Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2000-04-06
2002-03-26
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S225000
Reexamination Certificate
active
06362352
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to
18
F-labeled thia 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).
18
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,
18
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). Although 14F6THA tracks beta-oxidation of palmitate in a number of conditions, it was found to be insensitive to inhibition of beta-oxidation in myocardium in conditions of hypoxia with normal blood flow. Retention of tracer in hypoxic myocardium likely reflects retention of metabolic intermediates that precede beta-oxidation (long chain acyl-CoA, acyl-carnitine, and/or esterified lipids).
SUMMARY OF THE INVENTION
The present invention is based on the discovery that sulfur heteroatom substitution at the C4 position, instead of the C6 position, of
18
F-labeled fatty acids yields a tracer that is retained in proportion to the beta-oxidation rates in normoxic and hypoxic mammalian tissue, particularly normoxic and hypoxic myocardium. Most preferably, the invention is embodied in an [
18
F]fluoro-4-thia-fatty acid having a chain length of between 8 to 20 carbon atoms, and may be saturated or at least partially unsaturated (i.e., contain one or more double bonds).
The
18
F-labeled 4-thia fatty acids of this invention find particular utility in the noninvasive assessment of regional beta-oxidation rates using PET techniques which may allow early detection of abnormalities in the myocardium that might presage irreversible tissue injury.
Although not wishing to be bound to any particular theory, it is surmised that the 4-thia intermediates that precede beta-oxidation are poorly retained in the myocardium, possibly due to facile hydrolysis of the CoA and/or carnitine esters.
The [
18
F]fluoro-4-thia-fatty acids according to this invention are most conveniently synthesized by subjecting a hydrolyzable ester precursor of a 4-thia-fatty acid having a readily substitutable group at the terminal carbon or an odd-numbered carbon from the terminal carbon to
18
F substitution conditions. Thereafter, the
18
F-substituted hydrolyzable ester precursor of the 4-thia fatty acid may be subjected to hydrolysis conditions to form the corresponding [
18
F]fluoro-4-thia-fatty acid. Most preferably, the readily substitutable group is selected from bromo, iodo, tosylate, benzenesulfonylate and the like, while the group that makes the precursor readily hydrolyzable may be benzyl, methyl and the like. By way of example, methyl 16-bromo-4-thia-hexadecanoate is a synthetic precursor of 16-[
18
F]fluoro-4-thia-hexadecanoic acid. Bromo and iodo esters are preferable since their respective acids are easily separated from the radioactive product fatty acid.
The precursor is synthesized by conventional organic synthesis techniques. For example, methyl 16-bromo-4-thia-hexadecanoate is synthesized by reaction of methyl 3-mercaptopropionate with 1,12-dibromododecane in acetonitrile in the presence of potassium carbonate. The product ester is separated from reactants and other reaction products by silica gel liquid chromatography (hexane/ether 3:1, R
f
=0.6). Labeling at the &ohgr;-3 position requires two additional synthetic steps preceding the condensation reaction with methyl 3-mercaptopropionate, namely oxidation of &ohgr;-bromo-(1)alcohol to the (&ohgr;-bromo(1)aldehyde in dichloromethane using pyridinium chlorochromate followed by reaction of the aldehyde with propyl magnesium chloride in ether. The resultant (&ohgr;-3)-alcohol is then condensed with methyl 3-mercaptopropionate to yield the hydroxyester. The hydroxyester is converted to the corresponding tosyloxyester by reaction with Ts-Cl in pyridine. Finally, the tosyloxyester is converted to the bromide, for example, by reaction with LiBr in acetone. Liquid chromatography is used at each step to isolate the products.
18
F labeling may then conventionally be carried out as described in the literature cited above.
A further understanding of this invention will be obtained from the following non-limiting Examples.
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.
Degrado et al, Non-beta. -oxidizable omega. -[18F]fluoro long chain fatty Acid analogs show cytochrome P-450 mediated defluorination: implications for the design of PET tracers of myocardial fatty Acid utilization. Abs and ctation, 1992.*
Stone, CK et al; Effect of Hyperemia and Lactate Loading upon Myocardial Extraction of the Fatty Acid Analog F-18 Flouro-Thia; SCISEARCH AN 94:696070, Circulation, (10/94) vol. 90, No. 4, pT. 2 PP. 77 See abs. Oct. 1994.*
Degrado et al, Myocardial uptake of the fatty acid analog 14-flourine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate, 1998.*
Stone C.K. et al. Effect of Hyperemia and Lactate Loading Upon Myocardial Extraction of the Fatty Acid Analog 18F-Fluoro-Thia-Heptadxecanoic Acid. Circulation. Nov. 14-17, 1994, vol. 90, No. 4, Part 2; pp. 77, see abstract and attached database SDCISEARCH AN 94:696070 Citation.
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.
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.
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, Universit
DeGrado Timothy R.
Wang Shuyan
Duke University
Nixon & Vanderhye P.C.
LandOfFree
F18-labeled thia fatty acids and methods of making and using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with F18-labeled thia fatty acids and methods of making and using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and F18-labeled thia fatty acids and methods of making and using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2832211