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WO2012006038A2 - Agents et composés pour l'imagerie et autres applications, leurs procédés d'utilisation et de synthèse - Google Patents

Agents et composés pour l'imagerie et autres applications, leurs procédés d'utilisation et de synthèse Download PDF

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Publication number
WO2012006038A2
WO2012006038A2 PCT/US2011/042061 US2011042061W WO2012006038A2 WO 2012006038 A2 WO2012006038 A2 WO 2012006038A2 US 2011042061 W US2011042061 W US 2011042061W WO 2012006038 A2 WO2012006038 A2 WO 2012006038A2
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contrast agent
saturation transfer
group
paramagnetic
iii
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WO2012006038A3 (fr
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Dean A. Sherry
Yunkou Wu
Garry E. Kiefer
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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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
    • A61K49/06—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
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers

Definitions

  • the illustrative embodiments relate in general to the field of imaging agents and other agents, and specifically, to paramagnetic chemical exchange saturation transfer mechanism based magnetic resonance imaging (MRI) contrast agents.
  • MRI magnetic resonance imaging
  • MRI is one of the most widely used, noninvasive imaging modalities in clinical medicine.
  • An MRI system is a machine that may use magnetic field and pulses of radio wave energy to generate images of tissue and structures inside the body.
  • a powerful magnetic field may be applied to the body to cause the hydrogen atoms in the body to become aligned with the direction of the magnetic field.
  • Radio waves may then be briefly transmitted at the body to cause precession of protons within the patient based on the magnetic field conditions. Turning off the radio frequency energy may result in energy being released from the movement of the protons, which generates a signal that can be recorded by a computer.
  • One reason for the popularity of MRI in clinical medicine is that image contrast arises from inherent differences in water proton densities and relaxation rates between various tissue components.
  • tissue that has the least hydrogen atoms such as bones
  • tissue that has many hydrogen atoms such as fatty tissue
  • exogenous contrast agents that alter proton relaxation times may be used to enhance contrast between various tissue compartments.
  • Current imaging agents may have properties that render them less useful for imaging or determining certain parameters, such as a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, an oxygen concentration, or a presence of enzyme activity, among others, or for performing other chemical or biological functions or applications.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • Rj is selected from the group consisting of Ri, R 2 , R 3 , R4, R5, Re, R 7 , and R ⁇
  • Ri is selected from the group consisting of OR', O 2 R', SR', and SOR'
  • R 2 is selected from the group consisting of NHR', CO 2 R', S03(R') 2 , and P03(R') 2
  • R4 is selected from the group consisting of:
  • R5 is selected from the group consisting of:
  • R6 is selected from the group consisting of:
  • R 7 includes: includes: includes:
  • each R J is selected from the group consisting of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , and R 1 includes CR'H-CONH-(CH 2 ) n -C0 2 -R'.
  • n is an integer, and 0 ⁇ n ⁇ 20.
  • R 2 includes CR'H-CONH-(CH 2 ) n - PO-(OR') 2
  • R 3 includes CR'H-COCH 2 R'
  • R 4 includes CR'H-PO(OR')-(CH 2 ) n -C0 2 -R'
  • R 5 includes CR'H-PO(OR')-R'
  • R 6 includes:
  • R' is selected from the group consisting of H, an alkyl group having 20 carbon atoms or less, a cycloalkyl group having 20 carbon atoms or less, and an alkyloxy group having 20 carbon atoms or less and 10 oxygen atoms or less.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • Rj is selected from the group consisting of Ri, R 2 , R3, R4, R5, R6, R7, and R ⁇
  • Ri is selected from the group consisting of OR', 0 2 R', SR', and SOR'
  • R 2 is selected from the group consisting of NHR', C0 2 R', S0 3 (R') 2 , and P0 3 (R') 2
  • R4 is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R8 includes:
  • each R J is selected from the group consisting of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , and R 1 includes CR'H-CONH-(CH 2 ) n -C0 2 -R'.
  • n is an integer, and 0 ⁇ n ⁇ 20.
  • R 2 includes CR'H-CONH-(CH 2 ) n - PO-(OR') 2
  • R 3 includes CR'H-COCH 2 R'
  • R 4 includes CR'H-PO(OR')-(CH 2 ) n -C0 2 -R'
  • R 5 includes CR'H-PO(OR')-R'
  • R 6 includes:
  • a composition of matter includes a light-sensitive contrast agent usable as a composition for a drug delivery system including the formula:
  • the method also includes evaporating the water layer to form a solid, and subjecting the solid to high-performance liquid chromatography to form a product containing the first compound.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include: , and
  • each R' may be selected from the group consisting of CH2CONHCH2COOH, CH2CONHCH2COOC2H5, CH2CONH2, CH2CONHCH 2 PO(OC 2 H5)2, CH2CONHCH2PO3H2, CH 2 CONHCH 2 PO(OC(CH 3 )2)2,
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include:
  • each R' may be selected from the group consisting of CH2CONHCH2COOH, CH 2 CONHCH 2 COOC 2 H5, CH 2 CONH 2 , CH 2 CONHCH 2 PO(OC 2 H 5 ) 2 , CH 2 CONHCH 2 P0 3 H 2 , CH 2 CONHCH 2 PO(OC(CH 3 ) 2 ) 2 , CH 2 CONHCH 2 PO(OCH 2 CH 2 CH 3 ) 2 , CH 2 CONHCH 2 PO(OCH 2 CH 2 CH 2 CH 3 ) 2 , and CH 2 CONHCH 2 PO(OC(CH 3 ) 3 ) 2 .
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include:
  • each R' may be selected from the group consisting of CH 2 CONHCH 2 COOH, CH 2 CONHCH 2 COOC 2 H 5 , CH 2 CONH 2 , CH 2 CONHCH 2 PO(OC 2 H 5 ) 2 , CH 2 CONHCH 2 P0 3 H 2 , CH 2 CONHCH 2 PO(OC(CH 3 )2)2, CH 2 CONHCH2PO(OCH2CH 2 CH3)2, CH2CONHCH 2 PO(OCH 2 CH2 CH 2 CH 3 ) 2 , and CH 2 CONHCH 2 PO(OC(CH3)3)2.
  • a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent for determining a chemical parameter including a europium(III) DOTA-tris( amide) complex includes four side chains, and one of the four side chains connects an aromatic group by a carbonyl bond.
  • a method for determining one or more parameters includes obtaining a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including a europium(III) DOTA-tris(amide) complex including four side chains. One of the four side chains connects an aromatic group by a carbonyl bond.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent is adapted to provide a ratiometric imaging measurement.
  • the method also includes administering the paramagnetic chemical exchange saturation transfer MRI contrast agent to a patient, and detecting a signal in the patient that correlates to one or more parameters.
  • the one or more parameters includes at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, an oxygen concentration, a presence of enzyme activity, a temperature, a metabolite concentration, or an (3 ⁇ 4 partial pressure.
