Evaluation of Iodorotenone, A SPECT Perfusion Tracer

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最高的原因，也是医疗保健费用最高的原因。目前，心肌灌注成像（MPS）是最广泛应用的无创成像方法，用于已知或疑似CAD患者的诊断、定位和风险分层。铊-201和锝-99m标记的化合物使用最广泛。这些药物的摄取与血流不完全呈线性关系。在高流速下与线性的偏差限制了对不太严重的疾病的区域进行成像并将这些区域与正常灌注的组织区分开的能力。这反过来又降低了诊断的敏感性，导致低估疾病，损害风险评估和相关的管理决定。碘烯酮是一种与线粒体中电子传递链的复合物I结合的化合物，已发现其在心脏组织中具有分布、提取和保留特性，其上级优于铊和锝灌注剂。碘代烯酮在心脏组织中提取80-90%，与Tc-司他米比相比，与流量的线性更好，并且具有有限的肺蓄积，从而提供更好的心肺对比度。本研究的目的是验证我们的假设，即碘罗替酮是一种上级灌注示踪剂，通过提高病变检测的灵敏度和特异性，将成为一种更有益的临床药物。该方法包括收集必要的生物学、毒理学和辐射剂量学数据，以证明示踪剂的安全性，并获得批准，以评估新示踪剂在人体中的功效。为此，将按照GLP标准进行毒理学和药代动力学研究。将评价示踪剂的血液结合和亚细胞分布。将在正常犬中进行辐射剂量测定。犬缺血性冠状动脉疾病和低血流模型将用于进一步验证示踪剂动力学。最后，人类受试者研究将提供[123 I]碘罗替酮与99 mTc-sestamibi的直接比较，从而提供碘罗替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（如[123 I]碘罗替酮）的潜在临床影响是深远的。

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.