Synthesis of thyroid hormone derivatives and their role as calibrators for thyroid hormone immunoassays

Abstract

Sulfophenyl and polyethylene glycol derivatives of the thyroid hormones L-thyroxine (T4) and triiodothyronine (T3), and methods of making same, are disclosed. Advantageously, the thyroid hormone derivatives are water soluble, have long-term stability, and don't stick to the surface of common container materials. The derivatives were prepared as calibrators, in non-serum-based solutions, for in vitro thyroid immunoassays to measure the concentration of test samples and were found to perform as well as thyroxine / serum-based solutions.

Description

[0001] Docket No.15250WOO1 Synthesis of Thyroid Hormone Derivatives and Their Role As Calibrators For Thyroid Hormone Immunoassays RELATED APPLICATION INFORMATION This application claims priority to United States Provisional Application No. 63 / 568,256, filed on March 21, 2024, the contents of which are hereby incorporated by reference in their entirety. FIELD Provided herein are thyroid hormone derivatives and the use of same as working calibrator markers for the quantitation of thyroid hormones, such as triiodothyronine (T3) and thyroxine (T4), in competitive immunoassay applications. BACKGROUND Thyroid hormones T3 and its prohormone T4 are derivatives of the amino acid tyrosine and they play an important role in the regulation of a series of physiological and biological processes that include energy metabolism, body temperature, heart rate, body weight, and brain and body development in infancy and childhood. Measurement of these hormones is critical in diagnosis, classification, and treatment of thyroid diseases. Hundreds of millions of people worldwide suffer from thyroid disease. More than 12% of the U.S. population will develop a thyroid condition during their lifetime. The free, non-protein bound fraction of thyroid hormones in circulation are considered biologically and physiologically active, and serum free T4 (free T4) more closely correlates with disease states, such as hypo- and hyperthyroidism, than total T4. In clinical laboratories, most free T4 assays are performed using an immunoassay. Immunoassays (IA) are a sensitive and selective method for the accurate detection of analytes in patient samples. This technique relies on measuring the signal generated by the analyte in an assay against a set of calibrators, which contain a known concentration of the analyte. The nature and preparation of the calibrator solution is therefore paramount to the accuracy of the test. Ideally, the calibrator solution should resemble the patient sample as close as possible, however this is often far from practical or impossible to achieve. Several methods have been reported that prepare calibrator solutions with human serum being considered to have the best commutability with patient samples. However, lot-to-lot Docket No.15250WOO1 variation of human serum and a variable supply chain of human serum makes this medium difficult to maintain for commercialized IA analyzers. Therefore, artificial matrices have been proposed as an alternative. Another challenge in the preparation of calibrators is the stability of the analyte in the calibrator solution, where a stable analyte that provides reproducible results over a specific amount of time and can sustain environmental challenges, e.g. temperature, is required. However, there are many cases where the native calibrator molecule is not stable in solution and therefore requires modification. Preferably, the modified calibrators are more stable than the native antigen and can be used as surrogates in the calibrator formulation for assay testing. The T4 molecule is relatively stable in human serum, but disadvantageously has poor solubility in aqueous environments and has a propensity for sticking to the surface of various container materials, making the preparation of commercialized calibrator solutions difficult. The preparation of calibrators in human serum is not trivial as it takes over 12 hours to establish equilibrium when T4 is added to the serum. Also, availability of serum has been severely impacted due to the COVID pandemic. Because T4 has such an important role in the body, improved methods of detecting T4, using new calibrators, are needed. There remains a need for compounds and methods of synthesizing and using same as a calibrator in an artificial matrix. Surprising, the thyroid hormone derivatives described herein show greater stability compared to thyroid hormones they are based on. This serves to overcome formulation as well as surface interaction challenges that are commonly faced when developing T4 and T3 assays in non-serum-based matrices. SUMMARY In some aspects, a derivative of a thyroid hormone having the structure of Formula (I) is described: I wherein X is Docket No.15250WOO1 R is H or C1-C6alkyl; Z is H, C1-C6 alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In some other aspects, a calibration reagent for an immunoassay used for detecting free thyroxine (T4) and / or total T4 in a biological sample is described, said calibration reagent comprising a thyroid hormone derivative having the structure of Formula (I) described herein. In other aspects, a method of calibrating an immunoassay for detection of free thyroxine (T4) and / or total T4 in a biological sample is described, said method comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the calibration reagent comprises a thyroid hormone derivative having the structure of Formula (I) described herein. In still another aspect, an immunoassay kit for detection of free thyroxine (T4) and / or total T4 in a biological sample is described, said kit comprising at least two calibration reagents comprising a thyroid hormone derivative having the structure of Formula (I) described herein. In yet another aspect, a method of synthesizing a thyroid hormone derivative of formula (I) is described: I wherein X is R is H or C1-C6 alkyl; Z is H or C1-C6alkyl; and L is -[CH2CH2O]n-, wherein n = 4-30, said method comprising: Docket No.15250WOO1 combining a thyroid hormone, at least one base, at least one solvent, and a polyethylene glycol (PEG) ester to produce a reaction mixture; and isolating and purifying the thyroid hormone derivative of formula (I), wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). In another aspect, a method of synthesizing a thyroid hormone derivative of formula (I) is described: I X O ROOwherein X is R is H or C1-C6 alkyl; Z is -SO3H; and L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, said method comprising: combining at least one solvent, at least one sulfonate-containing compound, a coupling agent, and at least one base to produce a reaction mixture; adding a thyroid hormone to an agitated reaction mixture; isolating and purifying the thyroid hormone derivative, wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates the long-term stability data plotted against percent shift for T4, T4- PEG12, and T4-sulfophenyl-1. Docket No.15250WOO1 DETAILED DESCRIPTION 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Various embodiments of the methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. The term “alkenyl,” as used herein, refers to a straight or branched hydrocarbon chain containing from 2 to 16 carbon atoms and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2- methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3- decenyl. As used herein, the term “alkenylene” refers a divalent straight chain or branched alkenyl linking group. Examples of “alkenylene” include ethen-1,1-diyl, ethen-1,2-diyl, propen- 1,3-diyl, 2-buten-1,4-diyl, 3-penten-1,5-diyl, 3-hexen-1,6-diyl, 3-hexen-1,5-diyl, and the like. The term “alkoxy,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of Docket No.15250WOO1 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy. The term “alkyl,” as used herein, means a straight or branched saturated hydrocarbon chain containing from 1 to 16 carbon atoms (C1-C16alkyl), for example 1 to 14 carbon atoms (C1 -C14 alkyl), 1 to 12 carbon atoms (C1 -C12 alkyl), 1 to 10 carbon atoms (C1 -C10 alkyl), 1 to 8 carbon atoms (C1 -C8 alkyl), 1 to 6 carbon atoms (C1 -C6 alkyl), or 1 to 4 carbon atoms (C1 -C4 alkyl). Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl (or t-butyl), n-pentyl, isopentyl, neopentyl, n- hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n- decyl, n-undecyl, and n-dodecyl. The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms (C1-C10 alkylene), for example, of 1 to 6 carbon atoms (C1-C6 alkylene). Representative examples of alkylene include, but are not limited to, —CH2—, —CH2CH2—, —CH(CH)—, —CH2CH2CH2—, —CH2CH(CH)—, — CH2CH2CH2CH2—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH)—, —CH2CH2CH2CH2CH2—, —CH2CH(CH3)CH2CH2—, —CH(CH3)CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, — CH2CH2CH(CH3)CH2CH2—, —CH2CH(CH3)CH2CH2CH2—, and — CH(CH3)CH2CH2CH2CH2—. The term “alkynyl,” as used herein, refers to a straight or branched hydrocarbon chain containing from 2 to 16 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, ethynyl, propynyl, and butynyl. As used herein, the term “alkynylene” refers a divalent straight chain or branched alkynyl linking group. Examples of “alkynylene groups” include propyn-1,3-diyl, 2-butyn-1,4- diyl, 3-pentyn-1,5-diyl, 3-hexyn-1,6-diyl, 3-hexyn-1,5-diyl, and the like. For the purpose of the present application, an “calibration analyte of interest” is at least one thyroid hormone derivative, as described herein, which is included in calibrator reagents for the calibration of clinical assays useful in assessing thyroid function, including total T4, free T4, total T3, and free T3. The calibration analyte of interest, e.g., the thyroid hormone derivatives, can be analyzed in immunoassays in exactly the same manner as conventional analytes of interest are analyzed. Docket No.15250WOO1 “Antibody” and “antibodies” as used herein refers to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies (fully or partially humanized), animal antibodies such as, but not limited to, a bird (for example, a duck or a goose), a shark, a whale, and a mammal, including a non-primate (for example, a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, etc.) or a non-human primate (for example, a monkey, a chimpanzee, etc.), recombinant antibodies, chimeric antibodies, single-chain Fvs (“scFv”), single chain antibodies, single domain antibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, disulfide-linked Fvs (“sdFv”), and anti-idiotypic (“anti-Id”) antibodies, dual-domain antibodies, dual variable domain (DVD) or triple variable domain (TVD) antibodies (dual-variable domain immunoglobulins and methods for making them are described in Wu, C., et al., Nature Biotechnology, 25(11):1290-1297 (2007) and PCT International Application WO 2001 / 058956, the contents of each of which are herein incorporated by reference), and functionally active epitope-binding fragments of any of the above. Antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, namely, molecules that contain an analyte-binding site. Immunoglobulin molecules can be of any type (for example, IgG, IgE, IgM, IgD, IgA, and IgY), class (for example, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. For simplicity sake, an antibody against an analyte is frequently referred to herein as being either an “anti-analyte antibody” or merely an “analyte antibody” (e.g., an anti-UCH-L1 antibody or a UCH-L1 antibody). An antibody as used herein also refers non-Ig derived alternatives (so-called antibody ‘mimetics’) such as, e.g., aptamers (described previously above), as well as, DARPins, Affimers, Avimers, Knottins, Monobodies, and Affinity Clamps. As used herein, the term “aptamer” refers to a nucleic acid that has a specific binding affinity for an analyte of interest. It is recognized that affinity interactions are a matter of degree; however, in this context, the “specific binding affinity” of an aptamer for its analyte or target means that the aptamer binds to its analyte or target generally with a much higher degree of affinity than it binds to other components in a sample. An “aptamer” is a set of copies of one type or species of nucleic acid molecule that comprises a particular nucleotide sequence. An aptamer can include any suitable number of nucleotides, including any number of chemically modified nucleotides. “Aptamers” refers to more than one such set of molecules. Different aptamers can have either the same or different Docket No.15250WOO1 numbers of nucleotides. Aptamers can be DNA or RNA or chemically modified nucleic acids and can be single-stranded, double-stranded, or contain double-stranded regions, and can include higher ordered structures. An aptamer can also be a photoaptamer, where a photoreactive or chemically reactive functional group is included in the aptamer to allow it to be covalently linked to its corresponding analyte or target. In some aspects, an aptamer may include a detectable label. If an aptamer includes a detectable label, all copies of the aptamer need not have the same detectable label. Moreover, if different aptamers each include a detectable label, these different aptamers can have either the same detectable label or a different detectable label. “Antibody fragment” as used herein refers to a portion of an intact antibody comprising the antigen-binding site or variable region. The portion does not include the constant heavy chain domains (i.e., CH2, CH3, or CH4, depending on the antibody isotype) of the Fc region of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab fragments, Fab’ fragments, Fab’-SH fragments, F(ab’)2 fragments, Fd fragments, Fv fragments, diabodies, single-chain Fv (scFv) molecules, single-chain polypeptides containing only one light chain variable domain, single-chain polypeptides containing the three CDRs of the light-chain variable domain, single-chain polypeptides containing only one heavy chain variable region, and single-chain polypeptides containing the three CDRs of the heavy chain variable region. The term “aryl,” as used herein, refers to a phenyl group, or a bicyclic or tricyclic aromatic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group. Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups. Representative examples of bicyclic aryls include, but are not limited to, naphthyl. Representative examples of tricyclic aryls include, but are not limited to, anthracenyl and phenanthreneyl. The term “arylalkyl,” as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, phenylmethyl (i.e., benzyl) and phenylethyl. The term “arylalkylene” refers to a divalent or higher aliphatic hydrocarbon group having one or more aromatic moieties and one or more alkylene moieties, wherein the points of Docket No.15250WOO1 the attachment of the group are with at least one through the alkylene moiety and at least one through the aromatic moiety, with a non-limiting example being: . The term “arylene” refers to an aryl group having a valence of two. The term “aryloxy,” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. “Bead” and “particle” are used herein interchangeably and refer to a substantially spherical solid support. One example of a bead or particle is a microparticle. Microparticles that can be used herein can be any type known in the art. For example, the bead or particle can be a magnetic bead or magnetic particle. Magnetic beads / particles may be ferromagnetic, ferrimagnetic, paramagnetic, superparamagnetic or ferrofluidic. Exemplary ferromagnetic materials include Fe, Co, Ni, Gd, Dy, CrO2, MnAs, MnBi, EuO, and NiO / Fe. Examples of ferrimagnetic materials include NiFe2O4, CoFe2O4, Fe3O4 (or FeO.Fe2O3). Beads can have a solid core portion that is magnetic and is surrounded by one or more non-magnetic layers. Alternately, the magnetic portion can be a layer around a non-magnetic core. The microparticles can be of any size that would work in the methods described herein, e.g., from about 0.75 to about 5 nm, or from about 1 to about 5 nm, or from about 1 to about 3 nm. “Bispecific antibody” is used herein to refer to a full-length antibody that is generated by quadroma technology (also referred to as hybrid-hybridoma technology; see Milstein et al., Nature, 305(5934): 537-540 (1983)), by chemical conjugation of two different monoclonal antibodies (see, Staerz et al., Nature, 314(6012): 628-631 (1985)), or by knob-into-hole or similar approaches, which introduce mutations in the Fc region (see Holliger et al., Proc. Natl. Acad. Sci. USA, 90(14): 6444-6448 (1993)), resulting in multiple different immunoglobulin species of which only one is the functional bispecific antibody. A bispecific antibody binds one antigen (or epitope) on one of its two binding arms (one pair of HC / LC), and binds a different antigen (or epitope) on its second arm (a different pair of HC / LC). By this definition, a bispecific antibody has two distinct antigen-binding arms (in both specificity and CDR sequences), and is monovalent for each antigen to which it binds to. Docket No.15250WOO1 As used herein, the term “calibration curve” refers to a curve that is used to determine the concentration of an analyte of interest in a biological sample, as well as to calculate the limit of detection and limit of quantitation of an assay (such as, for example, an immunoassay, etc.). A calibration curve is created from the working range of the technique (e.g., instrument) being used to a set of calibrator reagents (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least night, or at least ten samples) comprising the calibration analyte of interest at a range of concentrations. As used herein, the term “capture reagent”, refers to a specific binding partner comprising (i) an antibody or antibody fragment thereof that binds to an antigen (e.g., polypeptide) of interest (e.g., analyte of interest or calibration analyte of interest) in a biological sample; or (ii) an antigen (e.g., polypeptide or fragment thereof) that binds to an antibody or antibody fragment thereof of interest (e.g., analyte of interest or calibration analyte of interest) in a biological sample. In some aspects, the capture reagent may be bound on to a solid support, such as a bead or particle. In other aspects, the capture reagent is not bound to a solid support. “Communicated” or “communicating” as used herein refers to the conveying, transmitting and / or reporting of an item of information. In some aspects, the information that is communicated is an item of information obtained by performing an assay (e.g., a immunoassay of the calibration analyte of interest to prepare a calibration curve). The amount or level of the analyte of interest in the sample may then be determined from the calibration curve. The information obtained by performing the assay can be communicated by a computer, in a document and / or spreadsheet, on a mobile device (e.g., a smart phone), on a website, in an e- mail, or any combination thereof. In some other aspects, information is communicated on or from an instrument or device. In other aspects, the information is communicated by being displayed, such as on an instrument or device. “Component,” “components,” or “at least one component,” refer generally to a capture reagent, a detection reagent or conjugate, a calibrator reagent, a control, a container, a buffer, a diluent, a salt, an enzyme, a co-factor for an enzyme, a pretreatment reagent / solution, a substrate (e.g., as a solution), a stop solution, and the like that can be included in a kit for assay of a test sample, such as a patient serum or plasma sample, in accordance with the methods described herein and other methods known in the art. Some components can be in solution or lyophilized for reconstitution for use in an immunoassay. Docket No.15250WOO1 “Controls” as used herein generally refers to a reagent whose purpose is to evaluate the performance of a measurement system in order to assure that it continues to produce results within permissible boundaries (e.g., boundaries ranging from measures appropriate for a research use assay on one end to analytic boundaries established by quality specifications for a commercial assay on the other end). To accomplish this, a control should somehow assess the impact of error on the measurement (e.g., error due to reagent stability, calibrator variability, instrument variability, and the like). The term “cycloalkyl,” as used herein, refers to a saturated carbocyclic ring system containing three to ten carbon atoms and zero heteroatoms. The cycloalkyl may be monocyclic, bicyclic, bridged, fused, or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[5.2.0]nonanyl. The term “cycloalkenyl,” as used herein, means a non-aromatic monocyclic or multicyclic carbocyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. Exemplary monocyclic cycloalkenyl rings include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and bicyclo[2.2.1]heptenyl. As used herein, the term “cycloalkylalkyl” refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclohexylmethyl. The term “cycloalkylene” means a divalent cycloalkyl group, such as 1,2- cyclohexylene, 1,3-cyclohexylene, or 1,4-cyclohexylene. As used herein, the term “detection reagent,” or “conjugate” as used interchangeably herein, refers to a specific binding partner that comprises (i) an antibody or antibody fragment thereof that is conjugated to one or more detectable labels; or (ii) an antigen (e.g., polypeptide or fragment thereof) that is conjugated to one or more detectable labels. “Dynamic range” as used herein refers to range over which an assay readout is proportional to the amount of calibration analyte of interest or analyte of interest in the sample being analyzed. Docket No.15250WOO1 “Epitope,” or “epitopes,” or “epitopes of interest” refer to a site(s) on any molecule that is recognized and can bind to a complementary site(s) on its specific binding partner. The molecule and specific binding partner are part of a specific binding pair. For example, an epitope can be on a polypeptide, a protein, a hapten, a carbohydrate antigen (such as, but not limited to, glycolipids, glycoproteins or lipopolysaccharides), or a polysaccharide. Its specific binding partner can be, but is not limited to, an antibody. The term “halogen” or “halo,” as used herein, means F, Cl, Br, or I. The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen. For example, one, two, three, four, five, six, seven or eight hydrogen atoms can be replaced by a halogen, or all hydrogen atoms can be replaced by a halogen. Representative examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2-fluoro-2- methylpropyl, and 3,3,3-trifluoropropyl. The term “haloalkoxy,” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkoxy include, but are not limited to, trifluoromethoxy. The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom such as N, O, P, or S. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides. The term “heteroalkylene,” as used herein, refers to an alkylene group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom such as N, O, P, or S. Representative examples of heteroalkylene groups include polyethylene oxide and polypropylene oxide chains, polyethyleneimine groups, and the like. The term “heteroaryl,” as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system or an aromatic tricyclic ring system. The aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five-membered aromatic monocyclic rings have two double bonds and the six membered six membered aromatic monocyclic rings have three double bonds. The Docket No.15250WOO1 bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended fused to a monocyclic aryl group, as defined herein, or a monocyclic heteroaryl group, as defined herein. The tricyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring fused to two rings independently selected from a monocyclic aryl group, as defined herein or a monocyclic heteroaryl group as defined herein. Representative examples of monocyclic heteroaryl include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4- thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, 1,2,4-triazinyl, and 1,3,5-triazinyl. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzodioxolyl, benzofuranyl, benzooxadiazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, chromenyl, imidazopyridine, imidazothiazolyl, indazolyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, pyridoimidazolyl, quinazolinyl, quinolinyl, quinoxalinyl, thiazolopyridinyl, thiazolopyrimidinyl, thienopyrrolyl, and thienothienyl. Representative examples of tricyclic heteroaryl include, but are not limited to, dibenzofuranyl and dibenzothienyl. The monocyclic, bicyclic, and tricyclic heteroaryls are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings. The term “heteroarylalkyl,” as used herein, refers to a heteroaryl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, 1H- imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, 6- chloropyridin-3-ylmethyl, pyridin-4-ylmethyl, (6-(trifluoromethyl)pyridin-3-yl)methyl, (6- (cyano)pyridin-3-yl)methyl, (2-(cyano)pyridin-4-yl)methyl, (5-(cyano)pyridin-2-yl)methyl, (2- (chloro)pyridin-4-yl)methyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl. The term “heteroarylene” refers to an heteroaryl group having a valence of two. The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered Docket No.15250WOO1 ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan- 2-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H- Docket No.15250WOO1 1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa- adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings. The term “heterocycloalkylene” means a divalent heterocycloalkyl group. As used herein, the term “heterocyclylalkyl” refers to a heterocyclyl group, as defined herein, appended to the parent molecular moiety through an alkylene group, as defined herein. Representative examples of heterocyclylalkyl include, but are not limited to, piperidin-4- ylmethyl, piperazin-1-ylmethyl, 3-methyl-1-pyrrolidin-1-ylbutyl, (1R)-3-methyl-1-pyrrolidin-1- ylbutyl, (1S)-3-methyl-1-pyrrolidin-1-ylbutyl, and 3-morpholinopropyl. The term “hydroxy,” as used herein, means an —OH group. The term “hydroxyalkyl,” as used herein, refers to an alkyl group, as defined herein, substituted with at least one hydroxy group. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2,3-dihydroxypentyl, 4-hydroxybutyl, 2-ethyl-4-hydroxyheptyl, 3,4-dihydroxybutyl, and 5- hydroxypentyl. In some instances, the number of carbon atoms in a group (e.g., alkyl, alkoxy, or cycloalkyl) is indicated by the prefix “Cx-Cy-”, wherein x is the minimum and y is the maximum number of carbon atoms in the group. Thus, for example, “C1-C3-alkyl” refers to an alkyl group containing from 1 to 3 carbon atoms. The term “label,” as used herein, refers to any atom or molecule that can be used to provide a detectable and / or quantifiable signal. In some cases, the label can be attached, directly or indirectly, to an antigen or antibody. Suitable labels that can be attached to an antigen or antibody include, but are not limited to, radioisotopes, fluorophores, chromophores, mass labels, electron dense particles, magnetic particles, spin labels, molecules that emit chemiluminescence, electrochemically active molecules, enzymes, cofactors, and enzyme substrates. “Non-point-of-care device” refers to a device that is not a point-of-care device or a single use device. A “point-of-care” device refers to a device used to provide medical diagnostic testing at or near the point-of-care (namely, outside of a laboratory), at the time and place of patient care (such as in a hospital, physician’s office, urgent or other medical care facility, a patient’s home, a nursing home and / or a long-term care and / or hospice facility). A point-of-care Docket No.15250WOO1 instrument does not perform an assay on more than one clinical sample simultaneously. Examples of point-of-care devices include those produced by Abbott Laboratories (Abbott Park, IL) (e.g., I-STAT® and I-STAT ALINITY®, Universal Biosensors (Rowville, Australia) (see U.S. Patent Publication No. 2006 / 0134713), Axis-Shield PoC AS (Oslo, Norway) and Clinical Lab Products (Los Angeles, USA). In some embodiments, the point-of-care device is a single- use device. The term “single-use device” or “single-use instrument” refers to a clinical diagnostic instrument that processes and performs a clinical diagnostic assay on a unit use basis (such as a single-use cartridge) for a single patient sample. A non-point-of-care device refers to any device that does not meet any of the above limitations of a point-of-care or a single use device. In some embodiments, the non-point-of-care device may be a relatively large instrument, such as a tabletop instrument. Accordingly, in some embodiments the non-point-of-care device is not a handheld instrument. In some embodiments, the non-point-of-care device is capable of performing an assay on more than one clinical sample simultaneously. Suitable non-point-of- care devices include, for example, the ALINITY® platform produced by Abbott Laboratories. “Quality control reagents” in the context of immunoassays and kits described herein, include, but are not limited to, calibrator reagents, controls, and sensitivity panels. A “calibrator reagent” or “standard reagent” or “calibrator” typically is used (e.g., one or more, such as a plurality) in order to establish calibration (standard) curves for interpolation of the concentration of an analyte of interest, such as a thyroid hormone. Multiple calibrators (i.e., more than one calibrator or a varying amount of calibrator(s)) can be used in conjunction to comprise a “sensitivity panel.” The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. As used herein, a “reaction vessel” refers to a holder or receiver, such as a container, receptacle, tube, and / or cartridge, in or upon which one or more assays is performed. A “reagent” refers broadly to any agent used in a reaction, other than the calibration analyte of interest or the analyte of interest. Illustrative reagents for immunoassay include, for example, antigens or antibodies specific for an analyte of interest, detection (e.g., labeled) antigens or antibodies, controls, diluents, buffers, and the like. The term “substituent” refers to a group substituted on an atom of the indicated group. Docket No.15250WOO1 When a group or moiety can be substituted, the term “substituted” indicates that one or more (e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2, or 3; and in other embodiments 1 or 2) hydrogens on the group indicated in the expression using “substituted” can be replaced with a selection of recited indicated groups or with a suitable group known to those of skill in the art (e.g., one or more of the groups recited below). Substituent groups include, but are not limited to, halogen, ═O, ═S, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, arylalkyloxy, amino, alkylamino, dialkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, carboxy (—COOH), ketone, amide, carbamate, phosphoryl, selenyl, and acyl. As used herein, the term “test sample” or “sample” generally refers to a biological material being tested for and / or suspected of containing an analyte of interest, such as a thyroid hormone. The test sample may be derived from any biological source, such as, a physiological fluid, including, but not limited to, whole blood, serum, plasma, and so forth. In some embodiments, the sample is a serum sample. In some embodiments, the sample is a plasma sample. In some embodiments, the sample is free of fibrin, red blood cells, and particulate matter. Methods of pretreatment may also involve filtration, precipitation, dilution, distillation, mixing, concentration, inactivation of interfering components, the addition of reagents, lysing, etc. “Solid phase” or “solid support” as used interchangeably herein, refers to any material that can be used to attach and / or attract and immobilize (1) one or more capture reagents or capture specific binding partners, or (2) one or more detection reagents or detection specific binding partners. The solid phase can be chosen for its intrinsic ability to attract and immobilize a capture reagent. Alternatively, the solid phase can have affixed thereto a linking agent that has the ability to attract and immobilize the (1) capture reagent or capture specific binding partner, or (2) detection reagent or detection specific binding partner. For example, the linking agent can include a charged substance that is oppositely charged with respect to the capture reagent (e.g., capture specific binding partner) or detection reagent (e.g., detection specific binding partner) itself or to a charged substance conjugated to the (1) capture reagent or capture specific binding partner or (2) detection reagent or detection specific binding partner. In general, the linking Docket No.15250WOO1 agent can be any binding partner (preferably specific) that is immobilized on (attached to) the solid phase and that has the ability to immobilize the (1) capture reagent or capture specific binding partner, or (2) detection reagent or detection specific binding partner through a binding reaction. The linking agent enables the indirect binding of the capture reagent to a solid phase material before the performance of the assay or during the performance of the assay. For examples, the solid phase can be plastic, derivatized plastic, magnetic, or non-magnetic metal, glass or silicon, including, for example, a test tube, microtiter well, sheet, bead, microparticle, chip, and other configurations known to those of ordinary skill in the art. “Specific binding” or “specifically binding” as used herein may refer to the interaction of an antibody or antibody fragment thereof, a protein, or a peptide (e.g., an antigen) with a second chemical species, wherein the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. “Specific binding partner” is a member of a specific binding pair. A specific binding pair comprises two different molecules, which specifically bind to each other through chemical or physical means. Therefore, in addition to antigen and antibody specific binding pairs of common immunoassays, other specific binding pairs can include biotin and avidin (or streptavidin), carbohydrates and lectins, complementary nucleotide sequences, effector and receptor molecules, cofactors and enzymes, enzymes and enzyme inhibitors, and the like. Furthermore, specific binding pairs can include members that are analogs of the original specific binding members, for example, an analyte-analog. Immunoreactive specific binding members include antigens, antigen fragments, and antibodies, including monoclonal and polyclonal antibodies as well as complexes and fragments thereof, whether isolated or recombinantly produced. “Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal and a human. In some embodiments, the subject may be a human or a non-human. The subject or patient may be undergoing forms of treatment. “Mammal” as used herein refers to any member of the class Mammalia, including, without Docket No.15250WOO1 limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats, llamas, camels, and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats, rabbits, guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term. As used herein, the “sulfonate-containing” compound used as a reactant can comprise a sulfonate salt or a sulfonic acid. As used herein, the “thyroid hormone” as used herein includes L-thyroxine (T4) and / or triiodothyronine (T3), whether total or free. I O HO I Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Docket No.15250WOO1 2. Thyroid Hormone Derivatives and Methods of Synthesizing Same For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. The compounds described herein may exist as stereoisomers wherein asymmetric or chiral centers are present. The stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5thedition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods. It should be understood that the compounds may possess tautomeric forms as well as geometric isomers, and that these also constitute an aspect of the invention. The present disclosure also includes isotopically-labeled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, and iodine, such as, but not limited to,2H,3H,13C,14C,15N,18O,17O,123I,125I and131I, respectively. Substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain advantages resulting from greater metabolic stability, for example increased in vivo half-life, and may therefore be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical Docket No.15250WOO1 imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of Formula (I) are11C,13N, and15O. Isotopically-labeled compounds of Formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent. A compound disclosed herein may be in the form of a salt. The salts may be prepared during the final isolation and purification of the compounds or separately, for example by reacting a basic group of the compound (e.g., an amino group) with a suitable acid or by reacting an acidic group of the compound (e.g., a carboxylic acid group) with a suitable base. Acid salts may be prepared during the final isolation and purification of the compounds or separately by reacting a suitable group of the compound, such as an amino group, with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water, and treated with at least one equivalent of an acid, such hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, Docket No.15250WOO1 procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and N,N′- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. In some aspects, a derivative of a thyroid hormone having the structure of Formula (I) is described: I X O ROO R is H or C1-C6 alkyl; Z is H, C1-C6 alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In some embodiments, Formula (I) is a polyethylene glycol (PEG) derivative of a thyroid hormone. In some embodiments, X is H and Formula (I) is a derivative of T3. In some embodiments, X is I and Formula (I) is a derivative of T4. In some embodiments, R is H. In some other embodiments, R is a C1-C6alkyl. In some embodiments, L is -[CH2CH2O]n-, wherein the terminal carbon of the repeating PEG chain is bonded to the carbonyl carbon in the amide of the thyroid hormone. In some embodiments, Z is H. In some other embodiments, Z is C1-C6 alkyl. In other embodiments, Z is methyl. In some embodiments, when L is - [OCH2CH2]n-, Z cannot be -SO3H. In some embodiments, n is 4-30. In