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Reagents for Lysergic Acid Diethylamide Immunoassay

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Reagents for Lysergic Acid Diethylamide Immunoassay ~™ llll III II III II III IMMII II 1 1 (19) J European Patent Office Office europeen des brevets (11) EP 0 81 6 364 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) int. CI.6: C07D 457/06, G01 N 33/94, 07.01.1998 Bulletin 1998/02 G01 N 33/532, G01 N 33/536, (21) Application number: 97110644.8 A61K 31/48, A61K 39/385 (22) Date of filing: 30.06.1997 (84) Designated Contracting States: • Vitone, Stephen S. AT BE CH DE DK ES Fl FR GB GR IE IT LI LU MC Piscataway, New Jersey 08854 (US) NL PT SE • Wu, Robert Sundoro West Orange, New Jersey 07052 (US) (30) Priority: 02.07.1996 US 21071 P (74) Representative: (71 ) Applicant: Cottong, Norbert A. et al F. HOFFMANN-LA ROCHE AG F.Hoffmann-La Roche AG 4070 Basel (CH) Patent Department (PLP), 1 24 Grenzacherstrasse (72) Inventors: 4070 Basel (CH) • Salamone, Salvatore Joseph Stockton, New Jersey 08559 (US) (54) Reagents for lysergic acid diethylamide immunoassay (57) The invention provides: noassay,noassE which comprises a label-conjugate of for- mula I lysergic acid diethylamide (LSD) derivatives of for- an improved immunoassay for quantitation of LSD mula and its metabolites in biological fluid samples which utilizes that label-conjugate. N-R wherein R1 and R2 are independently selected from H or R3R4; provided that at least one of R1 and R2 is H, but both R1 and R2 are not simultaneously H; R3 is a bond or a saturated straight or branched chain hydrocarbon of 1-10 carbon atoms when R4 is COR5, or R3 is a saturated straight or branched chain hydrocarbon of 1-10 carbon atoms wherein R4 is NHR5; R5 is selected from H, L or LX; CO L is a linking group; and CO X is a detector or carrier molecule bound CO through L, CO a for quantitation of lysergic acid and its o reagent metabolites in biological fluid samples by an immu- Q_ LU Printed by Xerox (UK) Business Services 2.15.7/3.4 EP 0 816 364 A1 Description This invention relates to novel lysergic acid diethylamide derivatives and to the use of these derivatives in producing anti-lysergic diethylamide antibodies and to the use of these antibodies as reagents in improved immunoassays for 5 lysergic acid diethylamide and its metabolites in biological fluid samples. (+)-Lysergic acid diethylamide 9,10-didehydro-N,N-diethyl-6-methylergoline-8p-carboxamide known as LSD, is a hallucinogen which acts on the central nervous system and alters sensory perception. An ingestion of from 20 to 80 ng of LSD is sufficient to induce hallucination (Nelson, C. and Foltz, R. Anal. Chem, 64, 1578-1585, 1992). The use of LSD has been and continues to be a problem for drug and law agencies around the world. Current methods used to deter- 10 mine the levels of LSD and its metabolites, for example N-desmethyl LSD (nor-LSD), in biological fluids such as serum arid urine include fluorescence spectroscopy, GC/tandem MS, HPLC and radioimmunoassay (RIA). Fluorescence spectroscopy, however, exhibits nonspecific interference and does not distinguish between LSD, its metabolites, and other ergot alkaloids. HPLC results in lower nonspecific interference with antibody binding. However this method is time consuming and not suitable for routine screening of large numbers of samples. Immunoassays offer many advantages 15 over the aforementioned analytical methods, including rapid drug screening and most importantly, high sensitivity. In immunoassays for drugs such as LSD, a biological fluid sample suspected of containing said drug or its metab- olites is contacted with antibodies in the presence of a labeled LSD derivative (label). To the extent that the drug or its metabolites are present in the sample, there will be competition for binding to the antibodies and the amount of the labeled derivative that remains bound will be reduced in proportion to the degree of competition with the drug or its 20 metabolites in the sample. A fluorescence immunoassay for LSD has been described (B. Law et al., Anal. Proc. 20, 606, 1983). The immuno- conjugate that is used to generate antibodies is prepared out of the carboxyl residue of lysergic acid (see e.g., H. Van Vunakis Proc. Nat. Acad. Sci. 68, 1483-1487, 1971) and antibodies derived therefrom would be expected to have high cross-reactivity with a number of ergot alkaloids. The tracer used in this method is produced by conjugating f luorescein- 25 amine to the acid residue of the molecule. The sensitivity of the assay system is in the range of 5-40 ng/ml of LSD. Although this method has the advantage of being rapid, it has a poorer limit of detection than the RIA. A radioimmunoassay for LSD is described wherein an LSD immunoconjugate is prepared out of the carboxy resi- due of lysergic acid (see e.g., H. Van Vunakis Proc. Nat. Acad. Sci. 68, 1483-1487, 1971). However, the antibodies derived from the immunoconjugate are not highly specific for LSD. Several ergot alkaloids such as ergosine, ergono- 30 vine, ergotamine and methysergide (also known as methylergonovine) are shown to compete for binding to the LSD antibodies, resulting in undesirable false positive results. Another radioimmunoassay for LSD in serum and urine samples is described (see W. A. Ratcliffe, Clin. Chem. 23(2), 169-174, 1977), wherein the immunoconjugate is prepared via a Mannich type reaction (J. March, Advanced Org. Chem. 4th ed., 900, 1992), by condensation of LSD and bovine serum albumin (BSA) in the presence of formal- 35 dehyde (Tauton-Rigby, Science, 181, 165, 1973). The immunoconjugate produced generates LSD antibodies having low cross-reactivity to a number of ergot alkaloids. The linkage formed in the condensation is derived out of the indole group of the LSD molecule. 40 This linkage is similar to an acetal and imidazoline (herein termed an "aminoketal") which serve as the nitrogen protect- ing groups of indole. As these groups are each susceptible to hydrolysis in an acidic medium, this linkage can also be readily cleaved by hydrolysis in an acidic medium (see e.g., A.J. Stern etal., J. Org. Chem. 54, 2953 (1989); D.A. Evans, so et al., J. Am. Chem. Soc, 103, 5813 (1981); and A. Giannis, et al., Tetrahedron, 44, 7177 (1988)). N,N'-diisopropyli- denephenylalanylleucine bearing the "aminoketal" linkage is cleaved simply by heating the material in 10 % aqueous solution at 60 °C at neutral pH. (see P.M. Hardy et al., Chem . Soc, Perkin I, 1954 (1977)). Therefore, a method result- ing in this unstable linkage is not suitable for making LSD derivatives to be used in preparing haptens and reagents bearing a stable linkage for immunoassay. 55 Therefore, a non-radioisotopic immunoassay method to rapidly detect LSD and its metabolites, especially in urine samples, is highly desirable. It is also desirable to have an LSD derivative bearing a stable noncleavable linkage from which stable haptens and immunogens can be generated. Furthermore, antibodies used to detect LSD and its metab- olites should be highly specific and should not cross-react with other ergot alkaloids. 2 EP 0 816 364 A1 The present invention provides hapten derivatives that are useful for the preparation of antigenic reagents, antibody reagents and tracer reagents having superior performance characteristics for use in immunoassays for the detection of lysergic acid diethylamide (LSD) and its metabolites. In one embodiment of the present invention, the LSD nucleus is derivatized out of the indole nitrogen to form an aminoalkyl haptenic derivative. In another embodiment, the derivatives 5 are produced out of the piperidine nitrogen of the nor-LSD molecule. The preferred derivatization is through alkylation forming a functional group which can be further modified for linking to an appropriate linking, antigenic or labelling group to provide stable reagents for the immunoassay. The compounds of the invention are derived from LSD and have the formula 10 15 wherein R1 and R2 are independently selected from H or R3R4, provided that at least one of R1 and R2 is H but both R1 and R2 are not simultaneously H; R3 is a bond or a saturated straight or branched chain hydrocarbon of 1-10 carbon 20 atoms when R4 is COR5, or R3 is a saturated straight or branched chain hydrocarbon of 1-10 carbon atoms when R4 is NHR5; R5 is selected from H, L or LX; L is a linking group; and X is a detector or carrier molecule bound through L. The stability of these compounds is provided by the introduction of suitable linkages between the drug moiety and a linking group, carrier proteins or detector molecules. Linking groups are known in the art. They are used to activate, i.e. provide an available site on, a drug derivative 25 for synthesizing a hapten. The use of a linking group may or may not be advantageous or needed depending on the specific hapten and carrier pairs. The selection of an appropriate linking group is within the skill of the art. See e.g., U.S. Pat. No. 5,144,030 and U.S. Pat. No. 5,237,057. It is well known to those skilled in the art that only combinations of atoms which are chemically compatible can comprise the linking group, e.g. that permit covalent bonding between a carrier and a hapten, resulting in the formation of an amide, thiourea, or thioether linkage depending on the nature of 30 the linking groups used. Conventional linking groups, including homobifunctional and heterobifunctional linkers, are suitable for coupling to the LSD amine derivatives of the present invention to activate the derivative for further synthesis of the novel LSD hap- tens and immunogens of the present invention.
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