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Coronary artery disease (CAD) is a major cause of death in Canada and the United States. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is a useful diagnostic test in the management of patients with CAD. The widely used SPECT MPI agents, 99mTc sestamibi and 99mTc tetrofosmin, exhibit less than ideal pharmacokinetic properties with decreasing uptake with higher flows. 123I has a similar energy as 99mTc, an ideal half life, and is readily available from cyclotrons. The objective of this study was to develop an 123I labeled MPI agent based on rotenone, a mitochondrial complex I inhibitor, as an alternative to currently available SPECT MPI agents. Methods: 123I-CMICE-013 was synthesized by radiolabeling rotenone with 123I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60°C for 45min, followed by RP-HPLC purification. The product was formulated in 5% EtOH in 10mM NaOAc pH 6.5. The inactive analog 127I-CMICE-013 was isolated and characterized by NMR and mass spectrometry, and the structure determined. Micro-SPECT imaging studies were carried out in normal and infarcted rats. Biodistribution studies were performed in normal rats at 2h (n =6) and 24h (n =8) post injection (p.i.). Results: 123I-CMICE-013 was isolated with >95% radiochemical purity and high specific activity (14.8–111GBq/μmol; 400–3000mCi/μmol). Structural analysis showed that rotenone was iodinated at 7′-position, with removal of the 6′,7′-double bond, and addition of a hydroxy group at 6′-position. MicroSPECT images in normal rats demonstrated homogeneous and sustained myocardial uptake with minimal interference from lung and liver. Absent myocardial perfusion was clearly identified in rats with permanent left coronary artery ligation and ischemia-reperfusion injury. In vivo biodistribution studies in normal rats at 2h p.i. showed significant myocardial uptake (2.01±0.48%ID/g) and high heart to liver (2.98±0.93), heart to lung (4.11±1.04) and heart to blood (8.37±3.97) ratios. At 24h p.i., the majority of 123I-CMICE-013 was cleared from tissues, and a significant amount of tracer was found in the thyroid, indicating in vivo deiodination of the tracer. Conclusion: 123I-CMICE-013 is a promising new radiotracer for SPECT MPI with high myocardial uptake, very good target to background ratios and favorable biodistribution characteristics. [ABSTRACT FROM AUTHOR]