US20030017111A1 - Fluorescent agents for real-time measurement of organ function - Google Patents

Fluorescent agents for real-time measurement of organ function Download PDF

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US20030017111A1
US20030017111A1 US10/228,807 US22880702A US2003017111A1 US 20030017111 A1 US20030017111 A1 US 20030017111A1 US 22880702 A US22880702 A US 22880702A US 2003017111 A1 US2003017111 A1 US 2003017111A1
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molecule
agent
fluorescence
time
excitation
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Carlos Rabito
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General Hospital Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0028—Oxazine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds

Definitions

  • This invention pertains to fluorescent agents, instruments, and techniques for measurement of organ function, and, more specifically, for real-time measurement of organ function.
  • Acute renal failure as a complication of multiple surgical, medical and obstetrical conditions, represents an important individual and public health problem.
  • ARF acute renal failure
  • This poor outcome contrasts with the almost unique ability of the kidney to undergo virtually complete recovery of function following an episode of transient ischemia or toxin-induced cellular destruction.
  • This discrepancy between mortality and the potential for reversibility emphasizes the need for a reconsideration of current diagnostic and therapeutic options with the goal of assuring complete recovery of organ function after an episode of ARF.
  • GFR glomerular filtration rate
  • This time most likely represents the time required for the ultrafiltrate to pass down the tubules, collecting ducts, and ureters before it reaches and equilibrates with the urine already contained in the urinary bladder. Since at least two samples are needed to determine that the measurement is done at equilibrium, the minimal ideal resolution time for this procedure will be about 1 hour. This, plus the usual delay in measuring the concentration of an agent in urine and blood samples, represents a significant limitation in the use of this procedure for bedside, real-time, monitoring of renal function in patients with ARF.
  • Renal function has traditionally been measured by creatinine clearance. It is now recognized, however, that in addition to the technical problems with creatinine measurement and with urine collection, creatinine clearance is not an accurate measure of GFR (Carrie, B., H. Golbertz, et al., Am. J. Med., 69: 177-182, 1980; Price, M., J. Urol., 107: 339-340, 1972). Quantitative methods for measuring renal glomerular and tubular function with clearance techniques have been available for many years. The nonendogenously produced substance inulin probably meets the requirements of an ideal GFR agent (Smith, 1951). Although it has remained the “gold standard”, the chemical methods of measurement are unfortunately too cumbersome for routine use.
  • the slope or rate constant can be calculated from several consecutive measurements of activity performed for a few seconds during a short interval of only a few minutes. This rate constant can be updated every minute or less after entering each new individual measurement.
  • the second assumption is that the measurement of the rate constant for the clearance of an “ideal” glomerular filtration agent from the extracellular space constitutes a precise and reproducible estimate of GFR.
  • GFR is usually calculated as the volume of distribution of the GFR agent multiplied by the rate constant.
  • the rate constant per se represents an accurate estimate of GFR.
  • the invention is a method of detecting a clearance function in a subject.
  • the method comprises providing an electroluminescent agent in a circulatory system of the subject, irradiating a tissue site with electromagnetic radiation having sufficient energy and intensity to be absorbed by the agent, detecting the intensity of emission from the tissue site, and repeating the step of detecting at known time intervals.
  • the agent is not metabolized by the subject and is only cleared by a single mechanism.
  • the agent does not bind plasma, protein, or extracellular components and is not reabsorbed by the subject.
  • the method may further comprise irradiating the tissue site with a laser, for example, a pulsed laser.
  • the step of repeating may be performed until elapsed time since the step of irradiating is about 90% of the decay time, for example, 50 ns or greater. After the step of detecting has been repeated a predetermined number of times, the step of irradiating may be repeated, and a background emission may have decayed to an insignificant level before the step of detecting is performed.
  • the agent may be cleared exclusively by the glomerulus and may comprise a polyaminopolyacetic acid derivative conjugated with an electroluminescent moiety, which may comprise a lanthanide ion.
  • the lanthanide ion may be trivalent and may comprise Ce +++ , Nd +++ , Sm +++ , Eu +++ , or Tb +++ .