  • Figure 1 illustrates a structure of the pH-responsive PARACEST agent, Eu-1 according to an illustrative embodiment
  • Figure 2 illustrates the UV-vis spectra of Eu-1 recorded as a function of solution pH according to an illustrative embodiment
  • Figure 3 is plot illustrating pH dependence of CEST spectra for Eu-1 (10 mM) recorded at 9.4 T and 298 K according to an illustrative embodiment
  • Figure 4 illustrates CEST images of phantoms water (w) or 10 mM containing either water or Eu-1 adjusted to the indicated pH (9.4 T, 298 K) according to an illustrative embodiment
  • Figure 5 illustrates a synthesis scheme for the preparation of Al according to an illustrative embodiment
  • Figure 6 illustrates the proton equilibrium in Eu(III)-Al complex according to an illustrative embodiment
  • Figure 7 is a plot illustrating pH dependence of CEST (scatter) and CEST fitting (line) spectra for Eu(III)-Al (30 mM) recorded at 9.4 T and 298 K according to an illustrative embodiment
  • Figure 8 is a plot illustrating pH dependence of CEST peak position for Eu(III)-Al according to an illustrative embodiment
  • Figure 9 is a plot illustrating pH dependence of CEST spectra for Eu(III)-Al (10 mM) recorded at 9.4 T and 298 K over the pH range 6.0 to 7.6 according to an illustrative embodiment
  • Figure 10 is a plot illustrating pH dependence of the ratiometric plot by exploitation of the ratio of CEST intensity at 55 ppm to 50 ppm according to an illustrative embodiment
  • Figure 11 illustrates the synthesis scheme for the preparation of Bl according to an illustrative embodiment
  • Figure 12 illustrates the reaction of Eu(III)-Bl with hROS producing Eu(III)-Al according to an illustrative embodiment
  • Figure 13 is a plot illustrating NaOCl concentration dependence of CEST spectra for Eu(III)-Bl (10 mM) recorded at 9.4 T and 298 K in 10 mM HEPES buffer according to an illustrative embodiment
  • Figure 14 is a plot illustrating NaOCl concentration dependence of the ratiometric plot for Eu(III)-Bl by exploitation the ratio of CEST intensity at 54 ppm to 49 ppm according to an illustrative embodiment
  • Figure 15 is a plot illustrating the CEST ratiometric responses (54 ppm / 49 ppm) of Eu(III)-Bl (10 mM) in the presence of 50 mM various hROS according to an illustrative embodiment
  • Figure 16 illustrates a synthesis scheme for the preparation of CI according to an illustrative embodiment
  • Figure 17 illustrates ?-galactosidase catalyzed hydrolysis of Eu(III)-Cl producing Eu(III)-Al according to an illustrative embodiment
  • Figure 18 is a plot illustrating time dependence of CEST spectra for Eu(III)-Cl (10 mM) in presence of 66 U ?-galactosidase recorded at 9.4 T and 298 K in 10 mM Tris buffer according to an illustrative embodiment
  • Figure 19 is a plot illustrating the time dependent ratiometric response (54 ppm / 48 ppm) of Eu(III)-Cl in presence of 66 U ?-galactosidase recorded at 9.4 T and 298 K in 10 mM Tris buffer according to an illustrative embodiment
  • Figures 20 and 21 illustrate chemical structures for Eu(III)-Al and Eu(III)-Bl and general structure transformation in response to the analytes according to an illustrative embodiment
  • Figure 22 is a schematic of the preparation of a ligand according to an illustrative embodiment
  • Figure 23 illustrates the 'H-NMR spectra for Eu(III)-Al complex (20 mM) recorded in D2O at 289K with a pD of (a) 5.0 and (b) 8.9 according to an illustrative embodiment
  • Figure 24 is a graph of pD dependence of chemical shift of aromatic proton according to an illustrative embodiment
  • Figures 25A and 25B are plots of pH dependence of UV-vis spectra for (a) Eu(III)-Al and (b) free ligand Al (20 ⁇ ) recorded in aqueous solution according to an illustrative embodiment;
  • Figure 26 is a plot of a normalized titration curve showing the increase in absorbance at 360 nm for Eu(III)-Al ( ⁇ ) and at 340 nm for free ligand Al (A) as a function of increasing pH according to an illustrative embodiment
  • Figure 27 is a schematic of the proton equilibrium of free ligand Al and resonance representation of the deprotonated Eu(III)-Al complexes according to an illustrative embodiment
  • Figure 30 is an image of a Jablonski diagram of the Eu(III)-Al according to an 5 illustrative embodiment showing that the proximity of the triplet energy level of the quinone group causes substantial back energy transfer;
  • Figure 31 is plot of pH dependence of CEST spectra for Eu(III)-Al recorded at 9.4 T and 310 K according to an illustrative embodiment
  • Figure 32 is a corresponding pH ratiometric plot for Eu(III)-Al by exploitation the ratio of CEST intensity at 55 ppm to 46 ppm;
  • Figure 33 shows the UV-vis spectral changes of Eu(III)-Bl as a function of OCT concentration according to an illustrative embodiment
  • Figures 34A and 34B are images of NaOCl concentration dependence of CEST spectra for Eu(III)-Bl recorded at 9.4 T and 298 K in 10 mM HEPES buffer and NaOCl concentration dependence of the ratiometric plot for Eu(III)-Bl by exploitation the ratio of CEST intensity at 15 54 ppm to 49 ppm according to an illustrative embodiment;
  • Figure 35 is a pH dependence of CEST ratiometric image according to an illustrative embodiment.
  • Figure 36 shows a decomposition of Eu(III)- to form Eu(III)-l by ROS according to an illustrative embodiment.
  • Magnetic resonance imaging is one of the most versatile diagnostic tools for exploitation of intrinsic tissue and structural differences.
  • the specificity and sensitivity of MRI may be further enhanced by the use of paramagnetic complexes or magnetic particles to shorten the water relaxation times (Ti, T , or T *).
  • Gd 3+ -based ⁇ -shortening contrast agents are widely used in clinical exams, an approach called chemical exchange saturation transfer (CEST) has been used to generate image contrast by taking advantage of slow-to-intermediate exchange conditions (k eK ⁇ ⁇ ) between the agent liable proton pool and bulk water pool.
  • CEST chemical exchange saturation transfer
  • Paramagnetic versions of CEST agents may be used instead of Gd 3+ -based imaging agents.
  • Image contrast produced by a PARACEST agent may be switched "on” or “off by application of frequency-selective radio frequency pulses. This feature may allow potential multiplexing of agents in a single study.
  • contrast in these systems may be based on chemical exchange of either liable protons or water molecules, the agents may be extremely sensitive to exchange rates (k ex ).
  • PARACEST agents may have exchangeable protons that are shifted well away from the bulk water resonance and this may be desireable over diamagnetic CEST agents.
  • the sensitivity to exchange rates may facilitate development of concentration-independent agents that respond to biological or physiological events (biologically responsive sensors).
  • PA ACEST sensors using a variety of design platforms may be utilized for measuring pH, temperature, Zn 2+ , glucose, nitric oxide, phosphate esters, enzyme activity, and other parameters.
  • the CEST contrast may be highly sensitive and dependent on the exchanging rate (fc x ) of mobile protons
  • modulation of k eK is normally used in the development of PARACEST sensor for detection of a variety of biological species such as glucose, lactate, nitric oxide, phosphate ester, and enzyme.
  • PARACEST sensors may have a CEST signal that changes intensity in response to external stimuli. This may require a separate measure of agent concentration (ratiometric imaging measurements) to obtain quantitative results.
  • Some exceptions may include agents that use either a cocktail of agents or single agents having multiple weakly shifted -NH exchangeable protons for ratiometric imaging. The latter design feature may rely on exchange sites that are relatively close to the bulk water frequency (e.g., ⁇ 15 ppm).
  • Responsive PARACEST contrast agents may lack the capacity for ratiometric imaging measurements, which limits their potential use in vivo because the agent concentration must also be known.
  • the illustrative embodiments may provide a solution to the problems above, among others, by presenting, in one embodiment, a novel europium(III) DOTA-monoketonetris(amide) complex comprising a single highly shifted water exchange peak whose frequency varies as a function of solution pH. Based on the observation that the CEST resonance frequency shifts in response to pH and that CEST ratiometric imaging may be used for taking direct measurements of pH, aspects of the illustrative embodiments may be converted to a general platform for imaging a variety of other biological parameters.
  • the illustrative embodiments describe a particular new class of molecules that act as sensors of biological and physiological parameters such as tissue acidity (pH), temperature, reactive oxygen species (ROS), and the presence of particular enzymes, and which may also be used in other clinical applications, including, but not limited to, drug delivery.
  • the agents in the illustrative embodiments may provide a direct quantitative readout of a parameter of interest using a standard clinical imaging scanner.
  • the agents of the illustrative embodiments may be used clinically for diagnosis of a variety of diseases including cancer, diabetes, and heart disease, among others.
  • the Eu 3+ -based PARACEST agents described in the illustrative embodiments may provide a concentration independent measure of pH by ratiometric CEST imaging.
  • the agent may be used to measure pH by use of ratiometric CEST imaging without the need of a second concentration marker as required with some existing PA ACEST agents.
  • ratiometric image data may be collected at CEST activation frequencies widely separated from the bulk water frequency, and the acid dissociation constant (pK a ) of the sensor may be suitable or nearly ideal for imaging pH over a range of interest for detecting abnormal physiology.
  • deprotonation (i.e., removal) of the phenolic proton may result in conjugation of the resulting quinone-like structure with the acetyl oxygen atom coordinated to the Eu3+ ion, as shown in the bottom of Figure 1.
  • Figure 2 illustrates the UV-vis spectra of Eu-1 (20 ⁇ ) recorded as a function of solution pH according to an illustrative embodiment.
  • the arrows in Figure 2 indicate the direction of the absorbance changes with increasing pH in one embodiment, and the figure insert illustrates an example of the titration curve showing the increase in absorbance at 360 nm as a function of pH.
  • the absorption spectrum of Eu-1 in Figure 2 displays a bathochromic shift from 310 to 360 nm as the phenolic proton is removed, consistent with extended derealization of the phenolate anion through the ⁇ system to form the quinone-like structure. This shift may place a more negative charge on the carbonyl oxygen atom coordinated to the Eu 3+ ion shown in the bottom of Figure 1.
