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(12) United States Patent (10) Patent No.: US 7,906,293 B2 Mattingly Et Al

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(12) United States Patent (10) Patent No.: US 7,906,293 B2 Mattingly Et Al US007906293B2 (12) United States Patent (10) Patent No.: US 7,906,293 B2 Mattingly et al. (45) Date of Patent: Mar. 15, 2011 (54) ACRIDINIUM PHENYL ESTERS USEFUL IN WO WO96,07912 A1 3, 1996 THEANALYSIS OF BIOLOGICAL WO OO31543 6, 2000 WO WO 2005.005385 A1 1, 2005 WO WO 2005/O15214 A1 2, 2005 (75) Inventors: Phillip G. Mattingly, Third Lake, IL WO WO 2005/O15215 A1 2, 2005 (US); Maciej Adamczyk, Gurnee, IL WO 20060130736 12/2006 (US); Roy Jeffrey Brashear, OTHER PUBLICATIONS Mundelein, IL (US) Adamczyk, et al., Analytica Chimica Acta, “Homogeneous (73) Assignee: Abbott Laboratories, Abbott Park, IL chemiluminescent assays for free choline in human plasma and whole blood”, 579, 61-67 (2006). (US) Adamczyk, et al., Bioorganic & Medicinal Chemistry Letters, "Rapid high-throughput detection of peroxide with and acridinium *) NotOt1Ce: Subjubject to anyy d1Sclaimer,disclai theh term off thisthi 9carboxamide: Ahomogeneous chemiluminescent assay for plasma patent is extended or adjusted under 35 choline”. In Press (2006). U.S.C. 154(b) by 380 days. Brown, et al., Analytical Biochemistry, “Employment of a Phenoxy Substituted Acridinium Ester as a Long-Lived Chemiluminescent (21) Appl. No.: 11/697.835 Indicator of Glucose Oxidase Activity and Its Application in an Alkaline Phosphatase Amplification Cascade Immunoassay, 256, 142-151 (1998). (22) Filed: Apr. 9, 2007 McCapra, et al., Photochemistry and Photobiology, “Chemiluminescence Involving Peroxide Decompositions', 4, 11 11 (65) Prior Publication Data 1121 (1965). US 2008/0248493 A1 Oct. 9, 2008 Razavi, et al., Luminescence, Stable and versatile active acridinium esters I, 15, 239-244 (2000). Razavi, et al., Luminescence, Stable and versatile active acridinium (51) Int. Cl. esters II, 15, 245-249 (2000). GOIN33/53 (2006.01) de Silva, et al., 13' Int. Symposium on Bioluminescence and (52) U.S. Cl. .......................................... 435/7.1:436/546 Chemiluminescence, Symposium Abstract. “Use of new (58) Field of Classification Search ........................ None chemiluminescent reagent in detectionofoxidasse enzymes and their See application file for complete search history. Substrates by a coupled enzyme reaction’. Aug. 2-6, 2004 Yokohama, Japan, (56) References Cited de Silva, et al., 13' Int. Symposium on Bioluminescence and Chemiluminescence, “Use of New Chemiluminescent Reagent in U.S. PATENT DOCUMENTS Detection of Oxidase Enzymes and Their Substrates by a Coupled Enzyme Reaction'. Aug. 2-6, 2004 Yokohama, Japan, Published on 5,241,070 A 8, 1993 Law et al. website of Lumigen Inc. on Jun. 7, 2006, pp. 1-10. 5,340,714 A 8, 1994 Katsilometes 5,491,072 A 2, 1996 Akhavan-Tafiti et al. Waldrop III, et al., Luminescence, “Chemiluminescent determina 5,523,212 A 6, 1996 Akhavan-Tafiti et al. tion of hydrogen peroxide with 9-acridinecarbonylimidazole and use 5,593,845. A 1/1997 Akhavan-Tafiti et al. in measurement of glucose oxidase and alkaline phosphatase activ 5,670,644 A 9, 1997 Akhavan-Tafiti et al. ity” 15, 169-182 (2000). 