研究。该应用的第三个目标是评估 18F-Nifene 是否能够在 PET 研究中检测神经递质乙酰胆碱水平的变化。这对于评估乙酰胆碱酯酶抑制剂在 AD 中的疗效具有重要价值。本申请中提出的总体研究还将支持其他疾病的研究，例如帕金森病和精神分裂症。