  • the pK ⁇ derived from these optical data (6.7 ⁇ 0.1) may be suitable or nearly ideal for pH measurements in biological systems.
  • FIG. 3 illustrates the pH dependence of CEST spectra for Eu-1 recorded at 9.4 T and 298 K according to an illustrative embodiment.
  • the figure insert provides an expanded view of the water exchange peak as a function of pH.
  • the CEST spectra of Eu-1 recorded at five different pH values in Figure 3 show a change in exchange frequency from pH 6.0 to 7.6.
  • the pK ⁇ of Eu-1 derived from the CEST data may be 6.5 ⁇ 0.1, which may be nearly identical to the value determined optically.
  • One example CEST feature of having an unusually large change in exchange frequency suggests it may be possible to image pH directly using Eu-1 and ratiometric CEST imaging. For example, the ratio of CEST intensities after activation of Eu-1 at 55 versus 49 ppm may be nearly linear between pH 6.0 and 7.6 and independent of Eu-1 concentration.
  • Eu-1 may offer several advantages over previously reported ratiometric pH indicators.
  • the pH measurement may be made using a single reagent rather than a cocktail of agents.
  • the exchange peak in Eu-1 may be shifted well away from the frequency of solvent protons, so the Eu-1 agent may be activated without concern about partial off-resonance saturation of bulk water protons.
  • Figure 4 illustrates various non-limiting example images of a phantom containing either water (w) or 10 mM Eu-1 adjusted to the indicated pH (9.4 T, 298 K), wherein image (a) shows proton density images, image (b) shows ratio water intensities after activation at 54 versus 47 ppm, and image (c) shows calculated pH values as determined by ratiometric CEST imaging in one embodiment.
  • image (a) shows proton density images
  • image (b) shows ratio water intensities after activation at 54 versus 47 ppm
  • image (c) shows calculated pH values as determined by ratiometric CEST imaging in one embodiment.
  • CEST images of a phantom prepared from five Eu-1 samples adjusted to different pH values (plus a control sample lacking Eu-1) are collected at two presaturation frequencies, 54 and 47 ppm.
  • the CEST intensity ratio in these two images is shown in Figure 4(b) as a color map.
  • the sample containing water alone may show nearly perfect cancellation, while the CEST ratio in samples of Eu-1 may vary from 0.43 (sample at pH 6.0) to 2.32 (sample at pH 7.6).
  • the pH values derived from the CEST images as illustrated in Figure 4(c) may match those values measured by use of a pH electrode as illustrated in Figure 4(a).
  • the bound water lifetimes ( ) of the protonated and deprotonated Eu-1 species may be determined by fitting CEST spectra recorded at pH 5.0 and 8.0, respectively, to the Bloch equations. This fitting procedure may give values of 239 /s at pH 5.0 and 120 /s at pH 8.0. This result may be considered to be consistent with the expected increase in water exchange rate as the acetyl oxygen donor atom gains a more negative charge at the higher pH value. The width of the water exchange peak in Eu-1 may broaden somewhat at high pH values, again consistent with faster water exchange.
  • Water exchange in Eu-1 may be even faster at 310 K as expected ( may be found to be 123 and 45 /s for the protonated versus deprotonated species at these same two pH values) while the frequency shifts in the bound water exchange peak may be similar to those found at 298 K. This indicates that Eu-1 may also be effective for ratiometric CEST imaging of pH at physiological temperatures as well.
  • Eu(III)-Al may be used to image pH by MRI using ratiometric CEST principles. Deprotonation of a single phenolic proton between pH 6 and 7.6 may result in an ⁇ 5 ppm shift in the water exchange CEST peak which may be detected by MRI. In one embodiment, ratiometric imaging may be achieved by collecting two CEST images at two slightly different activation frequencies providing a direct readout of solution pH without the need of a concentration marker.
  • a structurally novel complex Eu(III)-Al may be used to image pH by using ratiometric CEST principles. Deprotonation of a phenolic proton may result in an approximate 5 ppm downfield shift in the water exchange CEST resonance frequency over pH 6.0 ⁇ 7.6. In one example, this shift may enable the elimination of the need of a concentration marker required in the regular ratiometric CEST imaging by following two CEST images of single bound water CEST resonance frequency at two slightly different activation frequencies. Meanwhile, Eu(III)-Al may emit phenol- sensitized luminescence.
  • the luminescence may be switched "off" with the light-promoted deprotonation of the phenolic proton, which may open up the possibility of pH imaging by luminescence.
  • the Eu(III)-Al may be used as a basic platform in the development of other types of responsive imaging agents as well. This may be demonstrated in Eu(III)-B 1 , which may be built by replacing the phenolic proton in Eu(III)-Al with >ara-aminophenyl group.
  • Eu(III)-B 1 may irreversibly be degraded by some reactive oxygen species (ROS) such as OCl " and ⁇ to Eu(III)-Al. Still, downfield shift in the bound water CEST peak accompanying this structural transformation may render the ratiometric measure of hROS concentration without considering the use of concentration marker.
  • ROS reactive oxygen species
  • PARACEST-based MRI contrast agents for ex vivo, in vitro, or in vivo determination of chemical parameters of diagnostic interest such as pH, highly reactive oxygen species (hROS), biological metal ion concentrations, or enzyme activity, among others, may be created. Deprotonation or cleavage of a specific chemical bond in the agent may result in the downfield shift of CEST resonance frequency which may be used by ratiometric imaging of the above-mentioned parameters by MRI.
  • the PARACEST-based MRI contrast agents described in the illustrative embodiments may have a tetraazacyclododecane ligand and a paramagnetic ion that provides a ratiometric imaging measurement.
  • CEST effects may be made independently of the absolute concentration of the contrast agent by using a ratiometric method.
  • the ratiometric method may be applied to systems with two different pools of mobile protons, either present in the same molecule or provided by two different contrast agents, which may be activated sequentially and selectively.
  • a shift in the water proton resonance frequency (PRF) method may also be independent of agent concentration.
  • the PRF method may be used for MRI thermometry owing, at least in part, to the strong temperature dependence of the chemical shift of bound water in Eu(III)-DOTA-tetraamide complexes.
  • the bound water resonance in some Eu(III)-DOTA- tetraamide complexes may vary considerably due to the variation of local coordination environment by the introduction of different amide side-chains, from which multi-frequency PARACEST contrast agents may be developed.
  • PRF-based ratiometric sensors may be built in which the coordination environment changes are strong enough to shift the bound water resonance frequency of Eu(III)-DOTA-amide complexes by external stimuli.
  • the illustrative embodiments may include a pH responsive PARACEST agent that includes a tetraazacyclododecane ligand that may have a general formula:
  • Figure 5 illustrates a synthesis scheme for the preparation of Al according to one illustrative embodiment.
  • Figure 6 illustrates the proton equilibrium in Eu(III)-Al complex according to one illustrative embodiment.
  • Figure 8 is a plot illustrating pH dependence of CEST peak position for Eu(III)-Al according to one illustrative embodiment.
  • Figure 10 is a plot illustrating pH dependence of the ratiometric plot by exploitation of the ratio of CEST intensity at 55 ppm to 50 ppm according to one illustrative embodiment.
  • UV-vis pH titration results may demonstrate the proton equilibrium for the Eu(III)-Al as shown in Figure 6.
  • the acidity of phenol moiety may be greatly enhanced due, at least in part, to the extensive electron conjugation of phonate by forming a quinone-like resonance structure for the deprotonated form of Eu(III)-Al.
  • Eu(III) may experience a much stronger ligand field due to an increased electron donation to the metal center upon the phenol deprotonation, which in turn may result in not only a weakening of the metal- water coordination and accelerating water exchange, but also an increase in dipolar NMR shift of complex and downfield shift of the CEST resonance frequency.
  • the pH dependence of CEST profiles for Eu(III)-Al may confirm the above expectation (Figure 7).
  • the CEST profiles may show pH dependence of not only changes in CEST intensity (1-M Mo) but also in CEST resonance frequency.
  • the pH dependence of CEST resonance frequency ( Figure 8) may correlate with the ligand field of complex. Specifically, the CEST exchange frequency may shift from 50 ppm at pH 4.5 to 55 ppm at pH 8.4, a shift that is large enough for a ratiometric determination of pH.
  • hROS agents that are responsive to the highly reactive oxygen species (hROS) may be built on the pH responsive agent platform.
  • the embodiment of hROS agents comprising a tetraazacyclododecane ligand may have a general formula as follows:
  • Figure 11 illustrates a synthesis scheme for the preparation of Bl according to an illustrative embodiment.