some embodiments, n is 4-10. In some embodiments, n is 10-15. In some embodiments, n is 15-20. In some embodiments, n is 20-25. In some embodiments, n is 25-30. In some embodiments, the thyroid hormone derivative has a structure of formula (IV): I . Docket No.15250WOO1 In some other embodiments, Formula (I) is a sulfophenyl derivative of a thyroid hormone. In some embodiments, X is H and Formula (I) is a derivative of T3. In some embodiments, X is I and Formula (I) is a derivative of T4. In some embodiments, R is H. In some other embodiments, R is a C1-C6alkyl. In some embodiments, Z is -SO3H. In some embodiments, L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene. In some embodiments, L is an arylalkylene. In some embodiments, L has the , wherein the aryl group is in proximity to Z. In some C1-C6alkyl embodiments, L has the , wherein the aryl group is in CH2CH2CH2proximity to Z. In some embodiments, L has the , wherein the aryl group is in proximity to the Z. In some other In some embodiments, L is . In some embodiments, the thyroid hormone derivative has a structure of : I X OHO O; Formulas (II)-(IV), are free of Se or Se isotopes. In some embodiments, Formula (I), and by extension Formulas (II)-(IV), are not biotinylated. In some embodiments, the L group per se of Formula (I) does not comprise an ether group. In some embodiments, the L group per se of Formula (I) does not comprise an ester group. In some embodiments, the L group per se of Formula (I) does not comprise an amine group. In some embodiments, the L group per se of Formula (I) does not comprise an amide Docket No.15250WOO1 group. In some embodiments, the L group per se of Formula (I) does not comprise a thioether group. In some embodiments, the L group per se of Formula (I) does not comprise a urea group. In some embodiments, the L group per se of Formula (I) does not comprise a thiourea group. In some embodiments, the L group per se of Formula (I) does not comprise a carbonate group. In some embodiments, the L group per se of Formula (I) does not comprise a carbamate group. In some embodiments, the L group per se of Formula (I) does not comprise an oxoethyl group. In another aspect, a method of synthesizing a thyroid hormone derivative of formula (I) is described: I X O ROO R is H or C1-C6 alkyl; Z is H or C1-C6 alkyl; and L is -[CH2CH2O]n-, wherein n = 4-30, said method comprising: combining a thyroid hormone, at least one base, at least one solvent, and a polyethylene glycol (PEG) ester to produce a reaction mixture; and isolating and purifying the thyroid hormone derivative of formula (I), wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). In some embodiments, the method further comprises agitating the reaction mixture at room temperature following the combination of reactants. In some embodiments, the PEG ester comprises (PEG)n-N-hydroxysuccinimide ester, wherein n is 4-30. In some embodiments, X is H and Formula (I) is a derivative of T3. In some embodiments, X is I and Formula (I) is a derivative of T4. In some embodiments, R is H. In some other embodiments, R is a C1-C6alkyl. In some embodiments, the terminal carbon of the repeating PEG chain is bonded to the carbonyl carbon in the amide of the thyroid hormone. In some embodiments, Z is H. In some other embodiments, Z is C1-C6alkyl. In other embodiments, Z is methyl. In some embodiments, when L is -[OCH2CH2]n-, Z cannot be -SO3H. In some embodiments, n is 4-30. In some embodiments, n is 4-10. In some embodiments, n is 10- Docket No.15250WOO1 15. In some embodiments, n is 15-20. In some embodiments, n is 20-25. In some embodiments, n is 25-30. In some embodiments, the thyroid hormone derivative has a structure of formula (IV): I X OHO OO . of formula (I) is described: I X O ROO R is H or C1-C6 alkyl; Z is -SO3H; and L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, said method comprising: combining at least one solvent, a sulfonate-containing compound, a coupling agent, and at least one base to produce a reaction mixture; adding a thyroid hormone to an agitated reaction mixture; isolating and purifying the thyroid hormone derivative, wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). In some embodiments, the reaction mixture is agitated at room temperature. In some embodiments, the method further comprises agitating the reaction mixture after addition of the thyroid derivative. In some embodiments, X is H and Formula (I) is a derivative of T3. In some embodiments, X is I and Formula (I) is a derivative of T4. In some embodiments, R is H. In some other embodiments, R is a C1-C6alkyl. In some embodiments, Z is -SO3H. In some embodiments, L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, Docket No.15250WOO1 heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene. In some embodiments, L is an arylalkylene. In some embodiments, L has theC1-C6, wherein the aryl group is in proximity to Z. In some C diments, L has the formula1-C alkyl embo6, wherein the aryl group is in CH2CH2CH2proximity to Z. In some , wherein the aryl group is in proximity to the Z. In some other In some embodiments, L . In some embodiments, the thyroid hormone derivative has a structure of : I X OHO OSO3H ; comprises L. In some embodiments, the sulfonate-containing compound further comprises a carboxylic acid. In some embodiments, the sulfonate-containing compound is 4-(4-sulfophenyl)butanoic acid or 4- sulfobenzoic acid potassium salt. In some embodiments, the coupling reagent includes, but is not limited to, 4-(4- sulfophenyl)butanoic acid, 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TSTU), Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU), dicyclohexyl carbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), diisopropylcarbodiimide (DIC), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(7-Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium Docket No.15250WOO1 tetrafluoroborate (TATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3- yl)uranium tetrafluoroborate (TDBTU), 2-(5-Norborene-2,3-dicarboximido)-1,1,3,3- tetramethyluronium tetrafluoroborate (TNTU), and O-(2-Oxo-1(2H)pyridyl)-N,N,N′,N′- tetramethyluronium tetrafluoroborate (TPTU), Benzotriazole-1-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (BOP), Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), (7-Azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP), 1-Cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino- phosphonium hexafluorophosphate (PyOxim), and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP). In some embodiments, the coupling agent is TSTU. Regardless of the method used, the at least one base includes, but is not limited to, triethylamine, diisopropylmethylamine, diisopropylethylamine, tripropylamine, tributylamine, tetramethylethlenediamine (TMEDA), N,N-diethylisopropylamine, N,N- pentamethyldiethylenetriamine, N,N,N′,N″,N″-pentamethyl diethylenetriamine, pyridine, and 1,8-Diazabicyclo[5.4.0]undec-7-ene. In some embodiments, the at least one base comprises diisopropylethylamine. Regardless of the method used, the at least one solvent includes, but is not limited to, water, methanol, ethanol, isopropanol, butanol, higher alcohols, tetrahydrofuran (THF), N- methylpyrrolidinone (NMP), cyclohexylpyrrolidinone, N-octylpyrrolidinone, N- phenylpyrrolidinone, methyl formate, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetramethylene sulfone (sulfolane), diethyl ether, phenoxy-2-propanol (PPh), propriopheneone, ethyl lactate, ethyl acetate, ethyl benzoate, acetonitrile, acetone, ethylene glycol, propylene glycol, dioxane, butyryl lactone, butylene carbonate, ethylene carbonate, propylene carbonate, dipropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethylene glycol monohexyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether (DPGME), tripropylene glycol methyl ether, dipropylene glycol dimethyl ether, dipropylene glycol ethyl ether, propylene glycol n-propyl ether, dipropylene glycol n- propyl ether (DPGPE), tripropylene glycol n-propyl ether, propylene glycol n-butyl ether, Docket No.15250WOO1 dipropylene glycol n-butyl ether, tripropylene glycol n-butyl ether, propylene glycol phenyl ether, and combinations thereof, branched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, unbranched non-fluorinated ether- linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, branched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, unbranched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, dicarboxylic acids, tricarboxylic acids, and combinations thereof. In some embodiments, the at least one solvent comprises DMSO. Regardless of the method used, in some embodiments, the thyroid hormone derivative is purified using reverse phase high performance liquid chromatography (HPLC). In some embodiments, the purifying comprises a gradient method. In some embodiments, the purified thyroid hormone derivative is lyophilized to dryness. The sulfophenyl and PEG thyroid hormone derivatives are relatively hydrophilic and improve the stability of the thyroid hormone (e.g., T3 and / or T4) in aqueous solution. Advantageously, these thyroid hormone derivatives have long term stability and negligible or no sticking on container surfaces and proteins. 3. Methods, Systems, and Kits for Calibrating a Thyroid Hormone Immunoassay using Thyroid Hormone Derivatives In some aspects, the present disclosure further relates to methods, systems, and kits for calibrating a thyroid hormone immunoassay using the thyroid hormone derivatives described herein. In some embodiments, the present disclosure further relates to stabilized standard solutions comprising a thyroid hormone derivative described herein for the calibration of clinical assays useful in assessing thyroid function, including total T4, free T4, total T3, and free T3. It is well known that an understanding of thyroid function requires the quantitation of at least one of total T4, free T4, total T3, and / or free T3. In carrying out immunoassay procedures for determining concentrations of these thyroid analytes, a common practice is to use calibration solutions, each of which contains accurately predetermined quantities or concentrations of the thyroid analyte to be measured and quantitated. The calibration solutions have known concentrations of the thyroid analyte that are substantially lower and higher than normal. Since the immunoassay procedures are normally designed to analyze serum samples, it Docket No.15250WOO1 is preferred that the calibration solutions be formulated using a matrix that is identical to or bioactively equivalent to serum. In the prior art, human serum has been used as starting material for calibration solutions, however, the techniques used for stripping away endogenous thyroxine are known to produce process artifacts and wide lot-to-lot variations making it difficult to manufacture these solutions reproducibly. An additional disadvantage of calibration solutions containing human serum is that they cannot be stored for longer periods since serum contains many labile components which negatively affect the stability of the product. To overcome the problems known in the prior art, in another aspect, the present disclosure further relates to calibration reagents comprising at least one thyroid hormone derivative described herein, wherein the calibration reagents further comprise a non-serum-based matrix. Because human serum is not used, the problems seen in conventional methods where lot-to-lot variation of serum as a raw material easily leads to variability in performance (stability, reproducibility) is prevented. In some embodiments, the non-serum-based matrix comprises at least one blocking agent, at least one electrolyte, at least one buffering agent, and at least one antimicrobial / antifungal agent. In some embodiments, the non-serum-based matrix further comprises at least one cyclodextrin or cyclodextrin derivative. Blocking agents are routinely used in immunoassays to prevent non-specific adsorption and include, but are not limited to, bovine serum albumin (BSA), skim milk, and gelatin. In some embodiments, the blocking agent comprises BSA. In some embodiments, the concentration of blocking agent is in a range from about 1.0% to 10.0% by weight, or about 1.0 to about 6.0 % by weight or about 2.0 to about 7.0 % by weight or about 3.0 to about 8.0 % by weight or about 4.0 to about 9.0 % by weight or about 5.0 to about 10.0 % by weight. In some embodiments, the non-serum-based matrix comprises at least about 4 wt% BSA. The electrolyte is added to mimic the ionic environment in serum. In some embodiments, the electrolyte is NaCl and the concentration of NaCl is in a range from about 0.80% to 1.0% by weight. In some embodiments, the pH of the non-serum-based matrix is maintained in a range from about 6.0 to about 8.0. In some embodiments, the at least one buffering agent is selected from HEPES (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid), TRIS (2-Amino-2-(hydroxymethyl)propane-1,3-diol), MES (2-morpholinoethanesulfonic acid, monohydrate), and phosphate buffer solution as understood by the person skilled in the art. In some embodiments, the at least one antibacterial / antifungal agent is selected from polymyxin Docket No.15250WOO1 B, polyhexamethylene biguanide, sodium pyrithione, sodium azide, and any combination thereof. In some embodiments, when included, the at least one cyclodextrin or cyclodextrin derivative further stabilizes the non-serum-based matrix and is selected from β-cyclodextrin and γ-cyclodextrin or a cyclodextrin derivative. In some embodiments, the non-serum-based matrix comprises ARCHITECT® calibrator diluent (Abbott Laboratories, Abbott Park, IL), which comprises a buffer containing MES, another salt, a protein blocker and an antimicrobial. The calibrator reagents describe herein can be analyzed in immunoassays in exactly the same manner as thyroid hormones and conventional calibrator reagents of thyroid hormones of the prior art. Immunoassays of thyroid hormones per se are well known and immunoassay kits are commercially available. The calibrator reagents described herein can also be used as calibrator reagents for those commercially available immunoassay kits. Regardless of the immunoassay used, when preparing a calibration curve using the calibrator reagents described herein, a plurality of calibrator reagents comprising the thyroid hormone derivative at different known concentrations are first prepared. The number of the prepared calibrator reagents comprising the thyroid hormone derivative is at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10. In some embodiments, the at least one thyroid hormone derivative has the structure of Formula (I) as described herein, wherein when X is I, the calibration reagent is used for establishing a calibration curve for an immunoassay used for detecting free T4 and / or total T4 in a biological sample. In the case of free T4, several concentrations are predetermined normally in the range of 20 ng / dL or less, particularly in the range of 10 ng / dL or less. In the case of total T4, several concentrations are predetermined normally in the range of 50 µg / dL or less, particularly in the range of 30 µg / dL or less. In some embodiments, the at least one thyroid hormone derivative has the structure of Formula (I) as described herein, wherein when X is H, the calibration reagent is used for establishing a calibration curve for an immunoassay used for detecting free T3 and / or total T3 in a biological sample. In the case of free T3, several concentrations are predetermined normally in the range of 50 pg / mL or less, particularly in the range of 30 pg / mL or less. In the case of total T3, several concentrations are predetermined normally in the range of 15 ng / mL or less, particularly in the range of 8 ng / mL or less. Docket No.15250WOO1 In some embodiments, each of the plurality of calibrator reagents is subjected to an immunoassay, e.g., including, but not limited to, those as described herein, and signals are measured. Next, a calibration curve can be prepared by plotting the concentration of the thyroid hormone derivative in each calibrator reagent along the abscissa and the corresponding measured signal along the ordinate, as well understood to those skilled in the art. In some embodiments, a calibration curve from at least six calibration reagents with different concentrations is used since there is no linear relationship which would allow a two-point standard measurement. Accordingly, in another aspect, a method of calibrating an immunoassay for detection of free thyroxine (T4) and / or total T4 in a biological sample is described, said method comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the thyroid hormone derivative comprises a compound having the structure of formula (I): I X O RO O R is H or C1-C6alkyl; Z is H, C1-C6 alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In another aspect, a method of calibrating an immunoassay for detection of free triiodothyronine (T3) and / or in a biological sample is described, said method comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; Docket No.15250WOO1 subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the thyroid hormone derivative comprises a compound having the structure of formula (I): I X O ROO R is H or C1-C6 alkyl; Z is H, C1-C6 alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In some embodiments, the plurality of calibration reagents comprises 2, 3, 4, 5, 6, 7, 8, 9 or 10 different concentrations of a thyroid hormone derivative. In some embodiments, the plurality of calibration reagents have concentrations in a range from 0.0 to about 20.0 ng / dL for measuring free T4 in a biological sample or about 1.0 to about 50.0 µg / dL for measuring total T4 in a biological sample. In some embodiments, the plurality of calibration reagents have concentrations in a range from 0.0 to about 50 pg / mL for measuring free T3 in a biological sample or about 0.0 to about 15 ng / mL for measuring total T3 in a biological sample. In some embodiments, the non-serum-based matrix comprises at least about 4 wt% BSA. In some embodiments, the calibration reagents are substantially free of serum. In some embodiments, the immunoassay is a competitive immunoassay. In some embodiments, the immunoassay is a competitive two-step immunoassay. In some embodiments, the immunoassay is a chemiluminescent microparticle immunoassay (CMIA). In some embodiments, prior to performing a method of calibrating an immunoassay using the thyroid hormone derivatives described herein, the calibrator reagents are diluted with an appropriate solvent (e.g., a buffer such as PBS buffer). The calibrator reagents may be diluted about 1-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 10-fold, Docket No.15250WOO1 about 100-fold, or greater, prior to use, as understood by the person skilled in the art. In other cases, the fluid sample is not diluted prior to use in an immunoassay. 4. Competitive Immunoassays In a competitive immunoassay, a biological sample suspected of containing an analyte of interest is combined with one or more reagents comprising an analyte of interest labeled with a detectable label (a “competing analyte”), a capture reagent, and a detection reagent to form a reaction mixture. The competing analyte competes with the analyte of interest contained in the biological sample for binding to the capture reagent. The biological sample, competing analyte, capture reagent and detection reagent can be added in any order to form the reaction mixture. In some embodiments, the competing analyte is the same analyte as the analyte of interest or an analog thereof. In yet other embodiments, the capture reagent is immobilized on a solid support. The signal that is derived from the total volume of the reaction mixture of the competitive immunoassay (“competitive immunoassay detectable signal”) can be quantified using routine techniques known in the art. For example, if an enzymatic label is used, the labeled complex that is formed (capture reagent-analyte of interest-detection reagent) is reacted with a substrate for the label that gives a quantifiable reaction such as the development of color, chemiluminescence, fluorescence, or any other forms of light, or current. If the label is a radioactive label, the label is quantified using a scintillation counter. If the label is a fluorescent label, the label is quantified by stimulating the label with a light of one color (which is known as the “excitation wavelength”) and detecting another color (which is known as the “emission wavelength”) that is emitted by the label in response to the stimulation. If the label is a chemiluminescent label, the label is quantified detecting the light emitted either visually or by using luminometers, x-ray film, high speed photographic film, a CCD camera, etc. Any solid support known in the art can be used including but not limited to, solid supports made out of polymeric materials in the forms of wells of a reaction tray, test tubes, particles, or beads (for example, polystyrene beads, magnetic beads), nitrocellulose strips, membranes, microparticles (for example, latex particles, sheep and DURACYTES® (Abbott Laboratories, Abbott Park, IL; DURACYTES® are red blood cells that have been “fixed” by pyruvic aldehyde and formaldehyde)). Docket No.15250WOO1 The solid phase also can comprise any suitable porous material with sufficient porosity to allow access by a detection reagent and a suitable surface affinity to bind the analyte of interest. Microporous structures are generally used, but materials with gel structure in the hydrated state may be used as well. Such useful solid supports include, but are not limited to, nitrocellulose and nylon. Such porous solid supports are in the form of sheets of thickness from about 0.01 to 0.5 mm, including about 0.1 mm. The pore size may vary within wide limits, and can be from about 0.025 to about 15 microns, especially from about 0.15 to about 15 microns. The surface of such supports may be activated by chemical processes which cause covalent linkage of the capture reagent to the support. The irreversible binding of the capture reagent is obtained, however, in general, by adsorption on the porous material by poorly understood hydrophobic forces. The capture reagent can be bound to the solid support or solid phase by adsorption, by covalent bonding using a chemical coupling agent or by other means known in the art, provided that such binding does not interfere with the ability of the capture reagent to bind to the analyte of interest. Alternatively, the capture reagent can be bound with microparticles that have previously coated with streptavidin or biotin (for example, using Power-Bind^-SA-MP streptavidin coated microparticles, available from Seradyn, Indianapolis, Indiana, with a capture reagent that has been biotinylated using means known in the art). Alternatively, the capture reagent can be bound using microparticles that have been previously coated with anti-species specific monoclonal antibodies. Moreover, if necessary, the solid support can be derivatized to allow reactivity with various functional groups on the capture reagent. Such derivatization requires the use of certain coupling agents such as, but not limited to, maleic anhydride, N- hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The analyte of interest or analog thereof used as the competing analyte and the antigen or antibody or antibody fragment thereof used in detection reagent each comprise at least one detectable label. Any detectable label known in the art can be used. For example, the detectable label can be a radioactive label, such as,3H,125I,35S,14C,32P,33P, an enzymatic label, such as horseradish peroxidase, alkaline phosphatase, glucose 6-phosphate dehydrogenase, etc., a chemiluminescent label, such as, acridinium (e.g., acridium esters, acridinium SPSP (N10-(3- sulfopropyl)-N-(3-sulfopropyl, etc.), luminol, isoluminol, thioesters, sulfonamides, phenanthridinium esters, etc. a fluorescence label, such as, fluorescein (5-fluorescein, 6- Docket No.15250WOO1 carboxyfluorescein, 3’6-carboxyfluorescein, 5(6)-carboxyfluorescein, 6-hexachloro-fluorescein, 6-tetrachlorofluorescein, fluorescein isothiocyanate, etc.), rhodamine, phycobiliproteins, R- phycoerythrin, quantum dots (zinc sulfide-capped cadmium selenide), a thermometric label or an immuno-polymerase chain reaction label. An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Noorden, Introduction to Immunocytochemistry, 2nded., Springer Verlag, N.Y. (1997) and in Haugland, Handbook of Fluorescent Probes and Research Chemicals (1996), which is a combined handbook and catalogue published by Molecular Probes, Inc., Eugene, Oregon. The detectable label can be bound to the analyte of interest used in the competing analyte or to the antigen or antibody or antibody fragment thereof in the detection reagent either directly or through a coupling agent. An example of a coupling agent that can be used is EDAC (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, hydrochloride) that is commercially available from Sigma-Aldrich, St. Louis, MO. Other coupling agents that can be used are known in the art. Methods for binding a detectable label to an antibody are known in the art. Additionally, many detectable labels can be purchased or synthesized that already contain end groups that facilitate the coupling of the detectable label to the antibody, such as, N10-(3-sulfopropyl)-N-(3- carboxypropyl)-acridinium-9-carboxamide, otherwise known as CPSP-Acridinium Ester or N10- (3-sulfopropyl)-N-(3-sulfopropyl)-acridinium-9-carboxamide, otherwise known as SPSP- Acridinium Ester. Immunoassays of thyroid hormones per se are well known. In some