  • the conjugate may exhibit fluorescence when irradiated with red or infrared light.
  • the polyaminopolyacetic acid derivative may be selected from diethylenetriaminepentaacetic acid (DTPA) ethylene glycol N,N,N′,N′-tetraacetic acid (EGTA), or polyaminopolybis(2-aminoethyl ether) acetic acid.
  • DTPA diethylenetriaminepentaacetic acid
  • EGTA ethylene glycol N,N,N′,N′-tetraacetic acid
  • polyaminopolybis(2-aminoethyl ether) acetic acid may comprise
  • S may be a cyclic organic moiety having at least one oxygen or nitrogen atom, and R may be an organic functionality, for example, an acetate or a p-toluene sulfonyl group.
  • S may be aromatic, aliphatic, substituted, or unsubstituted.
  • S may comprise a furanyl, tetrahydrofuranyl, pyrrolidinyl, furoyl, pyrrolyl, or substituted derivatives of these.
  • Exemplary substituents include NO 2 , NH 2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetomido, and carboxyl groups.
  • the invention is an apparatus for detection of a clearance rate of a substance from extracellular fluid.
  • the apparatus comprises a light source capable of producing light having sufficient intensity and energy to be absorbed by an electroluminescent moiety in the subject's extracellular fluid, an optical fiber to deliver light from the light source to the subject, a detector, an optical fiber to deliver light emitted by the electroluminescent moiety to the detector, and processing means to calculate the rate of depletion of the electroluminescent moiety based on values measured by the detector.
  • the light source may be a pulsed laser having a frequency such that it emits light at a time interval which is a predetermined fraction of a decay time of the electroluminescent moiety.
  • the invention is an electroluminescent molecule.
  • the molecule comprises a polyaminopolyacetic acid derivative conjugated with an electroluminescent moiety and exhibits fluorescence when irradiated with red or infrared light.
  • the molecule may be attached to an antibody, a DNA fragment, an RNA fragment, an enzyme, or an enzyme co-factor attached to the polyaminopolyacetic acid derivative.
  • the molecule may also include an oligonucleotide.
  • the invention is a method of performing magnetic resonance imaging on a patient. The method comprises injecting the electroluminescent molecule into a patient, exposing the patient to a magnetic field, exposing the patient to a radio frequency pulse, and measuring the emission of hydrogen ions within the patient after removal of the pulse.
  • the invention is a method of performing immunochemical analysis.
  • the method comprises associating a first electroluminescent complex with an analyte, exposing the first electroluminescent complex to light at an absorbance wavelength of the complex, and detecting light emitted by the first electroluminescent complex.
  • the first complex comprises a bicyclic polyaminopolyacetic acid analog and an electroluminescent agent chelated to the bicyclic polyaminopolyacetic acid analog.
  • the electroluminescent agent may comprise a lanthanide ion.
  • the lanthanide ion may be trivalent and may comprise Ce +++ , Nd +++ , Sm +++ , Eu +++ , or Tb +++ .
  • the method may further comprise associating a second ligand labeled with a second electroluminescent complex with a second analyte, wherein the emission wavelength of the second complex is detectably different from the emission wavelength of the first complex.
  • the method may be performed with more than two ligands and complexes.
  • the electroluminescent complex may exhibit a decay time greater than 50 ns.
  • the steps of exposing and detecting may be repeated.
  • the method may further comprise attaching a first ligand to the analyte, wherein the first electroluminescent complex is associated with the analyte via attachment to the ligand; alternatively, the first electroluminescent complex may be attached to the first ligand via a second ligand.
  • the analyte may be immobilized on a support, for example, via a ligand. Association may comprise removing an electroluminescent agent associated with the analyte and coordinating the electroluminescent agent with the bicyclic polyaminopolyacetic acid analog to form the first electroluminescent complex.
  • the bicyclic polyaminopolyacetic acid analog is not attached to the analyte, and the electroluminescent agent is attached to the analyte via a ligand.
  • the bicyclic polyaminopolyacetic acid analog may be sequestered in a micelle.
