加压素V1a受体靶向PET示踪剂开发及其在自闭症动物模型的显像研究

自闭症是一种复杂的脑疾病，目前其病因不明、也无专门的治疗药物。加压素是一种神经内分泌激素，它对人类复杂的社会行为有着重要的调节作用，加压素受体V1a是自闭症的一个有潜力的新药研发靶点，利用PET分子影像技术分析自闭症的脑V1a受体的分布和含量，对自闭症药物的开发具有重要价值。申请人前期发展了靶向V1a受体的C-11标记探针，在猴脑PET显像中展现出较高的摄取量，但C-11标记的正电子示踪剂并不利于临床转化。本项目将依托申请人的前期研究基础，围绕对V1a具有高亲合力和选择性的配体进行结构优化，筛选活性最佳的目标化合物。通过螺环高价碘叶立德前体标记的方法，合成对应的F-18正电子示踪剂，并采用PET显像分析示踪剂在健康及自闭症模型动物体内的含量和分布。本项目拟发展一种进脑量高、选择性强、体内稳定性优异、合成及使用便捷的新型F-18标记PET示踪剂，为靶向加压素受体V1a药物的研发提供新的策略。

Autism is a highly variable, neurodevelopmental disorder without clear cause, mechanism, and drug therapy. Arginine vasopressin is a peptide hormone that plays a key regulatory part in social and affiliative behaviors, and the arginine vasopressin receptor 1a (V1a) is a potential target for new drug discovery for autism. To quantitatively analyze V1a receptor in the brain of autism patients and advance the discovery of novel V1a-targeted drugs, it is of great value for the development of novel V1a-targeted molecular probes by using positron emission tomography imaging technology. In the previous work by the applicant, V1a-targeted PET tracers with C-11 labeling were developed and showed sufficient blood-brain barrier permeability, but their further applications were limited by the short half-life of C-11. On the basis of the previous research, this project is to screen out the target molecules with both affinity and selectivity, synthesize F-18 labeled tracers by spirocyclic iodonium ylide labeling, and analyze the PET imaging in normal and autism models. The aim of the project is to develop a novel V1a-targeted PET tracer with high brain uptake, selectivity and stability, and provide new strategy for the research of V1A receptor-targeted drugs.