embodiments, for example, for the quantification of free T3, 3,5-diiodo-L-thyronine (T2)-coupled particles composed of carrier particles coupled with T2, a sample containing free T3, and a labeled anti- T3 monoclonal antibody are allowed to react; the particles are recovered; and then the labeled anti-T3 monoclonal antibody bound to the particles is measured to successfully quantify free T3 in the sample. In some embodiments, the carrier particles are magnetic particles to easily conduct bound / free (B / F) separation, but the carrier particles are not limited to same. In some embodiments, the label is enzyme label in immunoassays, such as alkaline phosphatase. In some embodiments, a substrate such as a chemiluminescence substrate or coloring substrate widely used in immunoassays may be used. In some embodiments, for example, for the quantification of free T4, T3-coupled particles, a sample containing free T4, and a labeled anti-T4 monoclonal antibody are allowed to react, and the labeled anti-T4 monoclonal antibody bound to the particles Docket No.15250WOO1 is measured to successfully quantify free T4 in the sample. It should be noted that although these methods are competitive assays based on the competition between the thyroid hormone coupled to particles and the thyroid hormone in the sample, the immunoassays are not limited to competitive assays, and other immunoassays such as sandwich assays and agglutination assays may also be used. In some other embodiments, the immunoassay of thyroid hormones is a chemiluminescent microparticle immunoassay (CMIA) as determined on the ALINITY® I analyzer (Abbott Laboratories, Abbott Park, IL). Briefly, this assay is a two-step immunoassay for the quantitative determination of total T4 in human serum and plasma using CMIA. In some embodiments, a sample and anti-T4 coated paramagnetic microparticles are combined and incubated. In some embodiments, bound T4 is removed from the binding sites on thyroxine binding globulin, prealbumin and albumin. The T4 present in the sample binds to the anti-T4 coated microparticles. The mixture is washed and T3 acridinium-labeled conjugate is added to create a reaction mixture, followed by additional incubation. Following a wash cycle, Pre- Trigger and Trigger Solutions are added. In some embodiments, the Pre-Trigger solution comprises hydrogen peroxide, nitric acid, and a non-ionic surfactant, e.g., TRITON™ X-100 or TERGITOL™. In some embodiments, the Trigger solution comprises sodium hydroxide and a non-ionic surfactant, e.g., TRITON™ X-100 or TERGITOL™. The resulting chemiluminescent reaction is measured as relative light units (RLUs), wherein there is an inverse relationship between the amount of total T4 in the sample and the RLUs detected by the system optics. The methods of the present disclosure involve obtaining a calibration curve for an analyte of interest using the calibration analyte of interest. The calibration curve can be generated using routine techniques known in the art. Typically, calibration curves are generated using varying concentrations or serial dilutions of calibrator reagents. In some embodiments, the calibration curve is generated by performing a competitive immunoassay on the calibration analyte of interest as described herein. By varying the concentrations of the calibration analyte of interest and repeating the immunoassay as many times as necessary (e.g., 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times) a calibration curve is generated using the signal ratios for each concentration of calibration analyte of interest. Once a calibration curve is obtained, the person of skill in the art understands how to use same to Docket No.15250WOO1 determine the concentration of the analyte of interest in a biological sample using the immunoassay. In some embodiments, the calibration curves are stored on instruments that are further used to quantitate the analyte of interest in biological samples, including non-point-of-care devices (e.g. the ALINITY® platform marketed by Abbott Laboratories) or point-of-care devices (such as the I-STAT® Abbott Point of Care devices). In some embodiments, the instrument contains software to execute one or more tasks. In some embodiments, the instrument contains software to automatically determine the next appropriate step in a method as described herein. For example, the instrument may contain software that determines the amount or level of an analyte of interest in a biological sample using the calibration curve. The software may display this determination, such as on a graphical user interface. In some embodiments, the instrument stores software that instructs a processor to execute a given task. In some embodiments, the software stores machine readable instructions that instruct a processor to execute a given task. The machine-readable instructions may be one or more executable programs or portion(s) of an executable program for execution by a computer. The programs may be embodied in software stored on a non-transitory computer readable storage medium such as a CD-ROM, a floppy disk, a hard drive, a DVD, a Blu-ray disk, or a memory associated with the processors. Alternatively, the entire programs and / or parts thereof could alternatively be executed by a device other than the processors and / or embodied in firmware or dedicated hardware. Additionally or alternatively, processes may be implemented by one or more hardware circuits (e.g., discrete and / or integrated analog and / or digital circuitry, an FPGA, an ASIC, a comparator, an operational-amplifier (op-amp), a logic circuit, etc.) structured to perform the corresponding operation without executing software or firmware. The machine-readable instructions may be stored in one or more of a compressed format, an encrypted format, a fragmented format, a compiled format, an executable format, a packaged format, etc. Machine readable instructions as described herein may be stored as data (e.g., portions of instructions, code, representations of code, etc.) that may be utilized to create, manufacture, and / or produce machine executable instructions. For example, the machine- readable instructions may be fragmented and stored on one or more storage devices and / or computing devices (e.g., servers). The machine-readable instructions may require one or more Docket No.15250WOO1 of installation, modification, adaptation, updating, combining, supplementing, configuring, decryption, decompression, unpacking, distribution, reassignment, compilation, etc. in order to make them directly readable, interpretable, and / or executable by a computing device and / or other machine. For example, the machine-readable instructions may be stored in multiple parts, which are individually compressed, encrypted, and stored on separate computing devices, wherein the parts when decrypted, decompressed, and combined form a set of executable instructions that implement a program such as that described herein. In another example, the machine-readable instructions may be stored in a state in which they may be read by a computer, but require addition of a library (e.g., a dynamic link library (DLL)), a software development kit (SDK), an application programming interface (API), etc. in order to execute the instructions on a particular computing device or other device. In another example, the machine-readable instructions may need to be configured (e.g., settings stored, data input, network addresses recorded, etc.) before the machine-readable instructions and / or the corresponding program(s) can be executed in whole or in part. Thus, the disclosed machine-readable instructions and / or corresponding program(s) are intended to encompass such machine-readable instructions and / or program(s) regardless of the particular format or state of the machine readable instructions and / or program(s) when stored or otherwise at rest or in transit. The machine-readable instructions described herein can be represented by any past, present, or future instruction language, scripting language, programming language, etc. For example, the machine-readable instructions may be represented using any of the following languages: C, C++, Java, C#, Perl, Python, JavaScript, HyperText Markup Language (HTML), Structured Query Language (SQL), Swift, etc. The machine-readable instructions may be stored on a non-transitory computer and / or machine readable medium such as a hard disk drive, a flash memory, a read-only memory, a compact disk, a digital versatile disk, a cache, a random-access memory and / or any other storage device or storage disk in which information is stored for any duration (e.g., for extended time periods, permanently, for brief instances, for temporarily buffering, and / or for caching of the information). As used herein, the term non-transitory computer readable medium is expressly defined to include any type of computer readable storage device and / or storage disk and to exclude propagating signals and to exclude transmission media. Docket No.15250WOO1 5. Kits and Systems In some embodiments, the present disclosure further provides kits and systems for calibrating a thyroid hormone immunoassay using the thyroid hormone derivatives described herein. In some embodiments, the kits or systems find use in multiplex and / or automated analysis methods. Exemplary reagents include, but are not limited to, antigens, antibodies, colorimetric reagents, enzymes, buffers, etc. In some aspects, an immunoassay kit for detection of free thyroxine (T4) and / or total T4 in a biological sample is described, said kit comprising at least one calibration reagent comprising a thyroid hormone derivative having the structure of formula (I): I X O RO O R is H or C1-C6alkyl; Z is H, C1-C6alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In some embodiments, the kit further comprises antibody specific for T4. In some other aspects, an immunoassay kit for detection of free triiodothyronine (T3) and / or total T3 in a biological sample is described, said kit comprising at least one calibration reagent comprising a thyroid hormone derivative having the structure of formula (I): I R is H or C1-C6 alkyl; Z is H, C1-C6 alkyl, or -SO3H; and Docket No.15250WOO1 L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. In some embodiments, the kit further comprises an antibody specific for T3. In some embodiments, the assays, kits and kit components of the disclosure are optimized for use on commercial platforms (e.g., immunoassays on the PRISM®, AxSYM®, ARCHITECT® and EIA (Bead) platforms of Abbott Laboratories, Abbott Park, IL, as well as other commercial and / or in vitro diagnostic assays). The kits can optionally include other reagents required to conduct a diagnostic assay or facilitate quality control evaluations, such as buffers, salts, enzymes, enzyme co-factors, substrates, detection reagents, and the like. Other components, such as buffers and solutions for the isolation and / or treatment of a test sample (e.g., pretreatment reagents), may also be included in the kit. The kit may additionally include one or more controls. One or more of the components of the kit may be lyophilized and the kit may further comprise reagents suitable for the reconstitution of the lyophilized components. The various components of the kit optionally are provided in suitable containers. As indicated above, one or more of the containers may be a microtiter plate. The kit further can include containers for holding or storing a sample (e.g., a container or cartridge for a blood or urine sample). Where appropriate, the kit may also optionally contain reaction vessels, mixing vessels and other components that facilitate the preparation of reagents or the test sample. The kit may also include one or more instruments for assisting with obtaining a test sample, such as a syringe, pipette, forceps, measured spoon, or the like. The kit further can optionally include instructions for use, which may be provided in paper form or in computer-readable form, such as a disc, CD, DVD or the like. The disclosure as described herein also can be adapted for use in a variety of automated and semi-automated systems (including those wherein the solid phase comprises a microparticle), as described, e.g., in U.S. Patent Nos. 5,089,424 and 5,006,309, and as, e.g., commercially marketed by Abbott Laboratories (Abbott Park, IL) including but not limited to Abbott’s ARCHITECT®, AxSYM®, IMX, PRISM®, and Quantum II instruments, as well as other platforms. Docket No.15250WOO1 All patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising,” “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, it should be understood that although the present disclosure includes various embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims. EXAMPLES Example 1. Synthesis of L-thyroxine polyethylene glycol (PEG12) derivative (T4-PEG12)