  • the ligand may comprise an antibody, a DNA fragment, an RNA fragment, an enzyme, or an enzyme co-factor.
  • the polyaminopolyacetic acid derivative may comprise
  • S may be a cyclic organic moiety having at least one oxygen or nitrogen atom, and R may be an organic functionality, for example, an acetate or a p-toluene sulfonyl group.
  • S may be aromatic, aliphatic, substituted, or unsubstituted.
  • S may comprise a furanyl, tetrahydrofuranyl, pyrrolidinyl, furoyl, pyrrolyl, or substituted derivatives of these.
  • Exemplary substituents include NO 2 , NH2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetomido, and carboxyl groups.
  • the invention is a molecule comprising
  • S may be a cyclic organic moiety having at least one oxygen or nitrogen atom, and R may be an organic functionality, for example, an acetate or a p-toluene sulfonyl group.
  • S may be aromatic, aliphatic, substituted, or unsubstituted.
  • S may comprise a furanyl, tetrahydrofuranyl, pyrrolidinyl, furoyl, pyrrolyl, or substituted derivatives of these.
  • Exemplary substituents include NO 2 , NH 2, isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetomido, and carboxyl groups.
  • FIG. 2 is a graph illustrating the principle of time-delayed fluorometry
  • FIG. 3 is a schematic of a laser-induced fluorescence instrument for use with the invention.
  • FIG. 4 is a graph showing the fluorescence excitation (continuous line) and emission (broken line) spectra of nile blue-DTPA;
  • FIG. 5 is a graph showing the fluorescence excitation (continuous line) and emission (broken line) spectra of Eu-EGTA;
  • FIG. 6 depicts a macrocyclic compound according to an embodiment of the present invention
  • FIG. 7 depicts an exemplary synthetic pathway for production of TABFTA
  • FIG. 8 displays exemplary starting materials, intermediates, and end products for use in the methods of the invention.
  • FIG. 9 illustrates the excitation and decay processes resulting in the advantageous emission properties of lanthanide atoms
  • FIG. 10 illustrates a finger sleeve with which an apparatus according to the invention can be operated.
  • the present invention provides laser fluorescent dye derivatives and lanthanide chelates for real-time, transcutaneous fluorescence measurements of organ function, for example, glomerular filtration rate, renal blood flow, and hepatic function.
  • the new fluorescent agent should have several additional characteristics besides the requirements described above.
  • the excitation wavelength of a new agent should be greater than 600 nm.
  • the emission wavelength will be in the red or infrared to maximize tissue penetration.
  • the new agent should be very soluble and stable in aqueous solutions.
  • the agent should be non-toxic.
  • the background level in fluorometric analysis is a sum of several factors, including scattering and the presence of other fluorescent compounds. Scattering from solvents, solutes, and particles results in background fluorescence in fluorometric measurements, especially when measuring fluorescent probes of short Stokes shift. In addition to scattering, sample constituents like protein, hemin, NADH, etc., cause background fluorescence extending from 300 nm to nearly 600 nm (Soini, 1979).
  • Another important characteristic of this background fluorescence is that its average decay time is less than 50 ns (Mathies, 1986).
  • Two different approaches can be used to reduce or eliminate background activity in the in vivo measurements.
  • One is, as proposed before, to select fluorescent agents with an emission wavelength higher than 600 nm.
  • the other is to use time-resolved fluorometry.
  • Time-resolved fluorometry is a method by which the fluorescence emission is counted after a certain delay time following pulse excitation (Soini, 1979). With this system, background fluorescence can be eliminated, provided that the decay time of the specific signal is substantially longer than the average decay of the background (FIG. 2).
  • lanthanide chelates for time-delayed fluorometry stems from the unique luminescence properties of these complexes. While the luminescence of these molecules is commonly described as fluorescence, the relaxation mechanism of the excited atom is actually much more complex. As shown in FIG. 9, when a lanthanide chelate is irradiated, the ligand molecule absorbs enough energy to be excited to state S n . The ligand quickly relaxes to singlet excited state S 1 , a non-radiative process. Relaxation from this state to ground state G is properly termed fluorescence; however, the resulting emission would not be useful for time-resolved techniques.
