Non-invasive Diagnostic Imaging Technology for Mitochondria Dysfunction in Man By Using Lipophilic Cations Labeled with F-18 and I-123
In the last decade a new field of ?Mitochondrial Medicine? has been created from the discovery that a wide array of diseases in humans are associated with mitochondrial dysfunction. A partial list of diseases includes Cancer, Autoimmune Disorders, Alcoholic Liver Disease, Cardiomayopathies, Ecphalomyopaties, Huntington Disease, Parkinson Disease, Alzheimer?s Disease and new pathologies are identified each year. Measurement of mitochondrial membrane potential (MMP) provides the most comprehensive reflection of mitochondrial dysfunction that underlies symptomatic and asymptomatic pathologies. Of special importance are the alterations in MMP at the very early stage of the apoptotic action of major cytotoxic drugs such as paclitaxel, doxorubicine, cisplatin, etoposide, to name a few. In recent years, we have developed a series of ?target-designed? lipophilic phosphonium cations (PhCs) labeled with F-18 for non-invasive measurement of MMP as diagnostic molecular probe for imaging and detection of mitochondria-mediated pathologies in humans using PET. The molecular structure and size, lipophilicity and electrostatic tension of charges are optimized to obtain maximum accumulation in cell, high sensitivity to membrane potential and minimal interference of multidrug-resistance efflux proteins. So far we have validated in animal models the suitability of some PhCs to detect solid tumors at high contrast, to differentiate neoplasm from inflammation on a single scan and to measure response of tumor to sub-clinical doses of anticancer drugs within hours-to-days of treatment. Cardiovascular toxicity studies in dogs show that [18F]PhCs at 1000-fold the dose introduced in humans are harmless. Despite its enormous diagnostic significance, there are not yet molecular probes in the clinical setting for an accurate measurement of MMP by PET. The [18F]PhCs probes have major advantages over SPECT tracers, such as 99mTc-MIBI, including greater sensitivity to alterations in MMP and greater preferential accumulation in tumor cells. Most importantly, PET phosphonium analogs allow exploitation of the better spatial resolution and sensitivity of PET as compared to SPECT. The relatively long half-life of F-18 enhances the availability of imaging molecular probes to a greater population of patients by using the rapidly proliferating model developed for distribution of [18F]FDG with regional cyclotron and satelite PET scanners. To further increase the clinical availability of the novel tracers, we will develop modules for automatic synthesis of PhCs. The better physiological accuracy of the phosphonium probe combined with the superior technology of PET will allow detection of pathologies not seen by any other approach. Description (Set) Proposed Use (Set) 1. Detection and diagnosis using whole body PET scan of diseases associated with mitochondrial dysfunction including Cancer, Autoimmune Disorders, Alcoholic Liver Disease, Cardiomayopathies, Ecphalomyopaties, Huntington Disease, Parkinson Disease, Alzheimer?s Disease. 2. Quantitative and sensitive assessment at molecular level of tumor response to sub-clinical doses of anticancer drugs within hours-to-days of treatment 3. High contrast differentiation of neoplasm from inflammation on a single PET scan. Patent (Set) I266634; 7,112,318 B2; WO 03/065882; 534496Type of Offer: Licensing
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