Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
2000-04-06
2001-06-12
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
Reexamination Certificate
active
06245317
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to
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F-labeled oxa fatty acids, and to methods of making and using the same, in particular, to methods of using such fatty acids as a tracer compound in positron emission tomography (PET).
BACKGROUND OF THE INVENTION
A radioiodinated 4-thia fatty acid analog has been previously reported (Gildehaus et al, J Nucl Med 38:124P, 1997, abstract).
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F-labeled fatty acids are known generally from U.S. Pat. No. 4,323,547 (incorporated hereinto by reference) as useful in PET studies of myocardial metabolism. More recently,
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F-labeled 6-thia fatty acid (14F6THA) has been synthesized and evaluated (DeGrado, J Lab Compd Radiopharm 24:989-995, 1991; DeGrado et al, J Nucl Med 32:1888-1896, 1991, each incorporated hereinto fully by reference). 4-thia and 6-thia fatty acid analogs track total beta-oxidation of palmitate in the liver. Beta-oxidation of long-chain fatty acids may occur in either mitochondria or peroxisomes. Investigation in isolated rat livers using specific inhibition of carnitine palmitoyl-transferase has suggested that
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F-labeled 4-thia fatty acids are trapped in the liver tissue in both organelles. A more specific probe of mitochondrial metabolic function is needed.
SUMMARY OF THE INVENTION
It has been discovered that uptake of
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F-labeled 3-oxa fatty acids correlate with mitochondrial fatty acid oxidation in the liver. The present invention therefore is embodied in
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F-labeled fatty acids having oxa-substitution at the C3 position of the chain. Most preferably, the invention is embodied in an [
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F]fluoro-3-oxa-fatty acids having a chain length of between 8 to 20 carbon atoms.
The
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F-labeled 3-oxa fatty acids of this invention find particular utility as tracers of hepatic mitochondrial beta-oxidation in mammalian livers with positron emission tomography (PET). In this regard, beta-oxidation of long chain fatty acids is a primary source of ATP for the liver. The total distribution volume of long-chain
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F-labeled 3-oxa fatty acids correlates with mitochondrial beta-oxidation rate.
A 3-oxa fatty acid analog of this invention may be used alone or in combination with other metabolic or perfusion tracers. For example, PET imaging in the same subject may be accomplished using both a 3-oxa fatty acid and a 4-thia fatty acid analog of the type disclosed more completely in copending U.S. patent application Ser. No. 09/543,899 filed even date herewith in the name of the same inventors as the present application and entitled “F
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-Labeled Thia Fatty Acids and Methods of Making and Using the Same”, the entire content of which is expressly incorporated hereinto by reference. PET imaging using both 3-oxa and a 4-thia fatty acid tracers may provide information on fatty acid oxidation specifically in mitochondria and peroxisomes.
PET measurements of hepatic beta-oxidation rates should provide important information on the metabolic function of the liver in a number of disease states including alcoholic steatohepatitis, non-alcoholic steatohepatitis, obesity and type-2 diabetes. Of particular interest is the possibility that inhibition of fatty acid oxidation is a contributory factor in the accumulation of complex lipids in fatty liver diseases. The specificity of the 3-oxa fatty acid accumulation to hepatic mitochondria may allow differential diagnosis of diseases that affect the mitochondria in liver.
REFERENCES:
patent: 4323547 (1982-04-01), Knust et al.
patent: 4524059 (1985-06-01), Elmaleh et al.
patent: 4764358 (1988-08-01), Knapp, Jr. et al.
patent: 3-285689 (1991-12-01), None
Scientific Papers, Proceedings of the 44thAnnual Meeting, The Journal of Nuclear Medicine, pp. 124-125, Wednesday, Jun. 4, 1997.
Journal of Labelled Compounds and Radiopharmaceuicals, vol. XXIX, No. 9, Synthesis of 14(R,S)-[18F]Fluoro-6-Thia-Heptadecamoic Acid (FTHA); Timothy R.. DeGrado, Institut für Chemie 1, Forschungszentrum Jülich, FRG, pp. 989-995, 1991.
8-[18F]Fluorooctanoic Acid and its &bgr;-Substituted Derivatives as Potential Agents for Cerbral Fatty Acid Studies: Synthesis and Biodistribution, Fumi Nagatsugi, Shigeki Sasaki and Minoru Maeda, Facility of Pharamaeutical Sciences, Xyushu University, Naidashi 3-1-1, Higashi-ku Fukuoka 812, Japan, pp. 809-817, 1994.
14(R,S)-[18F]Fluoro-6-Thia-Heptadecanoic Acid (FHTA): Evaluation in Mouse of a New Probe of Myocardial Utilization of Long Chain Fatty Acids, Timothy R. DeGrado, Heinz H. Coenen, and Gerhard Stocklin, Institut fur Chemie 1, Forschungszentrum Julich, Germany, pp. 1888-1896, The Journal of Nuclear Medicine, vol. 32, No. 10, Oct. 1991.
Free Fatty Acid Uptake in the Myocardium and Skeletal Muscle Using Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid, Maija T. Maki, Merja Haaparanta, Pirjo Nuutila, Vesa Oikonen, Matti Luotolahti, Olli Eskola and Juhani M. Knuuti, Departments of Nuclear Medicine, Medicine and Clinical Physiology, and Radiochemistry Laboratory, University of Turku, Turku, and Turku PET Centre, Turku, Finland, pp. 1320-1327, The Journal of Nuclear Medicine, vol. 39, No. 8, Aug. 1998.
Kinetics of 14(R,S)-Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid in Normal Human Hearts at Rest, During Exercise and After Dipyridamole Injection, Andreas Ebert, Hans Herzog, Gerhard L. Stocklin, Michael M. Henrich, Timothy R. DeGrado, Heniz H. Coenen and Ludwig E. Feinendegen, Institute fur Medizin und Nuklearchemie, Forschungszentrum Julich, and Nuklennedizinische Klinik der Heinrich-Heine-Universital Dusseldorf, Julich, Germany, pp. 51-56, The Journal of Nuclear Medicine, vol. 35, No. 1, Jan. 1994.
Myocardial Uptake of the Fatty Acid Analog 14-Fluorine-18-Fluoro-6-Thia-Heptadecanoic Acid in Comparison to Beta Oxidation Rates by Tritiated Palmitate, Charles k. Stone, Robert A. Pooley, Timothy R. DeGrado, Britta Renstrom, Robert J. Nickles, Stephen H. Nellis, A. James Liedtke and James E. Holden; Departments of Medicine (Cardiology), Radiology (Nuclear Medicine) and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin; and Department of Radiology, Duke University, Durham, North Carolina; The Journal of Nuclear Medicine, vol. 39, No. 10, Oct. 1998.
Comparison of Fatty Acid Tracers FTHA and BMIPP During Myocardial Ischemia and Hypoxia, Britta Renstrom, Stephen Rommelfanger, Charles K. Stone, Timothy R. DeGrado, Khristen J. Carlson, Emanual Scarbrough, Robert J. Nickles, A. James Liedtke and James E. Holden; Department of Medicine (Cardiology), Radiology and Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, and Department of Radiology, Duke University Medical Center, Durham, North Carolina, pp. 1684-1689, The Journal of Nuclear Medicine, vol. 39, No. 10, Oct. 1998.
DeGrado Timothy R.
Wang Shuyan
Duke University
Hartley Michael G.
Nixon & Vanderhye P.C.
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