  • the ligand may also relax from the singlet state S 1 to triplet state T via a non-radiative mechanism. Relaxation via emission from this state is called phosphorescence. This emission is relatively slow (on the order of milliseconds) in comparison to fluorescence (on the order of nanoseconds). However, if the energy is transferred to the metal ion (states d 1 or d 2 ); then the complex may relax to the ground state either directly from d 1 or d 2 or indirectly after relaxation from d 2 to d 1 . As can be seen in FIG. 9, the emission wavelength for this process is much different than for the absorption wavelength. In addition, relaxation from state d 2 or d 1 is even slower than relaxation from the state T.
  • the fluorescence lifetime of a conventional fluorophore rarely exceeds 100 ns; the fluorescence lifetime of a lanthanide ion ranges between 100 s and 1000 s (Diamandis, E. P., Electrophoresis, 14: 866-875, 1993).
  • the slow emission and large energy (and emission wavelength) difference between S 1 and either d 2 or d 1 make time-resolved fluorometry a very powerful technique.
  • the slow emission also facilitates real-time monitoring by maximizing the intervals during which measurements may be made and reducing the interruptions due to re-excitation of the fluorophore.
  • Superguide-G Fiberguide Industries, Stirling, N.J.
  • the fibers at the output end of this bundle were arranged linearly and served as a 0.1 mm ⁇ 2.5 mm entrance slit for a f/3.8, 0.275 m polychromator (Monospect 27; Anaspect, Acton, Mass.).
  • a long pass filter (CS 2-59; Swift Glass Co., Elmira, N.Y.) was inserted before the quartz fiber bundle to eliminate scattered light. Fluorescence for wavelengths between 300 and 800 nm was recorded using an intensified 1024-diode array controlled by an optical multichannel analyzer (OMA III; Princeton Applied Research, Princeton, N.J.). The intensifier was gated with 100 ns pulses centered on the 3 ns laser pulse.
  • LIF laser-induced fluorescence
  • Fluorescent Agents Two different procedures were used to obtain the new fluorescent agents. Both approaches employed an agent with clearance characteristics of an “ideal” GFR agent (for instance EDTA, DTPA, low molecular weight Dextran, or a polyazamacrocyclic molecule) as the primary reactant. Selecting a stable GFR agent as the basic starting reactant increases the likelihood that the final fluorescent product will retain most, if not all of the properties of the initial GFR agent.
  • the fluorescence marker was a laser dye with a long emission wavelength, e.g. nile blue, oxazine 750, or indocyanine green, and, in the other, a trivalent lanthanide such as neodymium.
  • nile blue-DTPA conjugate 0.1 g of DTPA dianhydride (ccDPTA) was dissolved in 6 ml of dimethyl sulfoxide (DMSO) in a round bottom flask.
  • DMSO dimethyl sulfoxide
  • the reaction mixture was then loaded onto a silica gel column and eluted with acetone:ethylacetate.
  • the fractions corresponding to the nile blue-DTPA conjugate were pooled and evaporated, yielding a magenta colored oil.
  • the oil was rechromatographed on a second silica gel column using acetone as eluant.
  • the nile blue-DTPA conjugated fractions were pooled and rotate-evaporated to give a magenta colored oil.
  • lanthanide chelates were also investigated. They are known to have a long decay-time for fluorescence, making them an optimal choice for time-resolved techniques. Trivalent lanthanide ions like Ce 3+ , Nd 3+ , Sm 3+ , Eu 3+ , and Tb 3+ exhibit a special kind of fluorescence characterized by narrow-banded emission lines and long fluorescence decay times. One of the limitations of lanthanide ions, however, is that alone they produce a very weak fluorescence signal. To improve the fluorescence signal, the lanthanide ions need to be combined with an appropriate enhancer. When chelated with suitable light absorbing ligands, the ion fluorescence is enhanced by several orders of magnitude.
  • the best known and most widely used ligands to produce fluorescent lanthanide chelates are the -diketones, especially their fluorinated aromatic forms (Hemmila, I., S. Dakubu, et al., Anal. Biochem., 137: 335-343, 1984; Hemmila, I., Anal. Chem., 57: 1676-1681, 1985).
