PET Imaging Agents for a4b2 Nicotinic Receptors

描述(申请人提供)：烟碱型A4？2受体与神经退行性变有关，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。其中包括：1)精神损伤和神经障碍研究所的阿尔茨海默病研究中心(ADRC)；2)与尼古丁依赖相关的研究计划；3)肺癌早期检测计划；以及4)学习和记忆的神经生物学。在之前的资助期间，我们已经成功地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，18F-Nifene在丘脑、外侧膝状体、皮质和其他脑区有选择性结合，在小脑中结合有限，特异性结合比为~3。血浆分析表明18F-Nifene存在，没有观察到脱氟现象。特定脑区的高比率和较短的扫描时间表明，18F-Nifene是最合适的激动剂之一，具有作为人类A4？2受体的PET显像剂的良好潜力。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于人类使用。因此，NIH申请的一个目标是用18F-Nifene进行第一次人体研究。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。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。该提案的第二个目标是完成18F-NiFrolene的临床前开发，18F-NiFrolene是该受体的假定拮抗剂。动物研究表明，在富含受体的大脑区域，扫描时间约为30分钟。90分钟，特定结合比~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。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。这项应用的第三个目标是评估18F-Nifene是否能够在PET研究中检测到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的疗效有重要价值。这项申请的总体拟议研究还将支持对其他障碍的研究，如帕金森氏症和精神分裂症。

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.