5,723,295 A 3, 1998 Akhavan-Tafiti et al. ISA/US, International Search Report (Search Completed Jul. 2, 5,750,698 A 5, 1998 Akhavan-Tafiti et al. 2008), International Application PCT/US2008/59710. 6,673,560 B1 1/2004 Sharpe et al. 2002/017724.0 A1* 11/2002 Kundu .......................... 436,518 * cited by examiner 2003/0232405 A1 12/2003 Akhavan-Tafiti et al. ....... 435/25 2008/0199973 A1* 8/2008 Evangelista et al. .......... 436,536 Primary Examiner — Jacob Cheu FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Audrey L. Bartnicki; Lisa V. EP O 625,510 A2 11/1994 Mueller; Polsinelli Shughart EP O 750 748 B1 5, 2001 EP O 778946 B1 10, 2002 (57) ABSTRACT EP O 625 510 B1 4/2003 WO WO 93.23756 A1 11, 1993 The present invention relates to methods and kits for detect WO WO94,26927 A1 11, 1994 ing an analyte in a test sample using acridinium-9-carboxy WO WO95/23971 A1 9, 1995 late aryl esters. WO WO95/28495 A1 10, 1995 WO 95.29255 11, 1995 8 Claims, 17 Drawing Sheets U.S. Patent Mar. 15, 2011 Sheet 1 of 17 US 7,906,293 B2 U.S. Patent Mar. 15, 2011 Sheet 2 of 17 US 7,906,293 B2 ?IdueS?seL U.S. Patent US 7,906,293 B2 ?IduueS?seL U.S. Patent US 7,906,293 B2 U.S. Patent US 7,906,293 B2 U.S. Patent Mar. 15, 2011 Sheet 7 Of 17 US 7,906,293 B2 25OOOOO 2OOOOOO 15OOOOO 1OOOOOO 5OOOOO FIGURE 7 25OOOOO 2OOOOOO 15OOOOO . 1 OOOOOO 5OOOOO O O 1O 2O 30 40 50 60 70 8O Choline (uM) FIGURE 8 U.S. Patent Mar. 15, 2011 Sheet 8 of 17 US 7,906,293 B2 16OOOOO 14OOOOO 12OOOOO 1OOOOOO 8OOOOO 6OOOOO 4OOOOO 2OOOOO FIGURE 9 16OOOOO 14OOOOO 12OOOOO 1OOOOOO 8OOOOO 6OOOOO 4OOOOO 2OOOOO O O 2O 40 60 8O 100 120 140 Choline FIGURE 10 U.S. Patent Mar. 15, 2011 Sheet 9 Of 17 US 7,906,293 B2 8OOOOO 7OOOOO 6OOOOO 500000 400000 3OOOOO 2OOOOO 1OOOOO FIGURE 11 U.S. Patent Mar. 15, 2011 Sheet 10 of 17 US 7,906,293 B2 80OOOO 7OOOOO 600 OOO 500 OOO 40OOOO 3OOOOO 20OOOO 1 OOOOO O O 20 40 60 80 1OO 120 140 Choline FIGURE 12 U.S. Patent Mar. 15, 2011 Sheet 11 of 17 US 7,906,293 B2 3OOOOOO 25OOOOO 2OOOOOO 15OOOOO 1 OOOOOO 5OOOOO FIGURE 13 U.S. Patent Mar. 15, 2011 Sheet 12 of 17 US 7,906,293 B2 3OOOOOO 25OOOOO 2OOOOOO 1500000 1OOOOOO 500000 O O 20 40 60 80 100 120 140 Choline (M) FIGURE 14 U.S. Patent Mar. 15, 2011 Sheet 13 of 17 US 7,906,293 B2 25OOOOO 2OOOOOO 15OOOOO 1OOOOOO 500000 FIGURE 15 25 OOOOO 2OOOOOO g 15OOOOO 1OOOOOO 5OOOOO O O 2O 40 60 80 1 OO 120 140 Choline (uM) FIGURE 16 U.S. Patent Mar. 15, 2011 Sheet 14 of 17 US 7,906,293 B2 12OOOOO 1OOOOOO 800000 6OOOOO 400000 200000 Time (s) FIGURE 1 7 U.S. Patent Mar. 15, 2011 Sheet 15 Of 17 US 7,906,293 B2 12OOOOO 1 OOOOOO 80OOOO 6OOOOO 4OOOOO 2OOOOO O O 20 40 60 8O 1 OO 120 140 Choline (uM) FIGURE 18 5OOOOO 45OOOO 4OOOOO 35OOOO 3OOOOO 25OOOO 2OOOOO 15OOOO 1OOOOO 5OOOO FIGURE 19 U.S. Patent Mar. 15, 2011 Sheet 16 of 17 US 7,906,293 B2 5OOOOO 45OOOO 4OOOOO 35OOOO 3OOOOO 2 5 O O O O 2OOOOO 15OOOO 1 OOOOO 5OOOO O O 2O 40 60 8O 100 12O 140 Choline (uM) FIGURE 20 16OOOOO 14OOOOO 12OOOOO 1 OOOOOO 8OOOOO 6OOOOO 4OOOOO 2OOOOO FIGURE 21 U.S. Patent Mar. 15, 2011 Sheet 17 Of 17 US 7,906,293 B2 . *..." t ---l" a ofa's NSO-( )- - Y. FIGURE 22 US 7,906,293 B2 1. 