PET Imaging Agents for a4b2 Nicotinic Receptors

 描述(由申请人提供)：尼古丁α4？2受体与许多病理生理学有关，目前正在进行广泛的研究。在加州大学欧文分校(UCI)，我们有几个主要的项目，可以从尼古丁受体成像中获益。这些计划包括：1)神经退行性疾病计划；2)与尼古丁依赖相关的研究计划；3)肺癌早期检测计划；4)学习和记忆的神经生物学计划。在之前的资助期间，我们已经成功地将一种新的显像剂18F-Nifene用于人体研究。18F-尼芬对α4？2受体有较高的亲和力，对健康受试者无不良反应，脑摄取迅速，45min内丘脑与胼胝体的比值达到3。45分钟的扫描时间被认为是最佳的。在人脑中，丘脑和丘脑外受体都清晰可见。特定脑区的高比率和短扫描时间表明18F-Nifene是最适合作为人类α4ü2受体的正电子发射计算机断层扫描显像剂之一。因此，我们这次更新NIH申请的目标是用18F-Nifene完成脑部人体研究。18F-Nifene在正常志愿者中的脑分布将以重测范式进行评估，以建立用于定量分析的重复性和成像方法学。人体辐射剂量学研究将使用PET/CT扫描仪对6名受试者进行。这项研究的第二个目标是评估尼古丁对健康受试者的影响，以评估18F-Nifene在不同大脑区域的置换程度，包括胼胝体。还将评估18F-Nifene对吸烟的敏感性，以评估其在烟草依赖研究中的有效性。该提案的第三个目标是完成一种新型PET/SPECT试剂Niofene的临床前开发，Niofene是该受体的假定拮抗剂，可以放射性标记用于PET的氟-18或用于SPECT研究的碘-123。有了激动剂和拮抗剂，就可以对各种疾病的这种受体系统进行比较研究。这项应用的第四个目标是评估18F-Nifene是否能够使用放射自显影方法检测阿尔茨海默氏症和帕金森病患者死后大脑中受体的变化。这将有助于翻译18F-Nifene在神经变性和其他中枢神经系统疾病的PET研究中的使用。

 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.