  • europium could be measured with high sensitivity as a -diketone chelate, this approach has important limitations.
  • the fluorescent GFR agent is distributed in a aqueous media (extracellular space)
  • the -diketone has to be solubilized with the use of a nonionic detergent (Hemmila, 1984).
  • the binding of the chelate's components is not strong enough to avoid spontaneous dissolution in water (Hemmila, 1984) and, as a result, loss of fluorescence and expression of possible toxic effects of the lanthanide and -diketone. All of these limitations can be circumvented by the use of an enhancer with strong chelating properties from which the lanthanide will dissociate very slowly, or not at all, under the required experimental conditions.
  • Ethylene glycol N,N,N′,N′-tetraacetic acid has two aminoethyl ether groups.
  • EGTA should show similar energy absorption and transfer properties to those found in the -diketones in addition to its strong metal chelating properties.
  • the chelate between europium and EGTA is fluorescent, eliminating the need for an additional enhancer.
  • FIG. 5 also shows that the chelate maintains the narrow emission bands characteristic of Eu (590 nm and 613 nm).
  • EGTA lanthanide chelates are not as stable in aqueous solution as the polyazamacrocyclic lanthanide chelates are.
  • the stability constant of EGTA-lanthanide complex is 10 17
  • Chelating agents based upon tetraazamacrocyclic backbones have proven to be extremely valuable for generating aqueous stable lanthanide chelates.
  • the superior nature of this class of chelates has made them useful for diagnostic and therapeutic medical applications.
  • paramagnetic chelates of these compounds based upon gadolinium (Gd) are currently used as contrast agents for magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the current tetraazamacrocyclic chelates of Gd used in MRI are either very weakly fluorescent or exhibit no fluorescence at all.
  • the addition of an aromatic moiety to the chelate can enhance luminescence.
  • a newly developed polyazamacrocyclic chelate incorporating a pyridine as the enhancer group exhibited fluorescence emission with a large difference between the excitation and emission wavelengths (>280 nm) and a high quantum yield of 0.51 (Costa, J. and R. Delgado, Inorg. Chem., 32: 5257-5265, 1993; Kim, D., G. Kiefer, et al., Inorg. Chem., 34: 2233-2243, 1995; Bornhop, D., D. Hubbard, et al., Anal. Chem., 71: 2607-2615, 1999).
  • the new molecule exhibits significant hepatic and bowel excretion in addition to renal excretion (Bornhop, 1999).
  • the pharmacodynamic characteristics of this compound render it totally unsuitable for the present application.
  • the starting reactants in the synthesis of the new agents are compounds with a well-recognized organ and function specificity.
  • the new fluorescent agent is based on lanthanide chelates derived from the polyazamacrocyclic compound of general formula ( 5 ), wherein the second cyclic group (S) is part of the macrocyclic backbone (FIG. 6).
  • the second cyclic group (S) may be a furan, a tetrahydrofuran, a pyrrole, a pyrrolidine, or a derivative such as 3-furoic acid.
  • TABFTA tetraazabycyclofurantetraacetate
  • DOTA tetraazacyclododecane tetraacetic acid
  • the chelates of TABFTA and a lanthanide such as neodymium will have biological characteristics similar to the chelates of DOTA and gadolinium, such as being excreted only by glomerular filtration and having an extracellular space distribution (Bousquet, 1988).
  • a lanthanide such as neodymium
  • measurement of renal function and, in particular, glomerular filtration will be pursued without further structural modifications of TABFTA.
  • TABFTA can also be used also as a bifunctional chelating agent for the labeling of antibodies, antibody fragments, hormones, hormone fragments, nucleic acids, neurotransmitters, or any other biologically active material.
  • TABFTA may be modified as depicted in formula 45 by introduction of a NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetomido or carboxyl group in position 15 (FIG. 8).
  • FIG. 7 provides a detailed description of the preparation of one of the compounds of this invention, a 15-member tetraazamacrocyclic structure possessing one dimethylfuran moiety. 2,5-dimethylfuran ( 10 ) is first converted to the chloromethyl derivative ( 15 ). In a separate step, triethylenetetraamine is tosylated and converted to the sodium salt.