  • Figure 12 illustrates a reaction of Eu(III)-Bl with hROS producing Eu(III)-Al according to an illustrative embodiment.
  • Figure 14 is a plot illustrating NaOCl concentration dependence of the ratiometric plot for Eu(III)-Bl by exploitation of the ratio of CEST intensity at 54 ppm to 49 5 ppm according to an illustrative embodiment.
  • Figure 15 is a plot illustrating CEST ratiometric responses (54 ppm /49 ppm) of Eu(III)-Bl (10 mM) in the presence of 50 mM various hROS according to an illustrative embodiment.
  • hROS Highly reactive oxygen species
  • O 2 "' superoxide
  • H 2 O 2 hydrogen peroxide
  • ⁇ hydroxyl radical
  • Colorimetric, chemiluminescent, or fluorescence-based assays may be used to measure cell-derived hROS.
  • Various fluorescence hROS sensors may be used to meet the different assay requirements and a variety of design mechanisms such as the formation of endoperoxide, deprotection, or O-dearylated may be employed to create the new sensors.
  • MRI may have high spatial resolution and the ability to extract, simultaneously,
  • hROS responsive PARACEST agent present in the illustrative embodiments is shown in Figure 12.
  • the agent may be O-dearylated upon reaction with hROS to yield a deprotonated pH responsive agent. This may enhance the ligand field experienced by the Eu(III) metal center, which in turn may downfield shift the CEST resonance frequency.
  • PARACEST agents in the illustrative embodiments are ⁇ - galactosidase responsive agents, which may be designed on the pH responsive agent platform.
  • the embodiment of ?-galactosidase responsive agents comprising a tetraazacyclododecane
  • 25 ligand may have a general formula as follows:
  • Figure 16 illustrates a synthesis scheme for the preparation of CI according to an illustrative embodiment.
  • Figure 17 illustrates a ?-galactosidase catalyzed hydrolysis of Eu(III)- Cl producing Eu(III)-Al according to an illustrative embodiment.
  • FIG. 17 The structure of a ?-galactosidase responsive agent is shown in Figure 17 according to an illustrative embodiment.
  • the ?-D-galactopyranoside-phenyl linkage may be hydrolyzed by the enzyme; ?-galactosidase may yield the pH responsive agent; ?-galactosidase catalysis removal of yff-D-galactopyranoside may produce the pH responsive agent.
  • Figure 18 in the absence of ?-galactosidase, the CEST spectrum for Eu(III)-Cl may exhibit a typical profile that may be characteristic of the regular complexes.
  • the CEST profile may change with a little decrease of the CEST resonance frequency at 48 ppm and the appearance of a shoulder in the 52-55 ppm range over time.
  • the ratiometric CEST intensity ratio (54 ppm / 49 ppm) may also experience a change from the initial value of 0.18 to 0.35 after four hours of reaction time in the presence of the enzyme ( Figure 19).
  • the ?-galactosidase concentration and ?-galactosidase catalyzed kinetics may be evaluated by using the Eu(III)-Cl.
  • Ligand Al may be prepared according to Figure 5 in one embodiment.
  • l-(4- (benzyloxy)phenyl)ethanone (6) and N,N',N"-[l,4,7,10-tetraazacyclododecane-l,4,7-triyltris(l- oxo-2,l-ethanediyl)]tris-glycine, ⁇ , ⁇ , ⁇ '-triethyl ester (4) may be synthesized by, e.g., established procedures.
  • THF Upon the disappearance of ethyl ester groups, THF may be evaporated under reduced pressure. The resulting solution may be adjusted to pH 2.0 by addition of HC1 and lyophilized to dryness giving the title compound as a pale yellow solid, which may be purified by preparative HPLC to give pure ligand Al as a white hygroscopic powder (136 mg, 83%).
  • Ligand Bl may be prepared according to Figure 11 according to one illustrative embodiment.
  • l-(4-(4-nitrophenoxy)phenyl)ethanone (7) may be synthesized by, e.g., established procedures.
  • Compound (9) (2.5 g, 2.9 mmol) may be dissolved in ethanol (50 mL), and 10% palladium on carbon (0.1 g) may be added.
  • the reaction mixture may then be shaken on a Parr hydrogenator under a H 2 pressure of 40 psi at room temperature for 12 h.
  • Compound (2) (0.5 g, 0.6 mmol) may be added into a mixture of LiOH (0.2 M, 14 mL) and THF (5 mL), and may be stirred at 0 °C for 2 hours, and then may be stirred at room temperature. The saponification reaction may be monitored by NMR.
  • THF may be evaporated under reduced pressure.
  • Ligand CI may be prepared according to Figure 16 according to an illustrative embodiment. N,N , ,N"-[[10-[2-[4-((2',3',4',6'-tetra-O-acetyl- y ff-D-galactopyranoside))phenyl]-2- oxoethyl]-l,4,7,10-tetraazacyclododecane-l,4,7-triyl]tris(l-oxo-2,l-ethanediyl)]tris-glycine, ⁇ , ⁇ ', ⁇ -triethyl ester (11).
  • Compound (11) (0.185 g, 0.25 mmol) may be added into a mixture solution of water (5 mL) and CH 3 CN (5 mL) and may be stirred at 0 °C.
  • the pH of solution may be tuned to 6.0, and stirring may occur for another 12 hours and the excess of free Eu 3+ may be checked. If no free Eu 3+ is detected, the aqueous solution may be lyophilized to give the complex as white powder. The complexes may be used without further purification.
  • NMR method 3 ⁇ 4 and 13 C NMR spectra may be recorded on, e.g., a Bruker AVANCE III 400 NMR spectrometer operating at 400.13 and 100.62 MHz, respectively.
  • CEST spectra of complexes in pure water may also be recorded on the same spectrometer operating at 400.13 MHz.
  • Pre-saturation pulses of 2 s duration may be applied at four saturation powers of 9.4, 14.1, 18.8, and 23.5 ⁇ .
  • the CEST spectra may be fitted to the Bloch equations with 3-pool model by use of a nonlinear fitting algorithm written in, e.g., MATLAB ® 7 (Mathworks Inc., Natick, MA).
  • FIG. 7 shows the pH dependence of CEST profiles for Eu(III)-Al at 298 K according to an illustrative embodiment.
  • the CEST profiles show pH dependence of not only the CEST intensity (1-M s Mo) changes but also CEST resonance frequency changes.
  • CEST intensities may increase from 28% at pH 2.5 with a CEST resonance frequency of 46.1 ppm to a maximum intensity of 55% at pH 4.5 with a CEST resonance frequency of 50.0 ppm.
  • the CEST intensities may level off over the pH range of 5 to 6. Then CEST intensities may decrease gradually to 51% at pH 7.6 but with a significant CEST resonance frequency increment to 54.7 ppm.
  • the CEST intensities may decrease to 28% at pH 8.4 with a CEST resonance frequency of 55.1 ppm.
  • the corresponding 3 ⁇ 4 at different pH which may be determined by fitting modified Bloch equations to the CEST spectra using a nonlinear fitting algorithm written in MATLAB ® , may correlate well with the CEST intensity changes.
  • x m of 150 to 200 over the pH range of 4.5 to 7.6 may be close to the optimal exchange rate for CEST producing.
  • the pH dependence of CEST frequencies ( Figure 8) may correlate well with the ligand field of complex.
  • a sigmoidal curve may be found by fitting the CEST frequencies over the pH range of 4.5 to 8.4, which gives a pAT a of 6.5.
  • hROS responsive PARACEST contrast agent Neutrophils are a population of circulating blood cells for defending against pathogenic microorganisms. PMA and fatty acids may activate the NADPH oxidase in neutrophils to generate (3 ⁇ 4 ' . Then (3 ⁇ 4 ' may be converted to 3 ⁇ 4(3 ⁇ 4 and (3 ⁇ 4, which are thought to be precursors of more potent oxidizing agents, such as HO, OCl " , and (3 ⁇ 4 "' . These highly reactive oxygen species may play key roles in killing bacteria.
  • ?-galactosidase responsive PARACEST contrast agent 25 [00102] ?-galactosidase responsive PARACEST contrast agent.
  • ⁇ - galactosidase catalyzed hydrolysis of Eu(III)-Cl may be performed under conditions as follows. A small solution of ?-galactosidase in Tris buffer (pH 7.4, 10 mM) may be added to a solution of the agent (500 uL, 10 mM ) in Tris buffer (pH 7.4, 10 mM) to get 66 units of ⁇ -galactosidase in solution mixtures. The mixtures may be incubated at 37 °C. The CEST of mixtures may then
  • Figure 18 displays the CEST spectral changes for Eu(III)-Cl in the absence and presence of 66 U ?-galactosidase according to an illustrative embodiment.
