Evaluation of Iodorotenone, A SPECT Perfusion Tracer

描述(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，也是医疗保健费用最高的原因。目前，心肌灌注显像(MPS)是目前应用最广泛的无创性成像方法，可用于诊断、定位和对已知或可疑冠心病患者进行危险分层。Tl-201和~(99)Tm标记化合物应用最广。这些药物的摄取并不完全与血流呈线性关系。高流率下的线性度偏差限制了成像不太严重疾病的区域并将这些区域与正常灌流组织区分开来的能力。这反过来又降低了诊断的敏感性，导致对疾病的低估，影响了风险评估和相关的管理决策。碘紧张素是一种与线粒体电子传递链复合体I结合的化合物，已被发现在心脏组织中具有分布、提取和保留特性，优于铊和氚灌注剂。在心脏组织中有80%-90%被提取，与TC-Sestamibi相比，它与血流的线性程度更高，并且有有限的肺蓄积，提供更好的心肺对比度。本研究的目的是通过提高病变检测的敏感性和特异性来验证我们的假设，即碘是一种更好的灌注示踪剂，将成为更有益的临床药物。该方法包括收集必要的生物、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类身上的疗效。为此，将按照GLP标准进行毒理学和药代动力学研究。将对示踪剂的血液结合和亚细胞分布进行评估。辐射剂量测定将在正常犬身上进行。将使用犬的缺血性冠状动脉疾病和低血流模型来进一步验证示踪剂动力学。最后，人体受试者研究将提供[123I]碘紧张素酮与99mTC-Sestamibi的直接比较，从而为碘紧张素酮作为灌注示踪剂的临床价值提供初步证据。一种改进的血流示踪剂，如[123I]碘紧张素会产生深远的临床影响。

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.