Mitochondrial Avid Radioprobes. Preparation and Evaluation of7'(Z)-[125I]Iodorotenone and 7'(Z)-[125I]Iodorotenol Page: 3 of 26
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Mitochondrial dysfunction has been linked to normal aging processes as well as a variety of
diseases including neurodegeneration (Alzheimer's, Huntingon's and Parkinson's diseases) ,
cancer, osteoarthritis and cardiovascular disease. Wallace and colleagues have gathered evidence
supporting a unified threshold hypothesis . Wallace posits that each individual is born with a
given mitochondrial mass. As one ages mutations to the mitochondrial DNA (mtDNA)
diminishes the mitochondrial energy capacity. Organ failure or disease may ensue if the
mitochondrial capacity falls below a certain threshold in a given organ system. Normal aging is
defined under this hypothesis as a slow loss of energy capacity over ones lifetime ultimately
leading to progressive system failure. Mitochondrial-related disease is characterized by either an
inherited genetic defect that significantly lowers the initial amount of mitochondria or
environmental factors such as oxidative damage to mtDNA that speeds up the energy capacity
loss as postulated in the case of Parkinson's Disease [3, 4].
Rotenone (1, Figure 1), a natural product found in the roots of the tropical Derris plant, has
been shown to be a potent reversible inhibitor (IC50 = 0.25 nM) of Complex I of the
mitochondrial electron transport chain . Rotenone and preparation of crude root extracts have
been widely used as "organic" insecticides and piscicides, due to their biological activity and
rapid breakdown to environmentally benign byproducts [6, 7]. Several rotenonids have been
isotopically labeled with 13C 14C, 2H and 3H for structural studies  and to assess Complex I
activity in vivo and in particular the loss of Complex I related to Parkinson's Disease (PD) .
Tritiated (6',7')-dihydrorotenone  has been used to determine the regional distribution of
Complex I in rodent brain [11, 12] as well as to assess binding to intact human platelets as a
potential biomarker of PD .
Positron labeled analogs have been developed and evaluated as prospective in vivo imaging
probes of Complex I activity. The brain distribution of two carbon-11 labeled radiotracers, (2-
[1"C]methoxy)rotenone and (2-["C]methoxy)-6',7'-dihydroroten-12-ol, were evaluated in balb/c
female mice [14, 15]. The regional distribution in the mouse brain was relatively equivalent with
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VanBrocklin, Henry F.; Hanrahan, Stephen M.; Enas, Joel D.; Nandanan, Erathodiyil & O'Neil, James P. Mitochondrial Avid Radioprobes. Preparation and Evaluation of7'(Z)-[125I]Iodorotenone and 7'(Z)-[125I]Iodorotenol, article, October 18, 2006; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc897429/m1/3/: accessed October 18, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.