  • the CEST resonance frequency for Eu(III)-Cl may be at 48 ppm.
  • the shape of the CEST spectrum may change significantly over time. Specifically, CEST intensity at 48 ppm may decrease with the appearance of a shoulder in the 52-55 ppm range, which may be considered to be consistent with the CEST resonance frequency of the expected hydrolyzed product.
  • ratiometric determination of ?-galactosidase may be possible using CEST.
  • the CEST intensity ratio (54 ppm / 49 ppm) for the complex only spectrum may be 0.18. After four hours, the value for the complex-enzyme mixtures may increase to 0.35 ( Figure 19).
  • the ?-galactosidase concentration and ?-galactosidase catalyzed kinetic may be evaluated by using the Eu(III)-Cl.
  • the CEST ratiometric measurement may be achieved by following the shifting of signal resonance frequency, an approach that may be analogous to those used in ratiometric optical sensors.
  • the CEST intensity and resonance frequency arising from the coordinated water molecule of Eu(III) DOTA-tetramide complexes may be independent of pH over 5-8, in a non-limiting example.
  • the bound water CEST properties in Eu(III) DOTA-tetramide and its derivatives may be considerably modulated by varying the electron donating ability of amide side chains to central metals, from which multi-frequency PARACEST agents may be subsequently developed.
  • identification of a system is possible whose CEST resonance frequency position may be regulated if the electronic donation properties of the ligand side chain were altered to a significant extent in response to the external stimulus.
  • Figure 20 is an image of the structure of the Eu(III)-Al and Eu(III)-Bl according to an illustrative embodiment.
  • the agent Eu(III)-Al ( Figure 20) is a complex that may show the CEST resonance frequency shifting with pH.
  • Eu(III)-Al may be built on a tradeoff between modulating electronic donation properties of side chain and meanwhile maintaining the slow water exchange for CEST generation by replacing only one of the glycinate side arm in Eu(III)-DOTA-(gly with acetyl-phenol unit, in one non-limiting example.
  • the phenolate electron may be transferred to Eu-carbonyl coordination over the aromatic bridge, thereby regulating the CEST properties.
  • the optical imaging modality may be introduced to and combined with the PARACEST imaging modality by utilizing the energy transfer ability of phenol subunit.
  • the optical imaging modality may compensate the MR imaging modality for its low sensitivity, in one example.
  • luminescence of Eu(III) complexes may be a tool for sensing biological parameters due to their unique photophysical properties such as long wavelength emission and long-lived excited states, based on which the time-resolved luminescent measurements may be scarcely affected by shorter-lived auto fluorescence present in vivo and interferences associated with Rayleigh scattering.
  • Ligand may be prepared according to the synthesis route shown in Figure 22 according to illustrative embodiments.
  • the bromination of compound S6 and S6' with brominating agent TBA Br 3 may give side arm S5 and S5' in good yields.
  • the side arms may be alkylated with compound 4 in acetonitrile with sodium hydrogen carbonate as a base affording macrocyclic intermediate 3 and 3 ', respectively.
  • the consequent hydrogenolysis step over a palladium on carbon catalyst may offer ester-contained compounds in fairly high yield.
  • the ethyl ester groups may be hydrolyzed under basic condition giving ligand Al and 1 ', which may be characterized on the basis of 3 ⁇ 4 and 13 C NMR, MS, and elemental analysis.
  • Complexations may be performed in water by mixing stoichiometric amounts of Eu(triflate)3 and ligands. The complexes may be fully formed within 12 hours at 70 °C.
  • Figure 23 is an image of the 'H-NMR spectra of Eu(III)-Al complex (20 mM) recorded in D2O at 289K with a pD of (a) 5.0 and (b) 8.9 according to an illustrative embodiment. Resonance frequency from HDO is marked by asterisk.
  • the ⁇ -NMR spectrum of Eu(III)-Al in D2O may be complicated due to the lack of molecular symmetry at pD 5.0 (a).
  • resonance frequencies may be broad. Broader singlet at 7.20 ppm and sharper singlet at 6.59 ppm may be assigned as aromatic protons based on COSY spectral analysis, meaning the dipolar NMR chemical shift effects from metal center on aromatic protons may be fairly small.
  • Ln(III) complexes of DOTA- tetraamide and its derivatives may normally exist in the form of two inter-converting coordination isomers: square anti-prism (SAP) and twisted square antiprism (TSAP).
  • the axial protons of macrocyclic backbone may be found between 24 and 36 ppm in the SAP isomers and between 5 and 12 ppm in the TSAP isomers for Eu(III) complexes. Based on this information, three singlet resonance frequencies integrated with an intensity ratio of 1 : 2 : 1 between 20 and 30 ppm may be from axial protons of a descent SAP isomer. Very weak signals from the descent TSAP isomer, less than 5%, may be observed between 7 and 9 ppm indicating Eu(III)- Al may exist predominantly as the descent SAP isomer in the solution.
  • Well-defined resonance frequencies may be observed after the pD rises to 8.9.
  • an expected number of 27 aliphatic C-H protons according to the structure may be matched by the observed number of resonance frequencies ( Figure 23(b)).
  • the axial protons may split into four singlet resonance frequencies with an integral intensity ratio of 1 : 1 : 1 : 1 and three of them may shift more than 5 ppm to downfield relative to those at pD 5.0, and may indicate significant changes in the local structure and coordination environment of Eu(III) center.
  • the aromatic protons may shift to upfield, which may be due to the increased shielding effects with the deprotonation of phenolic proton.
  • little upfield shifts of the aromatic protons may be observed over the pD 2.9 ⁇ 6.0. After that, very quick upfield shifts may be found until pD 8.3, in a non-limiting example.
  • Figure 24 is a graph of pD dependence on the chemical shift of an aromatic proton according to an illustrative embodiment.
  • the broader singlet resonance frequency at 7.20 ppm at pD 5.0 may be merged into solvent residue resonance frequency above pD 8.3.
  • the shifts of the sharper singlet aromatic resonance frequency as a function of pD may give a sigmoidal curve (Figure 24).
  • this result may be consistent with a simple proton equilibrium, from which the pK ⁇ * of equilibrium in D 2 O may be determined using standard least-squares fitting technique.
  • Figure 25A and 25B are plots of pH dependence of UV-vis spectra for (a) Eu(III)-Al and (b) free ligand Al (20 uM) recorded in an aqueous solution according to an illustrative embodiment. Arrow indicates the direction of changes as the pH increases. The protonation equilibrium of Eu(III)-Al was further examined through spectrophotometric titrations in the aqueous solution.
  • Figure 25A shows the UV-vis spectral changes of Eu(III)-Al as a function of pH, and the absorbance spectra of Eu(III)-Al may be highly pH dependent.
  • ⁇ - ⁇ * transition of the aromatic system may give an absorbance band with at 310 nm This transition band may begin to drop gradually when the solution pH is raised to 5.2, and a new charger transfer band with ⁇ ⁇ at 360 nm may appear with further pH increments. The full disappearance of ⁇ - ⁇ * transition may be observed above pH 7.7 accompanying no further rise in the charger transfer band.
  • Figure 26 is a plot of a normalized titration curve showing the increase in absorbance at 360 nm for Eu(III)-Al ( ⁇ ) and at 340 nm for free ligand Al (A) as a function of increasing pH according to an illustrative embodiment.
  • Symbols may represent experimental data, and lines may represent fitted data to simple sigmoidal function. There may exist three well-defined isobestic points at 238, 262, and 328 nm and the titration profile of pH versus absorbance intensities at 360 nm in Figure 26 may exhibit a sigmoidal curve supporting a simple phenol proton equilibrium. A pAT a of 6.7 ⁇ 0.1 from the UV-vis titrations may be close to that from the above NMR titrations.
  • UV-vis pH titrations may be carried out on free ligand 1.
  • Free ligand may display a ⁇ - ⁇ * transition with at 275 nm under acidic conditions and a charger transfer with Xmax at 340 nm under basic conditions (Figure 25B), both of which may experience a hypsochromic shift with respect to the corresponding Eu(III) complex ( Figure 25A).
  • Figure 25B a charger transfer with Xmax at 340 nm under basic conditions
  • Figure 25A hypsochromic shift with respect to the corresponding Eu(III) complex
  • no well-defined isobestic point may be observed during the entire pH titration suggesting, e.g., the complication of proton equilibrium.
