title: Characterization of the four isomers of (123)I-CMICE-013: a potential SPECT myocardial perfusion imaging agent.
abstract: Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) is widely used in the assessment of coronary artery disease (CAD). We have developed (123)I-CMICE-013 based on rotenone, a mitochondrial complex I (MC-1) inhibitor, as a promising new MPI agent. Our synthesis results in a mixture of four species of (123)I-CMICE-013 A, B, C, D. In this study, we separated the four species and evaluated their biodistribution and imaging properties. The cold analogs (127)I-CMICE-013 A, B, C, D were isolated and characterized and their chemical structures proposed.
  
  
  METHODS
  (123)I-CMICE-013 was synthesized by radiolabeling rotenone with Na(123)I in trifluoroacetic acid (TFA) with iodogen as the oxidizing agent at 60°C for 45min, and the four species were separated by RP-HPLC. The cold analogs (127)I-CMICE-013 A, B, C and D were isolated with a similar procedure and characterized by NMR and mass spectrometry. Biodistribution and microSPECT imaging studies were carried out on normal rats.
  
  
  RESULTS
  We propose the mechanism of the rotenone iodination and the structures of the four species. First, I(+) forms an intermediate three-membered ring with 6' and 7' carbons. Second, the lone electron pair of the water molecule attacks the 6' or 7'-carbon, following by the formation of 6'-OH, and 7'-I bonds as in major products C and D, or 6'-I and 7'-OH bonds as in minor products A and B. The weaker 6'-I bond in the intermediate prompts the nucleophilic attachment of water at the favorable 6'-carbon to generate C and D. MicroSPECT images of (123)I-CMICE-013 A, B, C, D in rats showed clear visualization of myocardium and little interference from lung and liver. The imaging time activity curves and biodistribution data showed complex profiles for the four isomers, which is not expected from the structure activity relationship theory.
  
  
  CONCLUSIONS
  (123/127)I-CMICE-013 A and B are constitutional isomers with C and D, while A and C are diastereomers of B and D, respectively. Overall, the biological characteristics of the four species are not correlated perfectly with their molecular structures.
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada. Electronic address: lihui.wei@nordion.com.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wei
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bensimon
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada.
authors.forename: Xuxu
authors.initials: X
authors.lastname: Yan
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Lockwood
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Gan
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: R Glenn
authors.initials: RG
authors.lastname: Wells
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Yin
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada; Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
authors.forename: Pasan
authors.initials: P
authors.lastname: Fernando
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada.
authors.forename: Bram
authors.initials: B
authors.lastname: Gottlieb
authors.affiliation: Nordion Inc., 447 March Road, Ottawa, ON K2K 1X8, Canada.
authors.forename: Wayne
authors.initials: W
authors.lastname: Mullett
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada; Canadian Molecular Imaging Center of Excellence (CMICE), Nordion Lab/University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON K1Y 4W7, Canada.
authors.forename: Terrence D
authors.initials: TD
authors.lastname: Ruddy
mesh_terms: D000818:Animals; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D015394:Molecular Structure; D055414:Myocardial Perfusion Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D012402:Rotenone
keywords: (123)I-CMICE-013; (127)I-CMICE-013; Myocardial perfusion imaging; SPECT