99M-TC BRIN IMAGING AGENTS FOR USE WITH SPECT

本研究的主要目的是阐明体内 现有和潜在99m-Tc药物的作用机制， 用于通过SPECT（单光子）监测局部脑血流 发射计算机断层扫描）。 这将通过合并 无机化学的技术和专业知识与核化学的技术和专业知识 医学产生一个综合的方法来了解化学品 这是99m-Tc药物被困在人脑内的基础。 这一方法的重要方面包括：（1）综合 和表征新的锝配合物，使用宏观 99-Tc的量，以便可以完成化学表征， "无载体" 99m-Tc用于放射性药物的制备。 新配合物的表征将在很大程度上依赖于单晶 X射线结构分析，快原子轰击质谱， 电化学分析和HPLC。(2)脑成像的发展 通过"氧化还原捕获"机制起作用的试剂， 大脑将中性分子转化为无法扩散的阳离子 穿过血脑屏障 (3)阐明 CERETEC（99m-Tc d，l-HM-PAO）的生物学作用机制， 目前批准在美国使用的99m-Tc脑灌注剂 states. 这将通过详细的化学、生物和 临床研究，比较的性质和反应性密切 相关但明显不同的99m-Tc PAO试剂。 此外，相关 含有5，7，5-螯合环的络合物，而不是5，6，5-螯合物 将制备HM-PAO环并在动物模型中进行评价， 以确定氧代Tc（V）核心的稳定性如何影响脑摄取 和保留。 (4)新的体内药物的开发和评价 确定实际化学形式的电化学方法，以及 形式之间的转换率，99m-Tc "氧化还原捕获"和PAO- 衍生的脑成像剂。 (5)相关临床评价 密切相关的99m-Tc PAO类似物在诊断 中风和老年痴呆症的患者。 间接受益于 这些机制研究预计将确定一个 99m-Tc PAO试剂，其不受CERETEC的体外稳定性的影响， 但仍具有与之相当或上级的诊断能力， CERETEC。

The primary objective of this research is elucidation of the in vivo mechanism(s) of action of existing and potential 99m-Tc agents that are useful for monitoring regional cerebral blood flow by SPECT (single photon emission computed tomography). This will be accomplished by merging the techniques and expertise of inorganic chemistry with those of nuclear medicine to generate an integrated approach to understanding the chemical basis by which 99m-Tc agents are trapped within the human brain. Important aspects of this approach include the following: (1) Synthesis and characterization of new technetium complexes, using both macroscopic amounts of 99-Tc so that chemical characterizations can be accomplished, and "no carrier added" 99m-Tc for the preparation of radiopharmaceuticals. Characterizations of new complexes will depend heavily on single crystal x-ray structural analysis, fast atom bombardment mass spectroscopy, electrochemical analyses, and HPLC. (2) Development of brain imaging agents that function by a "redox trapping" mechanism wherein oxidation in the brain converts neutral molecules into cations which cannot diffuse back out across the blood-brain barrier. (3) Elucidation of the biological mechanism of action of CERETEC (99m-Tc d,l-HM-PAO), the only 99m-Tc brain perfusion agent currently approved for use in the United States. This will be accomplished by detailed chemical, biological and clinical studies which compare the properties and reactivities of closely related, but definably different, 99m-Tc PAO agents. Moreover, related complexes containing 5,7,5-chelate rings, rather than the 5,6,5-chelate rings of HM-PAO will be prepared and evaluated in animal models in order to determine how the stability of the oxo-Tc(V) core affects brain uptake and retention. (4) Development and evaluation of new in vivo electrochemical approaches to determining the actual chemical forms, and rates of conversion between forms, of 99m-Tc "redox trapping" and PAO- derived brain imaging agents. (5) Evaluation of the relative clinical utilities of closely related 99m-Tc PAO analogs in the diagnosis of patients with stroke and Alzheimer's disease. An indirect benefit of these mechanistic studies is anticipated to be the identification of a 99m-Tc PAO agent which does not suffer the in vitro stability of CERETEC, but yet enjoys the equivalent, or superior, diagnostic capabilities of CERETEC.