  • the proton equilibrium associated with a charger transfer process may be evaluated.
  • Figure 27 is a schematic of the proton equilibrium of free ligand Al and resonance representation of the deprotonated Eu(III)-Al complexes according to an illustrative embodiment.
  • the extent of electron conjugation and the easiness of proton deprotonation may be dramatically enhanced, in one example, by forming a quinone-like resonance structure for the deprotonated Eu(III)-Al , by which the excess of electrons on the para ketone subunit may be consumed by forming a strong Eu(III)-oxygen coordination band, so it may be the presence of Eu(III) that facilitates the deprotonation of phenolic proton to give a relatively low pK ⁇ of equilibrium.
  • the above NMR and absorbance spectral studies may reveal the reversible structure changes and, in turn, extensive electron derealization in complex controlled by pH.
  • Eu(III) may experience much stronger ligand fields due to an increased ligand electron donation to the metal center upon the phenolic deprotonation. This may be detected as a change in Eu(III) emission intensity and CEST property.
  • All emission transitions may be particularly sensitive to pH, in one example.
  • the emission may be switched "off above pH 6.0.
  • the decrease in emission intensity may be paralleled with a decrease in the luminescent lifetime.
  • the contribution factor from phenol unit an unknown value
  • Endeavors to determine the q value at high pH may fail, in one example, because of a sharp drop of lifetimes with pH, the complex luminescent lifetimes may be smaller than 100 above pH 5, which may be too short to be measured accurately with the available instrumentation.
  • Figure 29 is a plot of the pH dependence of luminescence intensity changes at
  • the acidities of phenol and its derivatives may be greatly enhanced in the excited states due to the redistribution of the oxygen electronic densities upon excitation.
  • a ⁇ " ⁇ " ⁇ ,: ⁇ Q f 3 6 m excited state for phenol may be much lower than the ⁇ 81 TM 11 * 1 of 10.6 in the ground state.
  • a consequence for the existence of the ESPT processes may be a complication in the determination of the proton dissociation constants with fluorescence titrations because of a dependence of fluorescence on the acid-base chemistry of the excited state as well as the ground state.
  • the "inflection region" from the fluorescence titration curve may extend over the entire pH interval between the ground and excited state pK & values, and the resulting pj ⁇ "" mt from fluorescence titration may be a joint result of the ⁇ ⁇ ⁇ and the ⁇ 1 ⁇ 0 , lying just between them.
  • p ⁇ PP 3 TM 1 ' from luminescence titrations may be much lower than pX 8 TM 1 " 1 * 1 from UV-vis titrations, in one example.
  • Figure 30 is an image of a Jablonski diagram of the Eu(III)-Al according to an illustrative embodiment, which shows that the proximity of the triplet energy level of the quinone group may cause substantial back energy transfer. Structure change may occur with the deprotonation of phenolic proton, which may account for the significant "on-off ' switching in luminescence with the raising of pH.
  • the triplet energy of an aromatic chromophore may be at least above 22000 cm "1 ( Figure 30); otherwise, the back energy transfer from the excited 3 ⁇ 4o level to chromophore may quench the luminescence.
  • the quinone group may have an triplet energy around 18300 cm “1 , which may be smaller than the threshold value for efficient energy transfer.
  • the small energy difference between the quinone like moiety and the Eu(III) excited state 3 ⁇ 4o may tend to result in the occurrence of a significant back energy transfer process at the expense of Eu(III) emission.
  • an increased ligand electron donation to the Eu(III) metal center may result in not only a weakening of the metal- water coordination and accelerating water exchange but also an increase in Eu(III) ligand field strength and, consequently, dipolar NMR shift of ligand.
  • the downfield shifting of axial protons may be indicative of an increase in the ligand field strength with the deprotonation of phenolic proton, and bound water resonance may shift to downfield due to ligand field induced enhancement in the dipolar NMR shift ability of Eu(III).
  • a ratiometric measurement may be performed by following a single proton pool with a larger chemical shift difference ( ⁇ ⁇ 50 ppm) rather than following multiple proton pools from a cocktail of agents.
  • Bloch equations may correlates well with the CEST intensity and profile changes, in one embodiment.
  • x m of 200 at pH 6.0 may increase a little to 218 at pH 6.4 and then may steadily decline to 145 at pH 7.6, which may indicate that the Eu-water coordination gets
  • Eu(III)-Al as a platform for the design of hROS responsive agents.
  • the illustrative embodiments may show how the optical and PARACEST modality may be integrated into a single agent for pH sensing purpose and how the PARACEST agent may 15 ratiometrically be made to sense the pH without the need of a concentration marker.
  • Eu(III)- Al may be employed as a platform for building more responsive agents.
  • the illustrative embodiments may demonstrate Eu(III)-Bl herein as part of a program to develop PARACEST agent for potentially sensing the highly reactive oxygen species (hROS).
  • hROS are reactive molecule oxygen such as hydrogen peroxide (H 2 O 2 ) or
  • hROS may form as a natural by-product of the normal metabolism of oxygen.
  • H 2 O 2 myeloperoxidase into hypochlorite, OO " , another potent cytotoxic 25 species. Consequently, the detection of ROS may be used to understand the biological processes like oxidative stress which eventually leads to cell death.
  • Methods including chemiluminescence and fluorescence may be used to measure cell-related ROS production and accumulation, but these established assays may suffer from an inherent drawback of low spatial resolution. This may be compensated by the MRI based assays.
  • Aryloxyphenols or aryloxyaniline may be O-dearylated by hROS such as HO, reactive intermediates of peroxidase, and cytochrome P450, based on which several irreversible fluorescence probes for ROS may be developed.
  • hROS responsive PARACEST agent may be built if the phenolic hydroxyl proton is replaced with para-aniline ( Figure 36).
  • Eu(III)-l ' may be converted into Eu(III)-l after the O-dearylation reaction, and then the ratiometric CEST response may be observed as long as a proper condition is selected.
  • the new absorbance band may happen to be in the same position as that of deprotonated Eu(III)-Al ( Figure 25A), which may support the occurrence of O-dearylation reaction displayed in Figure 36.
  • a large excess of OC1 " may be needed to push this irreversible reaction forward.
  • no luminescence may be detected in Eu(III)-Bl, which may be ascribed to the fact that the HOMO level of aniline moiety may be high enough to induce the photoinduced electron transfer quench of the acetyl-aryloxy antenna adjacent to the Eu(III) metal center.
  • Figure 34A shows NaOCl concentration dependence of CEST spectra for Eu(III)-
  • the reactivity of Eu(III)-B 1 complex with OC1 " was examined by CEST titration in HEPES buffer with an agent concentration of 10 mM at 298 K as shown in Figure 34A.
  • a structurally novel Eu(III)-Al complex may be synthesized and characterized using a range of spectroscopic techniques.
  • Eu(III)-Al may shows pH controlled "off-on" luminescence, which may be potentially used as in vitro optical imaging agent for studies of acidic organelles such as lysosomes and endosomes of live cells.
  • the NMR experiments demonstrate the local coordination environment of Eu(III) may significantly be modulated by the deprotonation of phenolic proton resulting in the downfield shift in the bound water exchange CEST resonance frequency. This shift may enable the elimination of the need of a concentration marker required in the regular ratiometric CEST imaging.
  • the Eu(III)-Al may be employed as a basic platform in the development of other types of responsive imaging agents as well.
  • NMR spectrometer 400 NMR spectrometer.
  • a pre-saturation pulse of 2 s may be applied at saturation powers of 14.1 ⁇ during the CEST acquisitions.
  • CEST imaging may be recorded on, e.g., Varian 9.4 T small animal imaging system. pH values of the samples for CEST may be maintained by MES or HEPES buffers (5 mM).
  • the CEST spectra may be fitted to the Bloch equations with 3-pool model by use of a nonlinear fitting algorithm written in, e.g., MATLAB ® 7 (Mathworks Inc., Natick, MA). Melting points may be determined on, e.g., a Fisher-Johns melting point apparatus without correction.
  • the pH of titration samples may be measured with, e.g., a Denver Instrument
  • UltraBasic UB-5 pH meter and the pH may be adjusted by addition of concentrated solutions of KOH or HCl.
  • the D 2 O solutions of KOD or DCl may be used to adjust the pD for the titration performed in D 2 O.
  • pD values in D 2 O solutions may be calculated by adding a constant of 0.4 to the pH*, which may be a direct reading in a D 2 O solution ofH 2 0-calibrated pH meter.
  • ⁇ ⁇ of equilibrium may be determined using standard least-squares fitting technique from the corresponding titration data.