  • N-tosylated macrocycle 20
  • HBr acetic acid
  • the tetraacetic derivative ( 25 ) is then synthesized by reacting the secondary amines of the macrocycle with chloroacetic acid as described by Desreux (Desreux, J., Inorg. Chem., 19: 1319-1324, 1980).
  • the second cyclic group S may be varied to modify the electron density of the molecule and the electron distribution along the backbone.
  • compound 10 can be replaced with 2,5-dimethyltetrahydrofuran ( 30 ), 2,5-dimethylpyrrolidine ( 33 ), 2,5-dimethyl-3-furoic acid ( 35 ), or 2,5-dimethylpyrrole ( 40 ).
  • Use of compound 15 results in production of compound 50 instead of compound 20 as an intermediate.
  • substituents such as the isothiocyanate group in compound 45 , can be placed on the molecule by an appropriate choice of precursor for cyclic group S.
  • Neodymium, terbium or europium acetate (0.1M) and an equimolar amount of tetraazacycloalkene N, N′, N′′, N′′′′ derivative are mixed in water at 80° C.
  • the pH of the solution is adjusted to 10 by addition of concentrated NH 4 OH and the mixture stirred for 20 h.
  • the cooled reaction solution is evaporated to a solid and dried overnight in a vacuum oven to sublime the byproduct, ammonium acetate.
  • the fluorescence excitation system may incorporate either high intensity light-emitting photo diodes or laser diodes. These components have several properties that make them ideal for the present application by increasing safety and portability. They are current sensitive devices with low-power output, low operating voltage, and high-frequency response. Both types of diodes are very small and can be battery-operated with input power of 3.5 to 5.0 VDC and only 50-100 mA input currents.
  • Both light sources have the advantage of very high frequency response.
  • the emitted light beam can be pulsed with a regulated electronic pulse generator by turning the source on and off.
  • This electronic gating system offers several advantages over the mechanical system, including better control of the frequency, duration, and intensity of the light pulses.
  • the emitted light intensity measurements are performed during pulses; for lanthanide chelates, the measurements are performed between pulses, after the background fluorescence has decayed to minimal values.
  • FIG. 3 A diagram of the system is displayed in FIG. 3. Filters with an appropriate cut-on wavelength are selected for the specific fluorescent agent in use, e.g., 850 ⁇ 7 nm (for neodymium-chelates) or 700 ⁇ 6 nm (for indocyanine green-EDTA or oxazin-EDTA).
  • the 850 nm filter should reflect and re-direct a 830 nm beam from the laser source to the tissue while allowing full transmission of the 1,050 nm and 1,350 nm emission bands of neodymium-chelates.
  • the 700 nm filter should reflect and re-direct the 420-600 nm beam from the high intensity light-emitting photo diodes to the tissue while allowing full transmission from the tissue to the detector unit of the emission beam of the indocyanine green-EDTA or oxazin-EDTA.
  • the excitation pulses are launched into single or multiple 2000 m core-diameter fused silica optical fibers or liquid core lightguides with a 5 mm focal length lens. After a proximal short circular arrangement, the fibers are rearranged linearly to obtain a structure similar to a short band 55 (FIG. 10).
  • This excitation band is placed and secured over the skin or mucosa of a body part, for example, finger 60 , to excite the tissue underneath.
  • the volume of the excited tissue is changed by adjusting the intensity of the excitation beam or the number and/or core diameter of the liquid lightguides or silica optical fibers 65 .
  • excitation is accomplished with the use of laser diodes with very low power output (i.e., 2-5 mW) to avoid exceeding an exposure rate of 0.003 J/cm 2 .
  • the excitation beam is pulsed with an electronic pulse-generator to excite the tissue with very short laser pulses of only a few nanoseconds duration.
  • the wavelength of the excitation beam is always maintained over 420 nm.
  • conduction of the excitation beam is performed with large core fiber optic bundle to distribute the excitation laser beam over a large area. The low power and short pulses of the excitation beam should also reduce the possibility of photobleaching frequently observed with the use of standard fluorescent dyes.