2 ACRIDINUM PHENYLESTERS USEFUL IN SUMMARY OF THE INVENTION THEANALYSIS OF BIOLOGICAL In one embodiment, the present invention relates to a RELATED APPLICATION INFORMATION method of detecting an analyte of interestinatest sample. The 5 method comprises the steps of None. a) processing a test sample to separate the analyte from protein in the test sample; FIELD OF THE INVENTION b) adding an acridinium-9-carboxylate aryl ester to the processed test sample, the acridinium-9-carboxylate aryl The present invention relates to methods for detecting an 10 ester having a formula of analyte in a test sample. Specifically, the methods of the present invention employ certain acridinium-9-carboxylate aryl esters for detecting an analyte in a test sample. Addition RI xe ally, the present invention also relates to kits for detecting an 15 analyte in a test sample. 21 eN1 N R3-- --R2 BACKGROUND OF THE INVENTION Along with the progress in diagnostic or medical technol ogy, various methods for detecting analytes of interest in test O O samples (such as serum, plasma, whole blood, etc.) have been developed and put into use to enable the early detection of R8 R4 various diseases and for confirming the effects of therapy. For the purpose of qualitative or quantitative detection of an ana 25 lyte in a test sample, certain detectable compounds (also R7 R5 known as detectable labels or signal generating compounds) R6 are used. Typically, these detectable compounds are capable of being used to generate detectable signals in the presence of one or more analytes in a test sample. In certain instances, 30 wherein R' is an alkyl, alkenyl, alkynyl, arylalkyl, aryl, these detectable compounds are attached to Substances that sulfoalkyl or carboxyalkyl and R through Rare each inde have a certain affinity for the analyte to be detected and pendently selected from the group consisting of hydrogen, quantified. For example, an antibody can be conjugated to a alkyl, amino, alkoxy, hydroxyl, carboxyl, halide, nitro, cyano, detectable compound (the labeled antibody is referred to - SO, NHC(O)R, C(O)R, C(O)OR, C(O)NHR herein as a "conjugate'). The conjugate can then be used to 35 and—SCN, wherein Risan alkyl, alkenyl, alkynyl, arylalkyl, detect and quantify the amount of an antigen of interest in a aryl, Sulfoalkyl or carboxyalkyl, and X is an anion; test sample. In other instances, however, the detectable com c) adding a basic solution to the processed test sample to pound is simply added to the test sample alone, not attached generate a light signal; and or conjugated to another Substance (such as an antibody). d) quantifying the amount of analyte in the test sample by Regardless of whether a detectable compound is attached or 40 relating the amount of light generated in the test sample by conjugated to another Substance or used alone, once added to comparison to a standard curve for the analyte.
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