PET Imaging Agents for a4b2 Nicotinic Receptors

 描述（由申请人提供）：尼古丁α 4 β 2受体与许多病理生理学有关，目前正在进行广泛研究。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。其中包括：1）神经退行性疾病方案; 2）尼古丁依赖相关研究方案; 3）肺癌早期检测方案; 4）学习和记忆神经生物学。在上一个资助期间，我们成功地将一种新的显像剂18F-Nifene用于人体研究。对α 4 β 2受体具有高亲和力的18F-Nifene在健康受试者中没有副作用，显示出快速的脑摄取，丘脑与胼胝体的比率在45分钟内达到3。45分钟的扫描时间是最佳的。在人脑中，丘脑和丘脑外受体都清晰可见。在特定脑区的高比率和短扫描时间表明18F-Nifene是作为人体α 4 β 2受体的PET显像剂的最合适的激动剂之一。因此，我们在这次更新NIH申请中的目标是完成18F-Nifene的脑人体研究。将在正常志愿者中以测试-再测试模式评价18F-Nifene的脑分布，以建立定量分析的重现性和成像方法。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。该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（包括胼胝体）中的位移程度。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用性。该提案的第三个目标是完成新型PET/SPECT试剂Niofene的临床前开发，Niofene是该受体的假定拮抗剂，可以用氟-18进行放射性标记用于PET研究或碘-123用于SPECT研究。激动剂和拮抗剂的可用性将允许在各种疾病中对该受体系统进行比较研究。本申请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病和帕金森病患者死后大脑中受体的变化。这将有助于在神经变性以及其他CNS疾病的PET研究中使用18F- Nifene。

 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.