  • the detection system Fluorescence from the skin or mucosa and deeper tissues will be collected by the excitation band and conducted through liquid lightguides or silica optical fiber to the long wave pass filter.
  • the filter facilitates separation of the emission and excitation beams and reduces background contribution, as disclosed above. Fluorescence transmitted through the filter is recorded using an intensified photodiode array or IR detector for variable integration times.
  • the intensifier/detector unit is electronically gated to measure the fluorescence intensity emitted during (for standard fluorometry) or a time after (for time resolved fluorometry) the excitation pulse.
  • the operating system and data logger Tattletale® data loggers designed by Onset Computer are used to operate the system and record fluorescence vs. time. Several characteristics of this data logger make it ideal for the present application.
  • the data file size for this series ranges between 8 to 224 Kb, more than sufficient to allow the instrument to perform all its expected functions. All the models available are battery-operated, low power system with drains between 2 to 3 mA.
  • all the Onset Computer's Tattletale® loggers are pocket-sized, lightweight, sturdy units. The data logger, along with the batteries necessary to operate the system and the detector, are housed in a pocket-sized plastic box.
  • the loggers are assembled with an alphanumeric display to show the updated rate constant value at pre-set intervals. This feature is extremely useful in acute situations such as operating rooms and intensive care units.
  • the data loggers also have sufficient memory to determine the instant value of this constant for a long period of data collection.
  • the excitation/detector unit of the instrument is affixed to the skin covering a body part such as a fingertip or a section of the arm or to the nasal or oral mucosa of the patient.
  • Organ function is then measured in real time as rate of depletion in tissue of a fluorescent agent that is cleared exclusively by that particular organ.
  • organ function is measured as the efficiency with which a particular organ removes a function-specific fluorescent agent from the tissue.
  • the rate of depletion of the agent is measured from the change in the individual transcutaneous fluorescence measurements over time.
  • the individual transcutaneous tissue fluorescence measurements are performed by integrating the emitted tissue fluorescence for a very short period of time (50 nsec to 100 msec) during (standard fluorometry) or after (time-resolved fluorometry) the excitation pulse. Since the excitation pulses are very short, the individual fluorescence measurements may be performed very frequently with minimal interruption between measurements.
  • the rate of excretion is then determined by plotting the individual transcutaneous fluorescence measurements with respect to time for very short time intervals (2 to 5 minute intervals) after a bolus intravenous injection of the tracer. Since the system response follows first-order kinetics (Rabito, 1994), the slope of the correlation between the log of the individual fluorescence intensity measurements vs.
  • time represents the rate constant of the system.
  • the data collected is subjected to repetitive, on-line, least squares analysis to obtain the best fit between the log of fluorescence intensity (in arbitrary units) versus time (in minutes) at intervals of 2 to 5 minutes.
  • the new data is processed and added to the correlation to obtain a continuous update of the line.
  • Analysis of co-variance (ANOVA) is used to assess the differences between the slope (rate constant) for the previous and the current 2 to 5 minute intervals.
  • ANOVA is used to assess the differences between the slope (rate constant) for the previous and the current 2 to 5 minute intervals.
  • the basic software for the operation of the unit is a modification of the program developed initially for the renal monitor that works with radioactive tracer (Rabito, 1994).
  • the program is designed to control the type of excitation to be used (continuous or pulse excitation), duration of the excitation pulse, interval between pulses, the time between the excitation pulse and the measurement of the emission signal, and the integration period for the measurement of the emission signal.
  • the emitted fluorescence intensity is measured during each pulse.
  • the operating program is set to integrate the emission signal a few microseconds after the laser pulse to allow for full background decay.
  • the analysis software is based on the single compartment model described by Brochner-Mortensen (Brochner-Mortensen, J., Scand. J. Clin. Lab. Invest., 30: 271-276, 1974) as was previously published (Rabito, 1994).
