HEART IMAGING AGENTS--A STRUCTURA/-MECHANISTIC STUDY

心脏显像剂——结构/机制研究

• 批准号: 2216163
• 负责人: DONALD M WIELAND
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-08-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216163
• 关键词: cardiography; cardiotonic agents; chemical synthesis; dogs; dopamine beta monooxygenase; drug metabolism; enzyme activity; heart disorder; heart disorder diagnosis; heart imaging /visualization /scanning; heart innervation; heart metabolism; heart pharmacology; laboratory rat; mathematical model; neurotransmitters; norepinephrine; nuclear medicine; positron emission tomography; radionuclides; radiopharmacology; sympathetic nervous system

The intent of this proposal is two-fold: 1) to develop positron-emitting tracers that will quantify enzyme activity within the sympathetic nerves of the heart by means of "metabolic expulsion"; 2) to study by positron emission tomography(PET) the effect of cardioactive and abusive drugs on the efflux kinetics of these tracers and other neuronal markers previously developed in our laboratory. The synthetic false adrenergic neurotransmitter [11C]meta-hydroxyephedrine (MHED) and the natural neurohormone [11C]epinephrine have been successfully developed in our laboratory to map the sympathetic nerve density of the human heart. The retention of MHED in the heart is predominantly uptake(1) dependent whereas the retention of [11C]epinephrine is dependent on vesicular storage. The present proposal will shift our previous emphasis from developing metabolically-resistant tracers that map the intact, "healthy" neuron to that of focusing on tracers that can specifically assess the enzymatic "health" of the neuron. In particular, the cytoplasmic enzyme, monoamine oxidase (MAO-B), and the vesicular enzyme, dopamine-beta- hydroxylase (DBH) will be targeted. [11C]Phenylephrine, readily synthesized by 11C-methylation of meta-octopamine, is uniquely structured to map heart MAO-B activity; its efflux rate from the heart should represent elimination of metabolites derived solely from the action of MAO-B. This hypothesis will be validated by determining the deuterium isotope effect of alpha-di-deuteron-[11C]phenylephrine on heart efflux rate, drug blocking studies with selective MAO-B and MAO-A inhibitors, and HPLC analyses of metabolites in blood and heart tissue. A novel approach to mapping heart DBH activity will be tested which uses the neuron-specific DBH substrate beta-S-[18F]fluoro-MHED. This tracer is designed to be hydroxylated to the respective fluorohydrin which will rapidly eliminate [18F]fluoride ion. The efflux rate of [18F]fluoride from the heart will provide an index of heart neuronal DBH activity. This hypothesis will be validated by determining DBH action on the tracer in vitro, drug blocking studies in vivo with desipramine and reserpine, and HPLC analyses of blood and heart tissue. The cyclic sulfamate method of introducing 18F into the ethanolamine side chain of biogenic amines, developed in this laboratory, will be employed to synthesize beta-R-[18F]fluoro analogs of MHED, epinephrine, and norepinephrine. These tracers will not be metabolic probes of MAO-B or DBH, but will provide longer-lived radioactive mapping agents for the sympathetic neuron based on their cytoplasmic or vesicular retention. After the tracers proposed in this application are validated, the sympathetic nerve effects of possible cardioactive drugs such as amphetamine, sudafed, cocaine, bretylium MPTP, and deprenyl will be systematically evaluated by PET tracer kinetic studies in dogs.

该提案的意图是两个方面：1）发展正电子发射 可以量化交感神经内酶活性的示踪剂 通过“代谢驱逐”的方式； 2）通过正电子研究 排放断层扫描（PET）心活性和滥用药物对 这些示踪剂和其​​他神经元标记的外排动力学 在我们的实验室中开发。合成假肾上腺素能 神经递质[11C] Meta-羟基麻黄碱（MHED）和自然 神经激素[11C]肾上腺素已在我们的 实验室绘制人心的交感神经密度。这 MHED在心脏中的保留主要是摄取（1） 而[11c]肾上腺素的保留取决于水泡 贮存。目前的提议将使我们以前的重点从 开发代谢抗性的示踪剂，这些示踪剂绘制完整的“健康” 神经元专注于可以专门评估的示踪剂的神经元 神经元的酶“健康”。特别是，细胞质酶， 单胺氧化酶（MAO-B）和囊泡酶，多巴胺β- 羟化酶（DBH）将被靶向。 [11C]苯肾上腺素很容易 通过荟萃二哥胺的11C-甲基化合成的结构是独特的 绘制心脏MAO-B活动；它发自内心的流出率应该 代表仅根据作用而得出的代谢产物 毛。该假设将通过确定氘来验证 α-Di-Deuteron- [11C]苯肾上腺素对心脏外排的同位素效应 速率，具有选择性MAO-B和MAO-A抑制剂的药物阻断研究，以及 HPLC对血液和心脏组织中代谢产物的分析。 将测试一种新的映射心脏DBH活动的方法 神经元特异性的DBH底物β-S- [18F]氟-Hed。 这个示踪剂是 设计为羟基化至相应的氟氢蛋白 快速消除[18F]氟化物离子。 [18F]氟化物的外排率 心脏将提供心脏神经元DBH活性的索引。这 假设将通过确定对示踪剂的DBH作用来验证 体外的药物阻断研究在体内与二哌丁胺和相比性研究，以及 HPLC分析血液和心脏组织。 将18F引入乙醇胺侧的环硫酸盐法 该实验室开发的生物胺链将被采用 合成MHED，肾上腺素和 去甲肾上腺素。这些示踪剂不会是Mao-B的代谢探针或 DBH，但将为寿命更长的放射性映射剂 基于其细胞质或囊泡保留的交感神经元。 在验证了本应用程序中提出的示踪剂后， 可能的心活性药物（例如 苯丙胺，sudafed，可卡因，甲酸MPTP和脱肾将是 通过狗的宠物示踪剂动力学研究系统地评估。