Evaluation of Iodorotenone, A SPECT Perfusion Tracer

SPECT 灌注示踪剂碘藤酮的评估

• 批准号: 6865412
• 负责人: Henry F. VanBrocklin
• 金额: $ 58.72万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865412
• 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最高的原因，也是医疗保健费用最高的原因。心肌灌注显像（MPS）是目前对已知或疑似冠心病患者进行诊断、定位和风险分层应用最广泛的无创成像方法。铊-201和锝-99m标记化合物的应用最为广泛。这些药物的吸收并不完全与血流成线性关系。在高流速下对线性的偏离限制了对不太严重疾病区域的成像能力，并将这些区域与正常灌注的组织区分开来。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。碘洛藤酮是一种结合线粒体电子传递链复合体I的化合物，在心脏组织中具有分布、提取和保留特性，优于铊和锝灌注剂。碘罗替酮在心脏组织中提取80-90%，与Tc-sestamibi相比，与流量呈线性关系，并且肺积聚有限，提供更好的心肺对比。本研究的目的是验证我们的假设，即碘洛酮是一种优越的灌注示踪剂，通过提高病变检测的敏感性和特异性，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，以评估新的示踪剂对人体的功效。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。辐射剂量测定将在正常犬身上进行。缺血性冠状动脉疾病和犬低血流模型将用于进一步验证示踪剂动力学。最后，人体受试者研究将提供[123I]碘洛tenone与99mTc-sestamibi的直接比较，从而为碘洛tenone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]碘洛tenone的潜在临床影响是深远的。

项目成果

Myocardial uptake of 7'-(Z)-[(123)I]iodorotenone during vasodilator stress in dogs with critical coronary stenoses.

• DOI: 10.1161/circimaging.110.961763
• 发表时间: 2011-11
• 期刊: Circulation. Cardiovascular imaging
• 作者: Broisat A;Ruiz M;Goodman NC;Hanrahan SM;Reutter BW;Brennan KM;Janabi M;Schaefer S;Watson DD;Beller GA;VanBrocklin HF;Glover DK
• 通讯作者: Glover DK