新型F-18标记组胺H3受体PET示踪剂的研究

当前科学研究中只有极少数放射性配体利用PET显像技术来评价脑组胺H3受体，且不同程度地存在放射合成困难、放射化学产率低、产生放射性代谢产物等局限性。我们前期研究结果表明，以非咪唑2-氨乙基苯并呋喃为基本结构的18F-XB-1 PET放射性配体是目前科学研究中结果较好的一种组胺H3受体PET显像剂,如：高选择性、高脑部摄入量和无放射性氟脱落情况下较大的受体特异性信号等。本项目将在此基础上,进一步合成、筛选、F-18标记这类新型结构的放射性配体作为PET显像剂, 并以脑组胺H3受体为靶向,在活体动物中利用PET显像技术，对这类放射性配体进行综合性研究和评价。研究结果将有助于最终开发出一类应用于临床的脑组胺H3受体PET显像剂，用于评估患者在神经性精神疾病过程中，组胺H3受体在人体脑部的分布及其密度变化，并确定疾病治疗过程中治疗药物的使用剂量。

So far, few radioligands have been prepared and evaluated for imaging brain H3 receptors with PET. These radiotracers all suffer from one or more limitations,such as difficult radiosynthesis,low radiochemical yield ,or troublesome metabolism.Our previous reports showed that nonimidazole based 2-aminoethyl benzofurans structure, F-18 XB-1, demonstrated favorable properties as a PET radioligand for brain H3 receptors in monkey, including moderately high brain uptake and sizable receptor-specific signal in the absence of radiodefluorination.?To the best of our knowledge, this is the only example of 18F-labeled radioligand for brain H3 receptors that has been reported to give a sizable receptorspecific signal in vivo and showed encourging results.Here in this proposal, F-18 XB-1 will be served as a platform for further developing the improved 18F-labeled H3 receptor PET radioligands.We aim to use the selective H3 receptor radioligands with PET to elucidate any changes in the distribution and density of H3 receptors in living human brain during the progression of neuropsychiatric disorders, and to determine the dose-dependence of extent and duration of brain H3 receptor occupancy by candidate drugs that may be directed at the treatment of such disorders.