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 CNS 受体和信号转导机制的体内成像方法，正在生产具有适当 SAR 要求的放射性标记配体，并将其用于开发体内动物模型，并将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，以使用标准 β（C-14 或 H-3）或 γ（I-125）发射放射性配体在置换测定中测定 SAR。 如果冷标记化合物保留活性，则可以开发快速放射合成技术。 正电子（F-18、C-11、I-124）发射衍生物用于初步体内研究，以确定血脑屏障穿透性和体内活性；使用放射自显影和外部成像（高分辨率小动物 PET）技术。 示踪剂动力学（推注或平衡）模型已在啮齿类动物和灵长类动物中开发出来，并使用激活和位移技术进行验证。先前合成了毛喉素的冷氟化（氟乙基氨基甲酸酯）衍生物，并在体外证明了与腺苷酸环化酶的高亲和力（Kd < 40 nM）、可饱和结合。一项初步研究使用该化合物的 F-18 标记衍生物在啮齿类动物中使用放射自显影方法，以及在非人类灵长类动物中使用 PET 进行的研究已提交出版。 评估用于 PET 的电压敏感化合物的试点研究已经完成，并且使用 I-124 标记的 T3 进行中枢神经系统摄取和甲状腺激素加工的研究也已经开始。