  • Ultraviolet absorbance spectra may be recorded using, e.g., Varian Cary 300 Bio UV/Vis spectrophotometer equipped with thermostatted cell holders. Luminescent spectra and lifetime measurements may be recorded on, e.g., an Edinburgh Instruments FL/FS900CDT fluorometer equipped with a 450 W xenon arc lamp and a 100 W ⁇ 920H flash lamp. Full emission spectra may be recorded from 525-725 nm using a 0.5 nm step size.
  • Responsive PARACEST agents may have a CEST signal that changes intensity in response to external stimuli but these may require a separate measure of agent concentration.
  • Some exceptions may be agents that incorporate a cocktail of agents with weakly shifted -NH exchangeable protons for ratiometric imaging, but this design may have the exchange site relatively close to the bulk water frequency (typically ⁇ 15 ppm away).
  • This problem is addressed by presenting in the illustrative embodiments a novel europium(III) DOTA- monoketone-trisamide complex having a highly shifted water exchange CEST peak (50-55 ppm) that may switch frequency as a function of solution pH.
  • this single agent may be used for a direct readout of pH by ratiometric CEST imaging.
  • Eu 3+ -based PARACEST agents may have a highly shifted water exchange peak that is independent of pH between 5 and 8.4.
  • the chemical shift of the Eu 3+ - bound water exchange peak may be altered considerably by varying the electron density on even a single amide oxygen donor in these DOTA-tetraamide systems. This observation may be expanded to multi-frequency.
  • a graph of the pH dependence of the UV-vis spectrum of Eu(III)-Al (20 uM) recorded in aqueous solution is shown according to an illustrative embodiment.
  • the absorption spectrum of Eu(III)-Al may show not only hyperchromic effect but also bathochromic shift from 310 nm to 360 nm with increasing pH as the phenolic proton is removed. This may be considered to be consistent with extended derealization of the phenolate anion through the ⁇ system to form a quinone-like structure which places considerable negative charge on the carbonyl oxygen atom coordinated to the Eu 3+ ion.
  • the pK ⁇ derived from these optical data was 6.7 ⁇ 0.1, and usable for a biological pH sensor.
  • such a resonance structure may alter the water exchange rate and potentially the frequency of the exchanging water molecule.
  • CEST spectra of Eu(III)-Al at five pH values may show a surprisingly large change in chemical shift with increasing pH.
  • the pK ⁇ derived from the CEST data may be 6.5 ⁇ 0.1, which may be identical to that derived from absorption data ( Figure 2).
  • Eu(III)-Al may be used as a direct readout of pH by collecting two different CEST images and using the ratio as a concentration independent measure of pH.
  • a plot of the ratio of CEST intensity at 55 ppm versus 49 ppm may be linear over the pH range 6.0 to 7.6.
  • a measurement may be performed using a single reagent compared to a cocktail of agents.
  • the exchange peak may be ⁇ 50 ppm downfield of water so it may be activated without concern about off-resonance saturation of the bulk water resonance itself.
  • the width of the water exchange peak in Eu(III)-Al may broaden somewhat at high pH values, which may be consistent with faster water exchange. This may be quantified by fitting each CEST spectrum to the Bloch equations.
  • the bound water lifetime, x m may be -200 at pH 6.0 and -145 at pH 7.6. This result may be consistent with the expected increase in water exchange rate as the acetyl oxygen donor atom gains more negative charge. Water exchange may be even faster in this complex at 31 OK (x m varies from 70 and 44 over this same pH range) but the frequency shifts in the bound water exchange peak may be about the same as that seen at 298 K. This indicates that Eu(III)-Al may also be usable for ratiometric CEST imaging of pH at more physiological temperatures.
  • ratiometric imaging may be performed using two slightly different activation frequencies, both well away from the bulk water frequency.
  • the pK a of this system may be such that the largest changes in CEST may occur between pH 6 and 7.6, and usable for sensing physiological pH.
  • composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • Rj is selected from the group consisting of Rj, R 2 , R 3 , R4, R5, R6, R 7 , and Rg
  • Ri is selected from the group consisting of OR', O 2 R', SR', and SOR'
  • R 2 is selected from the group consisting of NHR', CO 2 R', S0 3 (R') 2 , and P0 3 (R') 2
  • R4 is selected from the group consisting of:
  • R is selected from the group consisting of:
  • R6 is selected from the group consisting of:
  • R 7 includes:
  • each R J is selected from the group consisting of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6
  • R 1 includes CR'H-CONH-(CH 2 )n-C0 2 -R'.
  • n is an integer, and 0 ⁇ n ⁇ 20.
  • R 2 includes CR'H-CONH-(CH 2 ) n - PO-(OR') 2
  • R 3 includes CR'H-COCH 2 R'
  • R 4 includes CR'H-PO(OR')-(CH 2 ) n -C0 2 -R'
  • R 5 includes CR'H-PO(OR')-R'
  • R 6 includes:
  • R' is selected from the group consisting of H, an alkyl group having 20 carbon atoms or less, a cycloalkyl group having 20 carbon atoms or less, and an alkyloxy group having 20 carbon atoms or less and 10 oxygen atoms or less.
  • This embodiment may also include a paramagnetic metal ion coordinated to the composition of matter to form the paramagnetic chemical exchange saturation transfer MRI contrast agent.
  • the paramagnetic metal may be selected from the group consisting of Eu 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Er 3+ , Tm 3+ , Fe 2+ , Fe 3+ , Mn 2+ , Co 2+ , Ni 2+ , V 2+ , Mo 3+ , and Cr 3+ .
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent may include a tetraazacyclododecane ligand. In one embodiment, the paramagnetic chemical exchange saturation transfer MRI contrast agent may consist of the formula:
  • each R j group in the paramagnetic chemical exchange saturation transfer MRI contrast agent may be the same.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent may include the formula: HzCHjJz
  • a method for determining pH may use magnetic resonance imaging with the paramagnetic chemical exchange saturation transfer MRI contrast agent having the above formula.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent may include the formula:
  • a method for determining enzymatic activity may use magnetic resonance imaging with the paramagnetic chemical exchange saturation transfer MRI contrast agent having the above formula.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent may include the formula:
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent may include the formula:
  • a paramagnetic ion may be associated with the paramagnetic chemical exchange saturation transfer MRI contrast agent having the above formula, among others, and the paramagnetic ion may be selected from the group consisting of iron (II) (high spin), iron (III), cobalt (II), nickel (II), praseodymium (III), neodymium (III), dysprosium (III), erbium (III), terbium (III), holmium (III), thulium (III), ytterbium (III), and europium (III), and a physiological acceptable salt thereof.
  • the composition of matter may include a single paramagnetic complex compound endowed with a metal bound water.
  • the Ri may be removable by a presence of a chemical parameter, and the chemical parameter may be at least one of a predetermined pH level, a highly reactive oxygen species, or an enzyme.
  • a method for determining a chemical parameter using the paramagnetic chemical exchange saturation transfer MRI contrast agent is provided, and the chemical parameter may be at least one of pH, a presence of a highly reactive oxygen species, or a presence of enzyme activity.
  • the method may use ratiometric chemical exchange saturation transfer imaging to determine the chemical parameter.
  • a method for determining a chemical parameter using the paramagnetic chemical exchange saturation transfer MRI contrast agent is provided; the chemical parameter may be at least one of pH, a presence of a highly reactive oxygen species, or a presence of enzyme activity, and the chemical parameter may be determined in vivo in at least one of a body, organ, fluid, or tissue of a human or animal.
  • a method for determining a chemical parameter using the paramagnetic chemical exchange saturation transfer MRI contrast agent is provided; the chemical parameter may be at least one of pH, a presence of a highly reactive oxygen species, or a presence of enzyme activity, and the chemical parameter may be determined either in vitro or ex vivo.
  • a method for delivering a drug into a patient using the composition of matter is provided.
  • the composition of matter may be labeled with a radionuclide to form a radionuclide- labeled contrast agent.
  • the radionuclide may include at least one of Bi-212, Bi213, Pb-203, Cu-64, Cu-67, Ga-66, Ga-67, Ga-68, Lu-177, In-I l l, In- 113, Y-86, Y-90, Dy-162, Dy-165, Dy-167, Ho-166, Pr-142, Pr-143, Pm-149 or Tb-149.
