In Vivo Neurochemical Imaging Studies

体内神经化学成像研究

• 批准号: 6531840
• 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/6531840
• 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; neuroimaging; neuropharmacology; positron emission tomography; radiochemistry; radionuclide imaging /scanning; radiotracer; Primates; Rodentias; adenylate cyclase; autoradiography; biological models; biological signal transduction; blood brain barrier; brain metabolism; chemical synthesis; fluorine; forskolin; model design /development; neurochemistry; neuroimaging; 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. Synthesis and biodistribution of a F-18 labelled Forskolin analogue, designed for visualization of adenylate cyclase activity in vivo has been reported (Journal of Fluorine Chemistry, 101(2), 297-304, 2000). PET studies using C-11 Raclopride, a D2 dopamine receptor antagonist, and amphetamine in stuttering subjects is scheduled to begin in October, 2001. This method makes it possible to evaluate both pre- and postsynaptic dopaminergic mechanisms within the CNS. Clinical responses to dopamine (DA) antagonists from patients with developmental stuttering have suggested that the pathophysiology of this disorder may involve an abnormality of central DA systems. Pilot studies evaluating voltage sensitive compounds, which permit direct visualization of transmembrane potentials in the CNS, for use in PET have been completed, and studies using these compounds in non-human primates are planned. Studies of CNS uptake and processing of thyroid hormone, using I-124 labeled T3, have been initiated as well.

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。据报道，据报道，标记为Forskolin类似物的F-18的合成和生物分布，据报道用于体内腺苷酸环化酶活性的可视化（氟化学杂志，101（2），297-304，2000）。计划在2001年10月开始使用C-11 RACLOPRIDE，D2多巴胺受体拮抗剂和口吃受试者中的苯丙胺进行研究。这种方法使得评估CNS内的启用前和突触后多巴胺能机制成为可能。对来自发育口吃的患者的多巴胺（DA）拮抗剂的临床反应表明，这种疾病的病理生理可能涉及中央DA系统的异常。已经完成了评估电压敏感化合物的试验研究，该化合物可以直接可视化中枢神经系统中的跨膜电位，以用于PET中，并计划在非人类灵长类动物中使用这些化合物进行研究。也已经开始对使用标有T3的I-124的甲状腺激素的CNS摄取和加工研究。