In Vivo Neurochemical Imaging Studies

体内神经化学成像研究

• 批准号: 6431976
• 负责人: ALLEN R BRAUN
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431976
• 关键词: Primates; Rodentias; adenylate cyclase; autoradiography; biological models; biological signal transduction; blood brain barrier; brain metabolism; chemical synthesis; fluorine; forskolin; model design /development; neurochemistry; neuropharmacology; positron emission tomography; radiochemistry; radionuclide imaging /scanning; radiotracer

To develop methods for in vivo imaging of CNS receptor and signal transduction mechanisms, radiolabeled ligands with appropriate SAR requirements are being produced and used to develop in vivo animal models, and will lead ultimately to studies in human subjects. Synthetic organic chemistry techniques are used to produce cold-labeled derivatives of candidate compounds to determine SAR in displacement assays using standard beta (C-14 or H-3) or gamma (I-125) emitting radioligands. If cold-labeled compounds retain activity, techniques are developed for rapid radiosynthesis. Positron (F-18, C-11, I-124) emitting derivatives are used in initial in vivo studies to determine blood brain barrier penetration and in vivo activity; both autoradiographic and external imaging (high resolution small animal PET) techniques are used. Tracer kinetic (bolus or equilibrium) models have been developed in rodents and primates, and validated using activation and displacement techniques. A cold-fluorinated (fluoroethyl-carbamate) derivative of forskolin was previously synthesized, and high affinity (Kd < 40 nM), saturable binding to adenylyl cyclase demonstrated in vitro. A preliminary study using an F-18 labeled derivative of this compound in rodents, using autoradiographic methods, and non-human primates, using PET has been submitted for publication. Pilot studies evaluating voltage sensitive compounds for use in PET have been completed, and studies of CNS uptake and processing of thyroid hormone, using I-124 labeled T3, have been initiated.

为了开发用于中枢神经系统受体和信号转导机制的体内成像的方法，正在产生和用于在体内动物模型中开发具有适当SAR要求的放射性标记的配体，并最终导致人类受试者的研究。 合成有机化学技术用于生产候选化合物的冷标记衍生物，以确定使用标准β（C-14或H-3）或Gamma（I-125）发射放射线的SAR在位移测定中的SAR。 如果冷标记的化合物保留活性，则开发了用于快速放射合成的技术。 正电子（F-18，C-11，I-124）发射衍生物用于初始体内研究中，以确定血脑屏障的渗透和体内活性。使用放射自显影和外部成像（高分辨率小动物宠物）技术。 示踪剂动力学（推注或平衡）模型已在啮齿动物和灵长类动物中开发，并使用激活和位移技术进行了验证。先前合成了一种冷氟化（氟乙基 - 氨基甲酸酯）衍生物，并在体外表现出高亲和力（Kd <40 nm），可与腺苷酸环化酶饱和结合。使用PET使用PET的Notiodiographic方法和非人类灵长类动物使用F-18标记的该化合物的F-18标记的衍生物进行了初步研究。 已经完成了评估用于PET的电压敏感化合物的试验研究，并且已经启动了使用标记为T3的I-124的CNS摄取和甲状腺激素的加工研究。