title: Toxicological evaluation of a rotenone derivative in rodents for clinical myocardial perfusion imaging.
abstract: Myocardial perfusion scintigraphy is a valuable clinical tool for assessing coronary blood flow deficits in patients. We recently synthesized a new iodinated compound ((123)I-CMICE-013) based on rotenone and showed that it has excellent performance as a radiotracer for myocardial perfusion imaging. Here, we describe the cellular toxicity and subacute toxicity of CMICE-013 in rats. Cultured hepatocytes displayed sensitivity to rotenone but not CMICE-013 at equimolar concentrations. Following i.v. injection of CMICE-013 for 14 days, body weight, ambulation, behavior, grooming, guarding (abdominal, muscular), pale conjunctivae, and food intake were observed. Biochemical, hematological, and histopathological changes in tissues (heart, liver, kidney, spleen, lung, and brain) and echocardiography at pre- and post-dosing were also examined. All animals responded well to the daily injections of CMICE-013 and showed no mortality or adverse reactions with respect to the parameters above. Subacute i.v. injections at high- (5 μg/kg) and low (1 μg/kg)-dose levels did not result in any significant changes to either biochemical or hematological parameters and no detectable changes in histopathology compared to the vehicle or untreated animals. Echocardiographic analyses, including the measurements of cardiac function and anatomy (wall thickness, left atrial size, and left ventricular mass), were not different at pre- versus post-dose measures and were not different compared to the vehicle or untreated animals. Our observations in small animals reveal that CMICE-013 induces minimal toxicity when delivered intravenously for 14 days.
authors.affiliation: Nordion, 447 March Road, Ottawa, ON, K2K 1X8, Canada, pfernando@ottawaheart.ca.
authors.forename: Pasan
authors.initials: P
authors.lastname: Fernando
authors.forename: Xuxu
authors.initials: X
authors.lastname: Yan
authors.forename: Julia
authors.initials: J
authors.lastname: Lockwood
authors.forename: Yin
authors.initials: Y
authors.lastname: Duan
authors.forename: Lihui
authors.initials: L
authors.lastname: Wei
authors.forename: R
authors.initials: R
authors.lastname: Glenn Wells
authors.forename: Corinne
authors.initials: C
authors.lastname: Bensimon
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Mullett
authors.forename: Terrence
authors.initials: T
authors.lastname: Ruddy
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001835:Body Weight; D002478:Cells, Cultured; D004452:Echocardiography; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D055414:Myocardial Perfusion Imaging / Q000379:methods*; D009929:Organ Size; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012402:Rotenone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D059551:Toxicity Tests, Subacute
chemical_list: D015415:Biomarkers; D019275:Radiopharmaceuticals; D012402:Rotenone