[0002] Docket No.15250WOO1 I O HO I OH NH2OH I ester were dissolved in 1.5 mL of dimethylsulfoxide. To this was added 0.05 mL of diisopropylethylamine (DiEA). The reaction was stirred for 4 hours before being diluted with 2 mL of 1:1 water:acetonitrile (ACN). The entire solution was purified by reverse phase HPLC on a YMC ODS AQ 50 x 250 mm I.D. steel column with a Waters Separation 200 system. Absorbance @ 254 nm. Recorder chart speed 5 mm / min. A manual step gradient method (flow rate 70 mL / min) was used with a mobile phase of ACN / H2O / H2O with 0.5% trifluoroacetic acid (TFA). Fractions containing product were collected and lyophilized to dryness. Yield – 30 mg clear tacky oil MS (ESI): m / z 1348.52 (M+H)+ Example 2. Synthesis of a L-thyroxine (T4)-sulfophenyl derivative (T4-sulfophenyl-1) Docket No.15250WOO1 SO H O3HO 3H was mg dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TSTU) and the reaction was stirred for 1 hour. Next, 15 mg of L-thyroxine (T4) was added to the reaction mixture and was stirred for an additional 6 hours before diluting with a 1:1 mixture of water:ACN. The entire reaction mixture purified by reverse phase HPLC on a YMC ODS AQ 50 x 250 mm I.D. steel column with a Waters Separation 200 system. Absorbance @ 254 nm. Recorder chart speed 5 mm / min. A manual step gradient method (flow rate 70 mL / min) was used with a mobile phase of ACN / H2O / H2O with 0.5% TFA. Fractions containing product were collected and lyophilized to dryness. Yield - 8 mg white powder MS (ESI): m / z 1004.17 (M+H)+ Example 3. Synthesis of L-thyroxine (T4)-sulfophenyl derivative (T4-sulfophenyl-2) IO OHI I ONaO O IOHO O dimethylaminopropyl)carbodiimide (EDCI) were dissolved in 0.5 mL of dimethylsulfoxide and stirred for 15 minutes. Next, 80 mg of thyroxine sodium was added, followed by 0.5 mL of pyridine, and the reaction stirred for 1 hour. The product was precipitated from solution by adding 2.5 mL of acetonitrile and 2.5 mL of methyl tert-butyl ether. The precipitate as collected by vacuum filtration and the solid dissolved in 1:1 water:acetonitrile. The crude product was Docket No.15250WOO1 purified by reverse phase HPLC on a YMC ODS AQ 50 x 250 mm I.D. steel column with a Waters Separation 200 system. Absorbance @ 254 nm. Recorder chart speed 5 mm / min. A manual step gradient method (flow rate 70 mL / min) was used with a mobile phase of ACN / H2O / H2O with 0.5% formic acid. Fractions containing product were collected and lyophilized to dryness. Yield – 15 mg white powder MS (ESI): m / z 961.91 (M+H)+ Example 4. The T4-sulfophenyl-1 and T4-PEG12 derivatives described herein are relatively hydrophilic and have improved long-term stability in aqueous solution, which prevented sticking to container surfaces and proteins, as described herein. The long-term stability of the thyroid hormone derivatives described herein was tested. The T4-sulfophenyl-1 and T4-PEG12 derivatives were found to have greater than or equal to long- term stability compared to the certified reference material (CRM) T4. Long term stability for free T4 indicates that the T4-PEG12 derivative is stable across a variety of formulations and pH conditions, with improved stability over T4 in four categories (FIG. 1). T4-sulfophenyl-1 had similar stability characteristics to the T4 in the free T4 assay (FIG. 1). Based on the long-term stability data, it is speculated that the T4 derivatives described herein provide a diversified set of molecules that can be used as immunoassay-based diagnostic tool for detection of free and total T4. For example, one week testing using a Total T4 immunoassay indicated that the T4-sulfophenyl-1 derivative in calibrator diluent containing 4% BSA performs analogous to the serum-based calibrators (FIG. 1). The T4 derivative molecules exhibited long term stability in non-serum based artificial matrix. Thyroxine was found to be stable only in human serum based matrices, whereas the T4-PEG12 and T4-sulfophenyl-1 derivatives displayed better stability for long periods of time in the various container types and matrix formulations. This is relevant since the methods described herein use these derivatives as alternative molecules that perform equally, if not better, than T4 as calibrators in non-serum-based matrices containing at least 4% BSA for free and total T4 assays. Concerns of free and total T4 sticking to surfaces were also addressed in the long-term stability study using glass, and ALINITY® (Abbott) and ARCHITECT® (Abbott) commodity Docket No.15250WOO1 containers. The studies were carried out on the ARCHITECT® instrument. Results showed that at both at 2–8°C and 37°C, the surface properties of the containers were determined to not affect assay signal. Advantageously, the T4 derivatives described herein were capable of being stable for long periods in various commodities ubiquitously used in diagnostics, with no significant impact to signal. Table 1. 15-day stability of T4 derivatives in glass, ALINITY®, and ARCHITECT® containers. Difference in relative light units (RLUs) from 2-8°C to 37°C 5 For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses: Clause 1. A derivative of a thyroid hormone having the structure of Formula (I): Docket No.15250WOO1 wherein X is R is H or C1-C6alkyl; Z is H, C1-C6alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30. Clause 2. The derivative of clause 1, wherein R is H. Clause 3. The derivative of clause 1, wherein R is a C1-C6 alkyl. Clause 4. The derivative of any of clauses 1 or 3, wherein L is -[CH2CH2O]n-. Clause 5. The derivative of clause 4, wherein Z is H. Clause 6. The derivative of clause 4, wherein Z is C1-C6 alkyl. Clause 7. The derivative of clause 4, wherein Z is methyl. Clause 8. The derivative of any of clauses 4 to 7, wherein n is 4-30, preferably 10-15. Clause 9. The derivative of any of clauses 1 or 3, wherein L is an arylalkylene. Clause 10. The derivative of clause 9, wherein Z is -SO3H. Clause 11. The derivative of any of clauses 1 or 3, wherein L is an arylene. Clause 12. The derivative of clause 11, wherein Z is -SO3H. Clause 13. The derivative of clause 1, having the structure of Formula (II): . Docket No.15250WOO1 Clause 14. The derivative of clause 1, having the structure of Formula (III): . Clause of Formula (IV): . Clause 16. The derivative of any of clauses 1 to 15, wherein X is H. Clause 17. The derivative of any of clauses 1 to 15, wherein X is I. Clause 18. A calibration reagent for an immunoassay used for detecting free thyroxine (T4) and / or total T4 in a biological sample, said calibration reagent comprising the thyroid hormone derivative any of clauses 1 to 15, wherein X is I. Clause 19. A calibration reagent for an immunoassay used for detecting free triiodothyronine (T3) and / or total T3 in a biological sample, said calibration reagent comprising the thyroid hormone derivative any of clauses 1 to 15, wherein X is H. Clause 20. A method of calibrating an immunoassay for detection of free thyroxine (T4) and / or total T4 in a biological sample, said method comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, Docket No.15250WOO1 wherein the calibration reagent comprises the thyroid hormone derivative any of clauses 1 to 15, wherein X is I. Clause 21. A method of calibrating an immunoassay for detection of free triiodothyronine (T3) and / or total T3 in a biological sample comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the calibration reagent comprises the derivative any of clauses 1 to 15, wherein X is H. Clause 22. The method of clauses 20 or 21, wherein the plurality of different dilutions of the calibration reagent comprises 2, 3, 4, 5, 6, 7, or 8 different dilutions. Clause 23. The method of any of clauses 20 to 22, wherein the plurality of different dilutions of the calibration reagent comprise calibration reagent having concentrations in a range from 0.0 to about 20.0 ng / dL for measurement of free T4 or about 1.0 to about 50.0 µg / dL for measurement of total T4. Clause 24. The method of any of clauses 20 to 23, wherein the plurality of different dilutions of the calibration reagent comprise at least about 4 wt% bovine serum albumin (BSA). Clause 25. The method of any of clauses 20 to 24, wherein the plurality of different dilutions of the calibration reagent are substantially free of serum. Clause 26. An immunoassay kit for detection of free thyroxine (T4) and / or total T4 in a biological sample, said kit comprising at least two calibration reagents comprising the thyroid hormone derivative any of clauses 1 to 15, wherein X is I. Clause 27. An immunoassay kit for detection of free triiodothyronine (T3) and / or total T3 in a biological sample, said kit comprising at least two calibration reagents comprising the thyroid hormone derivative any of clauses 1 to 15, wherein X is H. Clause 28. The kit of clauses 26 or 27, wherein the at least two calibration reagents have different concentrations of the thyroid hormone derivative in a non-serum based matrix. Clause 29. The kit of clauses 26 or 28, further comprising an antibody specific for T4. Docket No.15250WOO1 Clause 30. The kit of clauses 27 or 28, further comprising an antibody specific for T3. Clause 31. A method of synthesizing a thyroid hormone derivative of formula (I): wherein X is R is H or C1-C6 alkyl; Z is H or C1-C6alkyl; and L is -[CH2CH2O]n-, wherein n = 4-30, said method comprising: combining a thyroid hormone, at least one base, at least one solvent, and a polyethylene glycol (PEG) ester to produce a reaction mixture; and isolating and purifying the thyroid hormone derivative of formula (I), wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). Clause 32. The method of clause 31, further comprising agitating the reaction mixture at room temperature following the combination of reactants. Clause 33. The method of clauses 31 or 32, wherein the at least one base is selected from triethylamine, diisopropylmethylamine, diisopropylethylamine, tripropylamine, tributylamine, tetramethylethlenediamine (TMEDA), N,N-diethylisopropylamine, N,N- pentamethyldiethylenetriamine, N,N,N′,N″,N″-pentamethyl diethylenetriamine, pyridine, and 1,8-Diazabicyclo[5.4.0]undec-7-ene, preferably diisopropylethylamine. Clause 34. The method of any of clauses 31 to 33, wherein the at least one solvent comprises at least one species selected from water, methanol, ethanol, isopropanol, butanol, higher alcohols, tetrahydrofuran (THF), N-methylpyrrolidinone (NMP), cyclohexylpyrrolidinone, N-octylpyrrolidinone, N-phenylpyrrolidinone, methyl formate, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetramethylene sulfone (sulfolane), diethyl ether, phenoxy-2-propanol (PPh), propriopheneone, ethyl lactate, ethyl acetate, ethyl Docket No.15250WOO1 benzoate, acetonitrile, acetone, ethylene glycol, propylene glycol, dioxane, butyryl lactone, butylene carbonate, ethylene carbonate, propylene carbonate, dipropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethylene glycol monohexyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether (DPGME), tripropylene glycol methyl ether, dipropylene glycol dimethyl ether, dipropylene glycol ethyl ether, propylene glycol n-propyl ether, dipropylene glycol n-propyl ether (DPGPE), tripropylene glycol n-propyl ether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether, tripropylene glycol n- butyl ether, propylene glycol phenyl ether, and combinations thereof, branched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, unbranched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, branched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, unbranched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, dicarboxylic acids, tricarboxylic acids, and combinations thereof, preferably DMSO. Clause 35. The method of any of clauses 31 to 34, wherein the PEG ester comprises (PEG)n-N-hydroxysuccinimide ester, wherein n is 4-30. Clause 36. The method of any of clauses 31 to 35, wherein the thyroid hormone derivative is purified using reverse phase high performance liquid chromatography (HPLC). Clause 37. The method of clause 36, wherein the purifying comprises a gradient method. Clause 38. The method of any of clauses 31 to 37, wherein the purified thyroid hormone derivative is lyophilized to dryness. Clause 39. The method of any of clauses 31 to 38, wherein R is H. Clause 40. The method of any of clauses 31 to 39, wherein Z is methyl. Clause 41. The method of any of clauses 31 to 40, wherein n is 12. Clause 42. The method of any of clauses 31 to 41, wherein the thyroid hormone derivative has the structure of Formula (IV): Docket No.15250WOO1 . Clause 44. The method of any of clauses 31 to 42, wherein X is I. Clause 45. A method of synthesizing a thyroid hormone derivative of formula (I): wherein X is R is H or C1-C6 alkyl; Z is -SO3H; and L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, said method comprising: combining at least one solvent, at least one sulfonate-containing compound, a coupling agent, and at least one base to produce a reaction mixture; adding a thyroid hormone to an agitated reaction mixture; isolating and purifying the thyroid hormone derivative, wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4). Clause 46. The method of clause 45, wherein the reaction mixture is agitated at room temperature. Clause 47. The method of clauses 45 or 46, wherein the at least one solvent comprises at least one species selected from water, methanol, ethanol, isopropanol, butanol, higher alcohols, tetrahydrofuran (THF), N-methylpyrrolidinone (NMP), cyclohexylpyrrolidinone, N- Docket No.15250WOO1 octylpyrrolidinone, N-phenylpyrrolidinone, methyl formate, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetramethylene sulfone (sulfolane), diethyl ether, phenoxy-2- propanol (PPh), propriopheneone, ethyl lactate, ethyl acetate, ethyl benzoate, acetonitrile, acetone, ethylene glycol, propylene glycol, dioxane, butyryl lactone, butylene carbonate, ethylene carbonate, propylene carbonate, dipropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethylene glycol monohexyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether (DPGME), tripropylene glycol methyl ether, dipropylene glycol dimethyl ether, dipropylene glycol ethyl ether, propylene glycol n-propyl ether, dipropylene glycol n-propyl ether (DPGPE), tripropylene glycol n-propyl ether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether, tripropylene glycol n-butyl ether, propylene glycol phenyl ether, and combinations thereof, branched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, unbranched non-fluorinated ether- linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, branched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, unbranched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, dicarboxylic acids, tricarboxylic acids, and combinations thereof, preferably DMSO. Clause 48. The method of any of clauses 45 to 47, wherein the coupling reagent comprises at least one species selected from 4-(4-sulfophenyl)butanoic acid, 2-(2,5- dioxopyrrolidin-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TSTU), Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU), dicyclohexyl carbodiimide (DCC), 1-Ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDCI), diisopropylcarbodiimide (DIC), O-(1H-6- Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(7- Azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), N,N,N',N'- Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), 2-(5-Norborene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), and O-(2-Oxo-1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU), Docket No.15250WOO1 Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), (7- Azabenzotriazol-1-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP), 1-Cyano- 2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), preferably TSTU. Clause 49. The method of any of clauses 45 to 48, wherein the at least one base is selected from triethylamine, diisopropylmethylamine, diisopropylethylamine, tripropylamine, tributylamine, tetramethylethlenediamine (TMEDA), N,N-diethylisopropylamine, N,N- pentamethyldiethylenetriamine, N,N,N′,N″,N″-pentamethyl diethylenetriamine, pyridine, and 1,8-Diazabicyclo[5.4.0]undec-7-ene, preferably diisopropylethylamine. Clause 50. The method of any of clauses 45 to 49, wherein the sulfonate-containing compound comprises L. Clause 51. The method of any of clauses 45 to 50, wherein the sulfonate-containing compound comprises 4-(4-sulfophenyl)butanoic acid or 4-sulfobenzoic acid potassium salt. Clause 52. The method of any of clauses 45 to 51, further comprising agitating the reaction mixture after addition of the thyroid derivative. Clause 53. The method of any of clauses 45 to 52, wherein the thyroid hormone derivative is purified using reverse phase high performance liquid chromatography (HPLC). Clause 54. The method of clause 53, wherein the purifying comprises a gradient method. Clause 55. The method of any of clauses 45 to 54, wherein the purified thyroid hormone derivative is lyophilized to dryness. Clause 56. The method of any of clauses 45 to 55, wherein R is H. Clause 57. The method of any of clauses 45 to 56, wherein L is an arylalkylene. Clause 58. The method of any of clauses 45 to 56, wherein L is an arylene. Clause 59. The method of any of clauses 45 to 56, wherein the thyroid hormone derivative has the structure of Formula (II) or Formula (III): Docket No.15250WOO1 . thyroid hormone derivative has the structure of Formula (III): . Clause X is H. Clause 62. The method of any of clauses 45 to 60, wherein X is I.