  • an imaging method may include delivering the radionuclide-labeled contrast agent into a patient, and imaging a portion of the patient containing the radionuclide-labeled contrast agent using positron emission tomography.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • Rj is selected from the group consisting of Rj, R2, R3, R4, R5, R6, R7, and Rg
  • Ri is selected from the group consisting of OR', O2R', SR', and SOR'
  • R2 is selected from the group consisting of NHR', CO2R', S0 3 (R')2, and P0 3 (R')2
  • R4 is selected from the group consisting of:
  • each R J is selected from the group consisting of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 , and R 1 includes CR'H-CONH-(CH 2 ) n -C0 2 -R'.
  • n is an integer, and 0 ⁇ n ⁇ 20.
  • R 2 includes CR'H-CONH-(CH 2 ) n - PO-(OR') 2
  • R 3 includes CR'H-COCH 2 R'
  • R 4 includes CR'H-PO(OR')-(CH 2 ) n -C0 2 -R'
  • R 5 includes CR'H-PO(OR')-R'
  • R 6 includes:
  • a composition of matter includes a light-sensitive contrast agent usable as a composition for a drug delivery system (e.g., micelle, liposome, etc.) including the formula:
  • a method for delivering a drug to a patient includes combining the light- sensitive contrast agent with the drug to form a combined light-sensitive drug delivery system, delivering the combined light-sensitive drug delivery system into the patient, and exposing the combined light-sensitive drug delivery system to electromagnetic radiation to release the drug into the patient.
  • the method also includes detecting a concentration of the drug in the patient.
  • the electromagnetic radiation may include at least one of ultraviolet or near-infrared radiation.
  • the method also includes evaporating the water layer to form a solid, and subjecting the solid to high-performance liquid chromatography to form a product containing the first compound.
  • providing the second compound includes providing one molar equivalence of the second compound
  • providing the phosphoryl chloride includes providing four molar equivalences of the phosphoryl chloride
  • providing the triethylamine includes providing three molar equivalences of the triethylamine.
  • stirring the solution for the predetermined period of time includes stirring the solution for approximately 24 hours, and the solid is a yellow solid.
  • providing the second compound includes providing one molar equivalence of the second compound
  • providing the l-(bromomethyl)-4,5-dimethoxy- 2-nitrobenzene includes providing one molar equivalence of the l-(bromomethyl)-4,5- dimethoxy-2-nitrobenzene
  • providing the K 2 CO 3 includes providing one molar equivalence of the K 2 CO 3 .
  • stirring the mixture under N 2 for the predetermined period of time includes stirring the mixture under N2 for approximately 12 hours, and the solid is a yellow solid.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include:
  • each R' may be selected from the group consisting of CH2CONHCH2COOH, CH 2 CONHCH 2 COOC 2 H5, CH 2 CONH 2 , CH 2 CONHCH 2 PO(OC 2 H 5 ) 2 , CH 2 CONHCH 2 P0 3 H 2 , CH 2 CONHCH 2 PO(OC(CH 3 ) 2 ) 2 , CH 2 CONHCH 2 PO(OCH 2 CH 2 CH 3 ) 2 , CH 2 CONHCH 2 PO(OCH 2 CH 2 CH 2 CH 3 ) 2 , and CH 2 CONHCH 2 PO(OC(CH 3 ) 3 ) 2 .
  • a method for obtaining a ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent to determine at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, or a presence of enzyme activity is provided.
  • obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed either in vitro or ex vivo.
  • obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed in vivo.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent is associated with a europium (III).
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent produces a frequency shift in a chemical exchange saturation transfer exchange peak.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include:
  • each R' may be selected from the group consisting of CH2CONHCH2COOH, CH2CONHCH2COOC2H5, CH2CONH2, CH2CONHCH 2 PO(OC 2 H5)2, CH2CONHCH2PO3H2, CH 2 CONHCH 2 PO(OC(CH 3 )2)2, CH 2 CONHCH2PO(OCH2CH 2 CH3)2, CH2CONHCH 2 PO(OCH 2 CH2 CH 2 CH 3 ) 2 , and CH 2 CONHCH 2 PO(OC(CH3 )2-
  • a method for obtaining a ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent to determine at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, an oxygen concentration, or a presence of enzyme activity is provided.
  • obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed either in vitro or ex vivo. In another embodiment, obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed in vivo. In another embodiment, the paramagnetic chemical exchange saturation transfer MRI contrast agent is associated with a europium (III). In another embodiment, the paramagnetic chemical exchange saturation transfer MRI contrast agent produces a frequency shift in a chemical exchange saturation transfer exchange peak.
  • a composition of matter includes a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including the formula:
  • R may include:
  • each R' may be selected from the group consisting of CH2CONHCH2COOH, CH2CONHCH2COOC2H5, CH2CONH2, CH2CONHCH 2 PO(OC 2 H5)2, CH2CONHCH2PO3H2, CH 2 CONHCH 2 PO(OC(CH 3 )2)2,
  • a method for obtaining a ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent to determine at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, or a presence of enzyme activity is provided.
  • obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed either in vitro or ex vivo.
  • obtaining the ratiometric imaging measurement using the paramagnetic chemical exchange saturation transfer MRI contrast agent may be performed in vivo.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent is associated with a europium (III).
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent produces a frequency shift in a chemical exchange saturation transfer exchange peak.
  • a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent for determining a chemical parameter including a europium(III) DOTA-tris(amide) complex includes four side chains, and one of the four side chains connects an aromatic group by a carbonyl bond.
  • the europium(III) DOTA-tris(amide) complex consists of four side chains.
  • the one of the four side chains connects the aromatic group by -CH2-CO-.
  • the chemical parameter is at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, an oxygen concentration, or a presence of enzyme activity.
  • a method for determining one or more parameters includes obtaining a paramagnetic chemical exchange saturation transfer magnetic resonance imaging (MRI) contrast agent including a europium(III) DOTA-tris( amide) complex including four side chains. One of the four side chains connects an aromatic group by a carbonyl bond.
  • the paramagnetic chemical exchange saturation transfer MRI contrast agent is adapted to provide a ratiometric imaging measurement.
  • the method also includes administering the paramagnetic chemical exchange saturation transfer MRI contrast agent to a patient, and detecting a signal in the patient that correlates to one or more parameters.
  • the one or more parameters includes at least one of a pH level, a presence of a highly reactive oxygen species, a biological metal ion concentration, an oxygen concentration, a presence of enzyme activity, a temperature, a metabolite concentration, or an (3 ⁇ 4 partial pressure.
  • the one of the four side chains connects the aromatic group by -CH 2 -CO-.
  • any embodiment discussed in this specification may be implemented with respect to any method, kit, reagent, or composition of the illustrative embodiments, and vice versa. Furthermore, compositions of the invention may be used to achieve methods of the illustrative embodiments.
  • A, B, C, or combinations thereof refers to all permutations and combinations of the listed items preceding the term.
  • A, B, C, or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.
  • expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth.
  • the skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
  • compositions and/or methods disclosed and claimed herein may be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the illustrative embodiments have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the embodiments. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the illustrative embodiments as defined by the appended claims.

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Abstract

Selon un mode de réalisation illustratif, cette invention concerne des agents de contraste paramagnétiques pour IRM utilisant une technique de transfert de saturation dépendant des échanges chimiques contenant un ligand tétraazacyclododécane et un ion paramagnétique qui fournit une mesure d'imagerie ratiométrique qui peut être utilisée pour mesurer des paramètres biologiques comprenant le pH, la température, les espèces réactives de l'oxygène, et des enzymes spécifiques, entre autres. Les agents et les composés selon l'invention peuvent également être utilisés dans d'autres applications. Des procédés d'utilisation et de synthèse des agents et des composés de la présente sont également décrits.
PCT/US2011/042061 2010-06-28 2011-06-27 Agents et composés pour l'imagerie et autres applications, leurs procédés d'utilisation et de synthèse Ceased WO2012006038A2 (fr)

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US20040146463A1 (en) * 2000-05-04 2004-07-29 Meade Thomas J. Functional MRI agents for cancer imaging
EP1331012A1 (fr) * 2002-01-29 2003-07-30 BRACCO IMAGING S.p.A. Agents de contraste paramagnétiques responsifs pour l'imagerie par résonance magnétique
US7012140B1 (en) * 2003-07-14 2006-03-14 Board Of Regents, The University Of Texas System Selection of coordination geometry to adjust water exchange rates of paramagnetic metal ion-based macrocyclic contrast agents
FR2868320B1 (fr) * 2004-03-31 2007-11-02 Centre Nat Rech Scient Cnrse Agent de contraste pour l'imagerie par resonance magnetique
US20060057071A1 (en) * 2004-09-14 2006-03-16 Wing-Tak Wong Paramagnetic complexes with pendant crown compounds showing improved targeting-specificity as MRI contrast agents
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