PET Imaging Agents for a4b2 Nicotinic Receptors

描述（由申请人提供）：尼古丁a4¿2受体与神经退行性变有关，目前正在广泛研究。在加州大学欧文分校（UCI），我们有几个主要的项目将从尼古丁受体成像中获益。这些机构包括：1)精神损伤和神经障碍研究所（MIND）的阿尔茨海默病研究中心（ADRC）；2)尼古丁依赖相关研究项目；3)肺癌早期检测程序；4)学习与记忆神经生物学。在之前的资助期内，我们已经成功完成了一种新的显像剂18F-Nifene的临床前评估，该显像剂对a4¿2受体具有高亲和力，成像时间不到60分钟。在动物PET研究中观察到18F-Nifene在丘脑、外侧膝状、皮层等脑区选择性结合，在小脑区结合有限，特异性结合比为~3。血浆分析显示存在18f -尼芬，未观察到除氟。在特定脑区的高比率和短扫描时间表明，18f -尼芬是最合适的激动剂之一，具有良好的潜力作为人类a4¿2受体的PET显像剂。我们对尼芬的毒性结果表明，18f -尼芬的放射性示踪剂注射适合人类使用。因此，这项NIH申请的一个目标是进行18F-Nifene的首次人体研究。将使用PET/CT扫描仪对6名受试者进行人体辐射剂量学研究。我们将在正常志愿者中评估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，这是该受体的假定拮抗剂。动物研究表明，扫描时间约为1小时，在受体丰富的大脑区域具有高度结合。90分钟，特定结合比~4。拟在资助期内完成18f -硝基甲苯的动物显像、毒性试验和辐射剂量测定。激动剂和拮抗剂的可用性将使这种受体系统在各种疾病中的比较研究成为可能。该应用的第三个目标是评估18f -尼芬是否能够检测PET研究中神经递质乙酰胆碱水平的变化。这对评价乙酰胆碱酯酶抑制剂治疗AD的疗效具有重要价值。该应用程序的总体拟议研究也将支持其他疾病的研究，如帕金森病和精神分裂症。

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.