PET RADIOPHARMACEUTICALS FOR METABOLISM AND FLOW

该项目的目标是利用回旋加速器产生的， 发生器产生PET同位素，用于标记和评估新型示踪剂 来测量心脏生理参数 碘-122（3.6 min 半衰期）季胺对于快速、重复PET是有吸引力的 血流研究。 122 I将由122 I/122 I生产 发生器系统，用于快速合成化学， 标记的季胺。 我们会追查碘-125 三种季胺的标记（苯基三甲基 铵离子、碘苄基胍和哌嗪鎓离子）作为 潜在的心脏流动剂，并评估其对122 I的可行性 标记并评价其潜在的成像特征， 用红细胞灌流兔心脏， 低氧条件下。 有前途的示踪剂将被标记为122 I， 体内成像研究项目I。 此外，我们还打算 开始全自动发生器/化学系统的工作， 在最新的自动化技术，以显示这种可行性 作为放射性示踪剂生产的合适替代品的发生器。 一 大量证据表明线粒体缺失 或心肌病和正常衰老过程中的功能障碍， 心脏 线粒体密度和功能的丧失， 心脏病与线粒体DNA的突变有关。 在年轻和LD大鼠中的研究表明， 电子传递链酶功能随年龄增长而增加。 因此，一种非侵入性的成像剂来测量线粒体 密度和功能将大大提高我们的能力， 活动的损失，以及有助于了解 心肌病和衰老的病理生理学。 我们建议 评估两类线粒体探针，鱼藤酮和 罗丹明，用氟-18和碳-11标记。 具体地说， 我们将研究这些示踪剂的吸收和保留， 线粒体和培养的肝细胞。 鱼藤酮：阻止 复合物I与鱼藤酮和测量相对于NADH的摄取， 柠檬酸合成酶活性。罗丹明：测量整体摄取 细胞与培养基添加剂如哇巴因、CCCP和尼日利亚菌素 （膜电位的调节剂）。 一组类似的实验 在缓冲液中灌注离体大鼠心脏。 我们将 用红细胞灌注兔心确定示踪剂 正常、缺血和缺氧条件下的摄取和洗脱动力学 条件 我们将使用闭塞/再灌注兔模型， 将示踪剂摄取与线粒体密度的测量相关联， 功能 该项目的预期成果将是： 122 I季胺示踪剂的开发及应用 122 I化学的改进与自动化 发电机系统 ii）线粒体探针的开发， 电子传递功能的退化性丧失， 表明这些物质不仅被提取和保留， 流的功能。

The goals of this project are to use cyclotron produced and generator produced PET isotopes to label and evaluate novel tracers to measure parameters of cardiac physiology. Iodine-122 (3.6 min half-life) quaternary amines are attractive for rapid, repeat PET blood flow studies. 122I will be produced from a 122Xe/122I generator system and used in rapid synthetic chemistry to produce the labeled quaternary amines. We will pursue the iodine-125 labeling of three classes of quaternary amines (pheny1 trimethy1 ammonium ion, iodobenzylguanidine and piperazinium ion) as potential cardiac flow agents and assess their feasibility for 122I labeling as well as evaluate their potential imaging characteristics in the red blood cell perfused rabbit heart under normal, ischemic and hypoxic conditions. Promising tracers will be labeled with 122I for in vivo imaging studies in project I. Additionally, we also intend to begin work on a fully automated generator/chemistry system relying on the latest in automation technology to show the viability of this generator as a suitable alternative for radiotracer production. A considerable body of evidence exists implicating mitochondrial loss or dysfunction in cardiomyopathies and normal aging processes of the heart. The loss of mitochondrial density and function in the heart has been correlated with mutations in the mitochondrial DNA. Studies in young and ld rats have demonstrated that the lost of electron transport chain enzymatic function increases with age. Thus, a non-invasive imaging agent to measure mitochondrial density and function would greatly enhance our ability to define the loss of activity as well as contribute to the understanding of the pathophysiology of cardiomyopathies and aging. We propose to evaluate two classes of mitochondrial probes, rotenones and rhodamines, labeled with fluorine-18 and carbon-11. Specifically, we will study the uptake and retention of these tracers in isolated mitochondria and cultured liver cells. Rotenones: block the complex I with rotenone and measure uptake versus NADH and citrate synthetase activity. Rhodamines: measure uptake in whole cells versus media additives such as ouabain, CCCP and nigericin (modulators of membrane potentials). A similar set of experiments in the buffer perfused isolated rat heart will be performed. We will use the red blood cell perfused rabbit heart to define the tracer uptake and washout kinetics under normal, ischemic and hypoxic conditions. We will use an occlusion/reperefusion rabbit model to correlate tracer uptake with measures of mitochondrial density and function. The anticipated results from this project will be: I) the development 122I quaternary amines as flow tracers and the improvement of the 122I chemistry with automation of the generator system. ii) the development of mitochondrial probes for the degenerative loss of electron transport function provided we can show that these agents are not merely extracted and retained as a function of flow.