title: Mitochondrial avid radioprobes. Preparation and evaluation of 7'(Z)-[125I]iodorotenone and 7'(Z)-[125I]iodorotenol.
abstract: The loss of mitochondrial function has been implicated in a number of maladies such as Huntington's disease, Parkinson's disease (PD), cancer and cardiovascular disease. The objective of this research was to develop a radiolabeled mitochondrial probe. Two tracers, 7'-Z-iodorotenol and 7'-Z-iodorotenone, analogs of rotenone a natural product that inhibits Complex I of the mitochondrial electron transport chain, have been labeled with iodine-125 in 45-85% yield in a single step from the corresponding tributylstannyl precursor. In vivo distribution in adult male Sprague-Dawley rats for both compounds showed high accumulation in the heart (1.7-3.7 %ID/g at 1 h), a tissue with high mitochondrial content. Z-Iodorotenol did not washout of most tissues between 1 and 2 h postinjection, whereas Z-iodorotenone showed moderate washout (7-26%) over the same period. By 24 h, there was significant loss of both compounds from most tissues including the heart. Heart-to-blood, -lung and -liver ratios for Z-iodorotenone of 28.9, 10.7 and 2.4, respectively, were two- to fourfold higher than the Z-iodorotenol ratios. Compared to the current clinical perfusion tracers, 99mTc-sestamibi and 99mTc-tetrofosmin, Z-iodorotenone demonstrates similar 1 h heart accumulation and significantly higher heart-to-lung ratio (P<.001). Z-Iodorotenone heart-to-liver ratio is equivalent to 99mTc-sestamibi. 7'-Z-Iodorotenone possesses distribution characteristics of an improved tracer for SPECT perfusion studies.
authors.affiliation: Department of Functional Imaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. hfvanbrocklin@lbl.gov
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hanrahan
authors.forename: Joel D
authors.initials: JD
authors.lastname: Enas
authors.forename: Erathodiyil
authors.initials: E
authors.lastname: Nandanan
authors.forename: James P
authors.initials: JP
authors.lastname: O'Neil
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008929:Mitochondria, Heart / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C518596:7'-iodorotenol; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D012402:Rotenone