Claims

Docket No.15250WOO1 CLAIMS What is claimed is:

1. A derivative of a thyroid hormone having the structure of Formula (I): wherein X isR is H or C1-C6alkyl; Z is H, C1-C6alkyl, or -SO3H; and L is selected from -[CH2CH2O]n-, alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, and wherein n = 4-30.

2. The derivative of claim 1, wherein R is H.

3. The derivative of claim 1, wherein R is a C1-C6 alkyl.

4. The derivative of any of claims 1 or 3, wherein L is -[CH2CH2O]n-.

5. The derivative of claim 4, wherein Z is H.

6. The derivative of claim 4, wherein Z is C1-C6 alkyl.

7. The derivative of claim 4, wherein Z is methyl.

8. The derivative of any of claims 4 to 7, wherein n is 4-30, preferably 10-15.

9. The derivative of any of claims 1 or 3, wherein L is an arylalkylene.

10. The derivative of claim 9, wherein Z is -SO3H.

11. The derivative of any of claims 1 or 3, wherein L is an arylene.

12. The derivative of claim 11, wherein Z is -SO3H.

13. The derivative of claim 1, having the structure of Formula (II):Docket No.15250WOO1 .

14. The.

15. The: .

16. The derivative of any of claims 1 to 15, wherein X is H.

17. The derivative of any of claims 1 to 15, wherein X is I.

18. A calibration reagent for an immunoassay used for detecting free thyroxine (T4) and / or total T4 in a biological sample, said calibration reagent comprising the thyroid hormone derivative any of claims 1 to 15, wherein X is I.

19. A calibration reagent for an immunoassay used for detecting free triiodothyronine (T3) and / or total T3 in a biological sample, said calibration reagent comprising the thyroid hormone derivative any of claims 1 to 15, wherein X is H.

20. A method of calibrating an immunoassay for detection of free thyroxine (T4) and / or total T4 in a biological sample, said method comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix;Docket No.15250WOO1 subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the calibration reagent comprises the thyroid hormone derivative any of claims 1 to 15, wherein X is I.

21. A method of calibrating an immunoassay for detection of free triiodothyronine (T3) and / or total T3 in a biological sample comprising: preparing a plurality of calibration reagents having different concentrations of a thyroid hormone derivative in a non-serum based matrix; subjecting each calibration reagent to an immunoassay to prepare a calibration curve based on a relationship between a concentration of the thyroid hormone derivative contained in each calibration reagent and a signal in the immunoassay, wherein the calibration reagent comprises the derivative any of claims 1 to 15, wherein X is H.

22. The method of claims 20 or 21, wherein the plurality of different dilutions of the calibration reagent comprises 2, 3, 4, 5, 6, 7, or 8 different dilutions.

23. The method of any of claims 20 to 22, wherein the plurality of different dilutions of the calibration reagent comprise calibration reagent having concentrations in a range from 0.0 to about 20.0 ng / dL for measurement of free T4 or about 1.0 to about 50.0 µg / dL for measurement of total T4.

24. The method of any of claims 20 to 23, wherein the plurality of different dilutions of the calibration reagent comprise at least about 4 wt% bovine serum albumin (BSA).

25. The method of any of claims 20 to 24, wherein the plurality of different dilutions of the calibration reagent are substantially free of serum.

26. An immunoassay kit for detection of free thyroxine (T4) and / or total T4 in a biological sample, said kit comprising at least two calibration reagents comprising the thyroid hormone derivative any of claims 1 to 15, wherein X is I.

27. An immunoassay kit for detection of free triiodothyronine (T3) and / or total T3 in a biological sample, said kit comprising at least two calibration reagents comprising the thyroid hormone derivative any of claims 1 to 15, wherein X is H.Docket No.15250WOO1 28. The kit of claims 26 or 27, wherein the at least two calibration reagents have different concentrations of the thyroid hormone derivative in a non-serum based matrix.

29. The kit of claims 26 or 28, further comprising an antibody specific for T4.

30. The kit of claims 27 or 28, further comprising an antibody specific for T3.

31. A method of synthesizing a thyroid hormone derivative of formula (I): wherein X isR is H or C1-C6 alkyl; Z is H or C1-C6 alkyl; and L is -[CH2CH2O]n-, wherein n = 4-30, said method comprising: combining a thyroid hormone, at least one base, at least one solvent, and a polyethylene glycol (PEG) ester to produce a reaction mixture; and isolating and purifying the thyroid hormone derivative of formula (I), wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4).

32. The method of claim 31, further comprising agitating the reaction mixture at room temperature following the combination of reactants.

33. The method of claims 31 or 32, wherein the at least one base is selected from triethylamine, diisopropylmethylamine, diisopropylethylamine, tripropylamine, tributylamine, tetramethylethlenediamine (TMEDA), N,N-diethylisopropylamine, N,N- pentamethyldiethylenetriamine, N,N,N′,N″,N″-pentamethyl diethylenetriamine, pyridine, and 1,8-Diazabicyclo[5.4.0]undec-7-ene, preferably diisopropylethylamine.

34. The method of any of claims 31 to 33, wherein the at least one solvent comprises at least one species selected from water, methanol, ethanol, isopropanol, butanol, higher alcohols, tetrahydrofuran (THF), N-methylpyrrolidinone (NMP), cyclohexylpyrrolidinone, N-Docket No.15250WOO1 octylpyrrolidinone, N-phenylpyrrolidinone, methyl formate, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetramethylene sulfone (sulfolane), diethyl ether, phenoxy-2- propanol (PPh), propriopheneone, ethyl lactate, ethyl acetate, ethyl benzoate, acetonitrile, acetone, ethylene glycol, propylene glycol, dioxane, butyryl lactone, butylene carbonate, ethylene carbonate, propylene carbonate, dipropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethylene glycol monohexyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether (DPGME), tripropylene glycol methyl ether, dipropylene glycol dimethyl ether, dipropylene glycol ethyl ether, propylene glycol n-propyl ether, dipropylene glycol n-propyl ether (DPGPE), tripropylene glycol n-propyl ether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether, tripropylene glycol n-butyl ether, propylene glycol phenyl ether, and combinations thereof, branched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, unbranched non-fluorinated ether- linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, branched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, unbranched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, dicarboxylic acids, tricarboxylic acids, and combinations thereof, preferably DMSO.

35. The method of any of claims 31 to 34, wherein the PEG ester comprises (PEG)n-N- hydroxysuccinimide ester, wherein n is 4-30.

36. The method of any of claims 31 to 35, wherein the thyroid hormone derivative is purified using reverse phase high performance liquid chromatography (HPLC).

37. The method of claim 36, wherein the purifying comprises a gradient method.

38. The method of any of claims 31 to 37, wherein the purified thyroid hormone derivative is lyophilized to dryness.

39. The method of any of claims 31 to 38, wherein R is H.

40. The method of any of claims 31 to 39, wherein Z is methyl.

41. The method of any of claims 31 to 40, wherein n is 12.Docket No.15250WOO1 42. The method of any of claims 31 to 41, wherein the thyroid hormone derivative has the structure of Formula (IV): . 43.

44. The method of any of claims 31 to 42, wherein X is I.

45. A method of synthesizing a thyroid hormone derivative of formula (I): wherein X isR is H or C1-C6 alkyl; Z is -SO3H; and L is selected from alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, arylene, arylalkylene, heteroarylene, cycloalkylene, or heterocycloalkylene, said method comprising: combining at least one solvent, at least one sulfonate-containing compound, a coupling agent, and at least one base to produce a reaction mixture; adding a thyroid hormone to an agitated reaction mixture; isolating and purifying the thyroid hormone derivative, wherein the thyroid hormone is triiodothyronine (T3) or thyroxine (T4).

46. The method of claim 45, wherein the reaction mixture is agitated at room temperature.

47. The method of claims 45 or 46, wherein the at least one solvent comprises at least one species selected from water, methanol, ethanol, isopropanol, butanol, higher alcohols,Docket No.15250WOO1 tetrahydrofuran (THF), N-methylpyrrolidinone (NMP), cyclohexylpyrrolidinone, N- octylpyrrolidinone, N-phenylpyrrolidinone, methyl formate, dimethyl formamide (DMF), dimethylsulfoxide (DMSO), tetramethylene sulfone (sulfolane), diethyl ether, phenoxy-2- propanol (PPh), propriopheneone, ethyl lactate, ethyl acetate, ethyl benzoate, acetonitrile, acetone, ethylene glycol, propylene glycol, dioxane, butyryl lactone, butylene carbonate, ethylene carbonate, propylene carbonate, dipropylene glycol, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, diethylene glycol monoethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethylene glycol monohexyl ether, ethylene glycol phenyl ether, propylene glycol methyl ether, dipropylene glycol methyl ether (DPGME), tripropylene glycol methyl ether, dipropylene glycol dimethyl ether, dipropylene glycol ethyl ether, propylene glycol n-propyl ether, dipropylene glycol n-propyl ether (DPGPE), tripropylene glycol n-propyl ether, propylene glycol n-butyl ether, dipropylene glycol n-butyl ether, tripropylene glycol n-butyl ether, propylene glycol phenyl ether, and combinations thereof, branched non-fluorinated ether-linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, unbranched non-fluorinated ether- linkage carboxylic acids (CH3CH2)nO(CH2)mCOOH, where n=1 to 10 and m=1 to 10, branched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, unbranched non-fluorinated non-ether linkage carboxylic acids CH3(CH2)nCOOH, where n=1 to 10, dicarboxylic acids, tricarboxylic acids, and combinations thereof, preferably DMSO.

48. The method of any of claims 45 to 47, wherein the coupling reagent comprises at least one species selected from 4-(4-sulfophenyl)butanoic acid, 2-(2,5-dioxopyrrolidin-1-yl)-1,1,3,3- tetramethylisouronium tetrafluoroborate (TSTU), Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU), dicyclohexyl carbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), diisopropylcarbodiimide (DIC), O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HCTU), O-(7-Azabenzotriazole-1-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate (TBTU), N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo- 1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), 2-(5-Norborene-2,3- dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), and O-(2-Oxo-Docket No.15250WOO1 1(2H)pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TPTU), Benzotriazole-1-yl- oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), Benzotriazole-1-yl-oxy- tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), (7-Azabenzotriazol-1- yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyAOP), 1-Cyano-2-ethoxy-2- oxoethylideneaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyOxim), and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), preferably TSTU.

49. The method of any of claims 45 to 48, wherein the at least one base is selected from triethylamine, diisopropylmethylamine, diisopropylethylamine, tripropylamine, tributylamine, tetramethylethlenediamine (TMEDA), N,N-diethylisopropylamine, N,N- pentamethyldiethylenetriamine, N,N,N′,N″,N″-pentamethyl diethylenetriamine, pyridine, and 1,8-Diazabicyclo[5.4.0]undec-7-ene, preferably diisopropylethylamine.

50. The method of any of claims 45 to 49, wherein the sulfonate-containing compound comprises L.

51. The method of any of claims 45 to 50, wherein the sulfonate-containing compound comprises 4-(4-sulfophenyl)butanoic acid or 4-sulfobenzoic acid potassium salt.

52. The method of any of claims 45 to 51, further comprising agitating the reaction mixture after addition of the thyroid derivative.

53. The method of any of claims 45 to 52, wherein the thyroid hormone derivative is purified using reverse phase high performance liquid chromatography (HPLC).

54. The method of claim 53, wherein the purifying comprises a gradient method.

55. The method of any of claims 45 to 54, wherein the purified thyroid hormone derivative is lyophilized to dryness.

56. The method of any of claims 45 to 55, wherein R is H.

57. The method of any of claims 45 to 56, wherein L is an arylalkylene.

58. The method of any of claims 45 to 56, wherein L is an arylene.

59. The method of any of claims 45 to 56, wherein the thyroid hormone derivative has the structure of Formula (II):Docket No.15250WOO1 .

60. Thederivative has the structure of Formula (III): .

61. The62. The method of any of claims 45 to 60, wherein X is I.

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