  • FARM has several definite advantages over the radioactive monitoring technique described in the Background. First, the technique will eliminate the use of radioactivity with all its intrinsic limitations. Second, FARM can be assembled with more standard components than the radioactivity detectors. For instance, the laser diodes and laser detectors are very inexpensive ($50 to $125) and widely available laser components that have been tested extensively in everyday applications such as CD players, printers, facsimile machines, laser security fences, etc. On the contrary, the cadmium-telluride detectors for monitoring radioactive tracers are available from only two manufacturers in the USA, at a cost that is about 15 times higher ($2,500) than the laser components.
  • FARM Another advantage of FARM is that, as a result of a simpler design, the patient will be more comfortable wearing the instrument for extended periods of time.
  • the excitation/detection system of FARM can be arranged in a finger sleeve which is more comfortable and less bulky than the heavy lead-lined arm sheaths used in the radioactivty assay.
  • FARM can also be used for multi-label assays in which different fluorophores having different emission wavelengths are used simultaneously.
  • the fluorescent signal originates solely in the tissue volume excited by the laser beam (Frisoli, 1993), eliminating the scattered activity from adjacent body structures commonly found with the radioactive method and obviating the need for special shielding. This attribute should result in a significant decrease in the total weight of FARM and more comfort for the patient, especially during prolonged monitoring of renal function.
  • Two other important advantages of FARM over the radioactive technique are that the tissue volume probed during measurement remains relatively constant, and that the size of this volume can be adjusted by changing the excitation wavelength. This feature permits adjustment of the sensitivity of the instrument to a particular need without changing the dose of the fluorescent agent injected.
  • FARM especially when conducted with the novel molecules disclosed herein, provides a reliable method for real-time monitoring of renal function. This technique, in conjunction with appropriate agents, may be exploited to monitor metabolic function for other organs as well. It provides a powerful tool for health care providers to quickly identify patients experiencing kidney or other organ failure and apply appropriate remedies.
  • the molecules of the invention can also be used as labels for bioanalytical assays.
  • the molecules can be attached to specific binding reagents, or ligands, for a variety of analytes. For example, they can be attached to antibodies for use in immunoassays, DNA or RNA fragments for hybridization assays, or enzyme or enzyme cofactors for enzyme assays.
  • the molecules may be directly attached to the specific binding agent for the analyte or may be attached to a more general binding agent that acts as a secondary label. In the latter case, the secondary agent binds to a primary specific reagent.
  • the analyte may be immobilized on a substrate, following which the specific binding agent labeled with the luminescent molecule is allowed to bind to the analyte.
  • the labeled agent may be attached to the analyte and excess unbound agent washed away.
  • the molecule may be separated from the specific binding agent.
  • the concentration of the molecule will still reflect the quantity of analyte; however, the concentration of the molecule can be measured in solution instead of an immobilized solid phase.
  • the metal ion may be chelated to a non-luminescent label attached to the specific binding agent. After the excess agent is rinsed away, only the metal atom is detached, for example, by changing the pH of the solution. The metal ion is then solubilized into a micelle carrying the organic chelate which binds a metal ion to form a luminescent complex.
  • Suitable micellar materials include Triton X-100 (CAS 9002-93-1, available from Sigma-Aldrich, Inc.) detergent in phosphate buffer.
  • the micelles also contain a chelating agent such as the molecules of the instant invention.
  • This method has been commercialized using Eu as the metal ion and -naphthoyltrifluoracetone (NTA) and trioctylphosphine oxide (TOPO) as the chelate. Multiple antigens can be detected simultaneously by using different ions to label each.
  • Magnetic Resonance Imaging Contrast Agent The molecules of the invention, especially TABFTA and its derivatives, can also be used as contrast agents for magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • the resulting paramagnetic compound enhances the relaxation of hydrogen protons, increasing signal intensities in MRI imaging (Bousquet, 1988).
  • the increased signal increases the signal-to-noise ratio, reducing imaging time.
  • the contrast agent may increase specificity in diagnosis. Because TABFTA is water-soluble, the complex can be used as a contrast agent in blood, for example, to measure blood flow in patients at risk for stroke or other circulatory malfunctions.
  • the agent can also be used to image the functioning of the kidneys and bladder.
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