Novel Tc(I) Technetium-99m Labeled Fatty Acid analogs

该提案的目的是进一步开发BioStream公司开发的一类新的标记脂肪酸的新的化学和行为，作为心肌脂肪酸代谢的标志物。在正常的血液流动和氧气输送条件下，脂肪酸是心肌的主要能量来源。当血液流动减少(缺血)时，心脏缺乏足够的氧气供应来有效利用脂肪酸。为了补偿，心脏立即从脂肪酸代谢转变为葡萄糖代谢。这是BMIPP检测静息缺血心肌能力的基础，BMIPP是一种I-23标记的脂肪酸类似物，目前在日本上市。这项拟议的研究试图通过筛选一系列新的类似物来确定这类新化合物的最佳结构，以促进大鼠心脏的摄取和保留。机制评估将使用缺乏CD36蛋白的基因工程敲除小鼠对较小系列的先导化合物进行，CD36蛋白质是已知的负责将脂肪酸运输到心肌中的蛋白质。还将采用新的螯合技术，试图进一步优化这一新类别的有前景的放射性药物。拟议的商业应用：超过40%的急诊室胸痛患者(每年约300万人)被不必要地送入医院，估计每年的费用为100-130亿美元。用Tc-99m放射性标记的脂肪酸类似物为胸痛患者的分类提供了一种新的解决方案，潜在地为整个医疗保健系统节省了成本，并具有巨大的商业潜力。

The objective of this proposal is to further exploit the novel chemistry and behavior of a new class of Tc-99m labeled fatty acid derivatives developed by Biostream as markers of myocardial fatty acid metabolism. Fatty acids are the primary source of energy for heart muscle under normal conditions of blood flow and oxygen delivery. When blood flow is diminished (ischemic), the heart lacks an adequate supply of oxygen to utilize fatty acids efficiently. To compensate, the heart immediately shifts from fatty acid metabolism to glucose metabolism. This is the basis for the ability of BMIPP, an I-23-labeled fatty acid analog currently marketed in Japan, to detect ischemic myocardium at rest. The proposed research seeks to determine the optimal structure for this new class of compound by screening a series of new analogs for heart uptake and retention in rats. Mechanistic evaluations will be performed on a smaller series of lead compounds using genetically engineered knock-out mice that are lacking the CD36 protein known to be responsible for fatty acid transport into the myocardium. New chelate technology will also be employed in an attempt to optimize further this new class of promising radiopharmaceuticals. PROPOSED COMMERCIAL APPLICATIONS: More than 40% of ER chest pain patients (ca. 3 million annually) are admitted to hospitals unnecessarily at an estimated cost of $10-$13 billion per year. Fatty acid analogs radiolabeled with Tc-99m present a novel solution to the triage of the chest pain patient, potentially offering both cost savings to the overall heath care system as well as significant commercial potential.