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

Background-There is a well-recognized need for a new generation of single photon emission computed tomography (SPECT) perfusion tracers with improved myocardial extraction over a wide flow range. Radiotracers that target complex I of the mitochondrial electron transport chain have been proposed as a new class of myocardial perfusion imaging agents. 7-(Z)-[ ¹²⁵I]iodorotenone ( ¹²⁵I-ZIROT) has demonstrated superior myocardial extraction and retention characteristics in rats and in isolated perfused rabbit hearts. We sought to fully characterize the biodistribution and myocardial extraction versus flow relationship of ¹²³I-ZIROT in an intact large-animal model. Methods and Results-The ¹²³I-ZIROT was administered during adenosine A _2Aagonist-induced hyperemia in 5 anesthetized dogs with critical left anterior descending (LAD) stenoses. When left circumflex (LCx) flow was maximal, ¹²³I-ZIROT and microspheres were coinjected and the dogs were euthanized 5 minutes later. ¹²³I-ZIROT biodistribution was evaluated in 2 additional dogs by in vivo planar imaging. At ¹²³I-ZIROT injection, transmural LAD flow was unchanged from baseline (mean±SEM, 0.90±0.22 versus 0.87±0.11 mL/[min ·g]; P=0.92), whereas LCx zone flow increased significantly (mean±SEM, 3.25±0.51 versus 1.00±0.17 mL/[min ·g]; P<0.05). Myocardial ¹²³I-ZIROT extraction tracked regional myocardial flow better than either thallium-201 or ^99mTc-sestamibi from previous studies using a similar model. Furthermore, the ¹²³I-ZIROT LAD/LCx activity ratios by ex vivo imaging or well counting (mean±SEM, 0.42±0.08 and 0.45±0.1, respectively) only slightly underestimated the LAD/LCx microsphere flow ratio (0.32±0.09). Conclusions-The ability of ¹²³I-ZIROT to more linearly track blood flow over a wide range makes it a promising new SPECT myocardial perfusion imaging agent with potential for improved coronary artery disease detection and better quantitative estimation of the severity of flow impairment.