PET RADIOPHARMACEUTICALS FOR METABOLISM AND FLOW

该项目的目标是使用生产的回旋加速器和 Generator生产的PET同位素用于标记和评估新型示踪剂 测量心脏生理参数。碘-122(3.6分钟 半衰期)季胺对快速、重复的PET很有吸引力 血液流动研究。122I将由122Xe/122I生产 发电机系统，用于快速合成化学生产 标记的季胺类化合物。我们将继续研究碘-125 三种季胺类化合物(苯基-1-三甲基-1)的标记 铵离子、碘苄基胍和哌嗪离子)作为 潜在的心脏血流制剂及其122I的可行性评估 标记并评价其潜在的影像特征 正常、缺血和缺氧状态下兔心脏红细胞灌流 低氧状态。有希望的示踪剂将被标记为122I 项目I中的活体成像研究。此外，我们还打算 开始研究全自动发电机/化学系统，依靠 最新的自动化技术表明了这一点的可行性 发电机作为放射性示踪剂生产的合适替代品。一个 有大量证据表明线粒体丢失 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 心脏与线粒体DNA的突变有关。 对幼年和老年大鼠的研究表明， 电子传递链酶功能随年龄增长而增强。 因此，一种测量线粒体的非侵入性显像剂 密度和功能将极大地增强我们定义 活动的丧失以及有助于理解 心肌病和衰老的病理生理学。我们建议 评价两类线粒体探针鱼藤酮和鱼藤酮 罗丹明，用氟-18和碳-11标记。具体来说， 我们将研究这些示踪剂在体外的摄取和滞留。 线粒体和培养的肝细胞。鱼藤酮：阻挡 与鱼藤酮形成络合物I，并测量摄取与NADH和 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和黑素 (膜电位调节器)。一组类似的实验 在灌流的缓冲液中进行大鼠离体心的实验。我们会 用红细胞灌流的兔心确定示踪剂 正常、缺血和低氧条件下的摄取和洗脱动力学 条件。我们将使用一种阻断/再灌流的兔模型 示踪剂摄取与线粒体密度和 功能。该项目的预期结果将是：i) 作为流动示踪剂的122I季胺的开发和 ~(122)I化学的自动化改进 发电机系统。二)开发线粒体探针 电子传输功能的简并损失假设我们可以 表明这些毒剂不仅仅是作为一种 流的作用。

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.