Evaluation of Iodorotenone, A SPECT Perfusion Tracer

SPECT 灌注示踪剂碘藤酮的评估

• 批准号: 6558795
• 负责人: Henry F. VanBrocklin
• 金额: $ 38.91万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-10 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6558795
• 关键词: blood chemistry; clinical biomedical equipment; clinical research; coronary disorder; diagnosis procedure safety; dogs; heart disorder diagnosis; heart imaging /visualization /scanning; high performance liquid chromatography; human subject; laboratory rat; mass spectrometry; noninvasive diagnosis; perfusion; pharmacokinetics; radiochemistry; radiotracer; single photon emission computed tomography; toxicology

DESCRIPTION (provided by applicant):Coronary artery disease (CAD) is the greatest cause of morbidity and mortality in the USA and the greatest health care cost. Currently, myocardial perfusion scintigraphy (MPS) is the most widely applied noninvasive imaging method for the diagnosis, localization and risk stratification of patients with known or suspected CAD. Thallium-201 and technetium-99m labeled compounds are most widely used. The uptake of these agents is not completely linear with the blood flow. The deviation from linearity at high flow rates limits the ability to image regions of less severe disease and distinguish these regions from normally perfused tissue. This, in turn, reduces diagnostic sensitivity and leads to the underestimation of disease, prejudicing risk assessment and related management decisions. Iodorotenone, a compound that binds to complex I of the electron transport chain in mitochondria, has been found to have distribution, extraction and retention characteristics in heart tissue, superior to thallium and the technetium perfusion agents. Iodorotenone is extracted 80-90% in heart tissue, is more linear with flow than Tc-sestamibi and has limited lung accumulation giving better heart-to-lung contrast. The goal of the present research is to validate our hypothesis that iodorotenone is a superior perfusion tracer that will be a more beneficial clinical agent by improving the sensitivity and specificity of lesion detection. The approach involves gathering the requisite biological, toxicological and radiation dosimetry data to prove the safety of the tracer and gaining approvals to evaluate the efficacy of the new tracer in humans. To this end toxicological and pharmacokinetic studies will be performed to GLP standards. Blood binding and sub-cellular distribution of the tracer will be evaluated. The radiation dosimetry will be performed in normal canines. Models of ischemic coronary disease and low flow in canines will be used to further validate the tracer kinetics. Finally, human subject studies will offer a direct comparison of [123I]iodorotenone to 99mTc-sestamibi thereby providing initial evidence of the clinical value of iodorotenone as a perfusion tracer. The potential clinical impact of an improved flow tracer such as [123I]iodorotenone is far-reaching.

描述（由申请人提供）：冠状动脉疾病（CAD）是美国发病率和死亡率的最大原因，也是最大的医疗保健费用。目前，心肌灌注闪烁显像（MPS）是用于诊断，定位和风险分层的已知或疑似CAD患者的最广泛应用的无创成像方法。 Thallium-2010和Technetium-99M标记化合物的使用最广泛。这些药物的摄取并不是与血流完全线性的。在高流量下线性的偏差限制了对较严重疾病的区域形象的能力，并将这些区域与正常灌注的组织区分开。反过来，这会降低诊断敏感性，并导致疾病低估，偏见风险评估和相关管理决策。碘甲酮是一种与线粒体电子传输链的复合物结合的化合物，在心脏组织中具有分布，提取和保留特性，优于thallium和Technetium灌注剂。碘龙酮在心脏组织中提取80-90％，与TC-Sestamibi相比，具有线性的线性更高，并且肺积累有限，从而可以更好地心对肺对比。本研究的目的是验证我们的假设，即碘龙酮是一种出色的灌注示踪剂，它通过提高病变检测的敏感性和特异性而成为一种更有益的临床药物。该方法涉及收集必要的生物学，毒理学和辐射剂量测定数据，以证明示踪剂的安全性并获得批准以评估新示踪剂在人类中的功效。为此，将按照GLP标准进行毒理学和药代动力学研究。将评估示踪剂的血液结合和亚细胞分布。辐射剂量测定法将在普通犬科动物中进行。犬类缺血性冠状动脉疾病和低流量的模型将用于进一步验证示踪剂动力学。最后，人类学科的研究将直接比较[123i]碘龙酮与99mtc-Sestamibi，从而提供了碘龙酮作为灌注示踪剂的临床价值的初步证据。改进的流动示踪剂（例如[123i]碘龙酮）的潜在临床影响是深远的。