Flow-Dependent Uptake of ¹²³I-CMICE-013, a Novel SPECT Perfusion Agent, Compared with Standard Tracers

Abstract

Rotenone derivatives have shown promise in myocardial perfusion imaging (MPI). CMICE-013 is a novel 123 I-labeled rotenone derivative developed for SPECT MPI. The objective of this study was to assess the image quality of CMICE-013 and compare its uptake with tetrofosmin, sestamibi, and 201 Tl in vivo in a porcine model of stress-induced myocardial ischemia. Methods: Microspheres were injected simultaneously with the radiotracer injections at rest and stress to measure blood flow. Mimicking a 1-d tetrofosmin protocol, stress imaging used 3 times as much activity and occurred 1 h after the rest injection. SPECT images were obtained at both rest and stress. After imaging, the heart was sectioned into 44-50 pieces. In each heart sample, the tracer uptake was measured in a γ counter. The images were aligned, and the decay-corrected ratio of the signals at rest and stress was used to separate the well-counter signal into rest and stress components. The uptake at rest and stress was compared with microsphere flow measurements. Results: The CMICE-013 images showed good contrast between the heart and surrounding organs, with heart-to-liver and heart-to-lung uptake ratios similar to those of the standard tracers. Uptake of CMICE-013 was 1.5% of the injected dose at rest and increased more rapidly with increased blood flow than did the standard SPECT tracers. The percentage injected dose of CMICE-013 taken up by the heart was greater (P , 0.05) than 201 Tl, tetrofosmin, or sestamibi at flows greater than 1.5 mL/min/g. Conclusion: CMICE-013 is a promising new SPECT MPI agent. Repeat ed unexpected shutdowns of several of the major nuclear reactors producing 99 Mo has led to ongoing concern over the stability of the supply of 99m Tc and, consequently, interest in developing alternative tracers. Myocardial perfusion imaging (MPI) remains one of the more common tests performed with 99m Tclabeled agents. For MPI, PET is a potential option using either 82 Rb or 13 N ammonia, because the parent isotope for 82 Rb generators ( 82 Sr) and ammonia are both cyclotron-produced. Interest in PET MPI is growing; however, the number of MPI SPECT scans obtained annually in North America is still orders of magnitude larger and likely to remain so for many years. Thus, a SPECT alternative to 99m Tc MPI tracers remains an important goal.Clinical trials of the 18 F-labeled PET tracer flurpiridaz (1,2) have shown excellent contrast between the heart and surrounding organs and performance superior to standard 99m Tc-based tracers for the identification of disease. This tracer inhibits mitochondrial complex I and derives its specificity for cardiac imaging from the high concentration of mitochondria in the heart. Other compounds that target mitochondrial complex I have been studied previously in SPECT. An iodinated rotenone compound (I-ZIROT) was shown to have excellent uptake in the heart and excellent extraction at higher blood flows (3,4), which is in contrast to the standard SPECT 99m Tc tracers that have a roll-off in their extraction, prod...

Quantitative Assessment of Coronary Microvascular Function

“…37, 40 Recently, radioactive iodinated rotenone derivatives ( 123 I-ZIROT; 123 I- CMICE-013) have shown great promise for dynamic SPECT MPI. 41, 42 These tracers, similarly to the PET tracer 18 F-flurpiridaz, target mitochondrial complex-1 of the electron transport chain, and demonstrate a high extraction fraction and high correlation of myocardial uptake with microsphere flow even at higher flow rates. 41, 42 …”

“…41, 42 These tracers, similarly to the PET tracer 18 F-flurpiridaz, target mitochondrial complex-1 of the electron transport chain, and demonstrate a high extraction fraction and high correlation of myocardial uptake with microsphere flow even at higher flow rates. 41, 42 …”

Mitochondrial-Targeted Molecular Imaging in Cardiac Disease

“…123 I-labeled rotenone derivative ( 123 I-CMICE-013) has been produced using a simple one-step synthetic procedure with an improved radiochemical yield and high stability compared with its uptake with tetrofosmin, sestamibi, and 201 Tl in a porcine model of stress-induced myocardial ischemia [37]. In contrast, 125 I-labeled tracers based on rotenone, which is a neutral and lipophilic MC-I inhibitor, involved multistep syntheses, resulting in a low yield of product [38].…”