WO2001042220A2 - Nouveaux ligands de podate et methodes d'utilisation correspondantes - Google Patents
Nouveaux ligands de podate et methodes d'utilisation correspondantes Download PDFInfo
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- WO2001042220A2 WO2001042220A2 PCT/IB2000/001988 IB0001988W WO0142220A2 WO 2001042220 A2 WO2001042220 A2 WO 2001042220A2 IB 0001988 W IB0001988 W IB 0001988W WO 0142220 A2 WO0142220 A2 WO 0142220A2
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- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- AWSFICBXMUKWSK-UHFFFAOYSA-N ytterbium(3+) Chemical compound [Yb+3] AWSFICBXMUKWSK-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- 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
-
- 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
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
-
- 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
- A61K51/0478—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 complexes from non-cyclic ligands, e.g. EDTA, MAG3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- the invention relates the synthesis of the podate ligand H 4 L' [l ,2,4,5-tetr ⁇ /ts(pyrazol- l -ylmethyl-3-carboxylic acid)benzene] and to complexes including the ligand and a metal ion.
- X-rays have long been used to-produce images of human and non-human animal tissue, e.g., the internal organs of a patient.
- the patient is positioned between a source of X-rays and a film sensitive to the rays. Where organs interfere with the passage of the rays, the film is less exposed and the resulting developed film is indicative of the state of the organ.
- NMR nuclear magnetic resonance
- MRI magnetic resonance imaging
- image enhancers or contrast agents, prior to image acquisition.
- increased contrast of internal organs such as the kidneys, the urinary tract, the digestive tract and the vascular system of the heart may be obtained by administering a radiopaque agent to the patient.
- increased contrast of internal organs and tissues may be obtained by administering compositions containing paramagnetic metal species, which increase the relaxation rate of surrounding protons.
- improved contrast is obtained by administering compositions having acoustic impedances which are different than that of blood or other tissues.
- contrast agents are those in which organic acid ligands are coordinated to a metal atom or cation.
- the nature of substituents of the ligand, or complexing agent, can have a significant impact on tissue specificity of the contrast agent.
- hydrophilic complexes tend to concentrate in the interstitial fluids, whereas lipophilic complexes tend to associate with cells.
- differences in hydrophilicity can lead to different applications ofthe compounds.
- the metal-ligand complex may be charged or neutral, and the charge may be altered to affect solubility.
- the hydrogen atoms of an acidic ligand are coordinated by the central (metal) ion (or central ions)
- it may be advantageous to increase the solubility of the complex salt by substituting the remaining hydrogen atoms with cations of inorganic and/or organic bases or amino acids.
- the hydroxides, carbonates or bicarbonates of sodium, potassium or lithium are suitable inorganic cations.
- Suitable cations of organic bases include, among others, those of primary, secondary or tertiary amines, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine or especially N- methylglucamine.
- Lysines, arginines or ornithines are suitable cations of amino acids, as generally are those of other basic naturally occurring such acids. If the complex salts contain several free acid groups, it is then often advantageous to produce neutral mixed salts which contain both inorganic and organic cations as counterions.
- the complexing agents can also be coupled as conjugates with biomolecules that are known to concentrate in a particular organ or the part of an organ to be examined.
- biomolecules include, for example, hormones (e.g., insulin), prostaglandins, steroid hormones, amino sugars, peptides, proteins, lipids, etc.
- Conjugates with albumins e.g., human serum albumin
- antibodies e.g., monoclonal antibodies specific for tumor associated antigens or proteins such as myosin, etc.
- the diagnostic agents formed therefrom can be used, e.g. , to diagnose tumors and mycoardial infarctions.
- Conjugates with liposomes, or inclusion of salts of the contrast agent in liposomes, are suitable for liver imaging.
- the central ion in the contrasting agent is derived from an element with a high atomic number in order to promote sufficient absorption of X-rays.
- Diagnostic media containing a physiologically well tolerated complex salt containing a central ion chosen from elements with atomic numbers of 57 to 83 are suitable for this purpose. These include, for example, lanthanum(III), and other di- and tri-valent ions of the lanthanide group, gold(III), lead(II) or, especially, bismuth(III).
- Chemical compounds with paramagnetic central ions are useful for MRI imaging.
- Two important MRI imaging parameters are spin-lattice (Tl ) and spin-spin and spin-echo (T2) relaxation times.
- the relaxation phenomena are essentially mechanisms whereby the initially imparted radio-frequency energy is dissipated to the surrounding environment.
- relaxation times are influenced by the environment of the nuclei, (e.g., viscosity, and temperature).
- the rate of energy loss, or relaxation can also be influenced by neighboring paramagnetic nuclei.
- chemical compounds incorporating paramagnetic nuclei may substantially alter the Tl and T2 values for nearby protons.
- Nuclei which are useful in MRI contrasting agents include organic free radicals or transition or lanthanide metals which have from one to seven unpaired electrons.
- paramagnetic species such as ions of elements with atomic numbers of 21 to 29, 42 to 44 and 58 to 70 are effective.
- suitable ions include chromium(III), manganese(II), manganese(III), iron(II), iron(III), cobalt(II), nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III), and ytterbium(III).
- Gadolinium(III), terbium(III), dysprosium(III), holmium(III), and erbium(III) are preferred.
- Gadolinium(III) ions have been particularly useful as MRI contrasting agents.
- paramagnetic ions have been administered in the form of complexes with organic complexing agents.
- a necessary prerequisite of any ligand that binds a metal to form a contrast agent is that the resulting contrast agent be stable so as to prevent the loss of the metal and its subsequent accumulation in the body.
- Such complexes provide the paramagnetic ions in a soluble, non-toxic form, and facilitate their rapid clearance from the body following the imaging procedure.
- gadolinium(III) with diethylenetriamine-pentaacetic acid (“DTPA").
- Paramagnetic ions such as gadolinium(III), have been found to form strong complexes with DTPA, ethylenediamine-tetra acetic acid
- EDTA tetra aza-cyclododecane-N,N',N",N'"-tetra acetic acid
- DOTA tetra aza-cyclododecane-N,N',N",N'"-tetra acetic acid
- lanthanide(III) poly-aminocarboxylates are also widely used as luminescent probes in fluoroimmunoassays.
- Gd(III),-containing contrast agents are mainly limited by their fast rotational motion
- the incorporation of Gd chelates in large structures slows their rotational motion and increases relaxivity properties.
- Such structures can include polymers (Desser, et al., J. Magn. Reson. Imaging 1994, 4, 467); dendrimers (Tacke, et al., J. Magn. Reson. Imaging, 1997, 7, 678); proteins (Lauffer and Brady, J. Magn. Reson. Imaging, 1985, 3, 1 1) and micelles (Andre, et al., Chem. Eur. J, 1999,
- One important approach to developing efficient MRI contrast agents can involve the association of monomers into reversible supramolecular structures. This is accomplished by exploiting short distance interactions, (i.e., hydrogen bonds, aromatic ⁇ -stacking and van der
- Waal's interactions which can be used for molecular recognition based upon complementary size, shape and chemical functionalities.
- the monomers used for the formation of supramolecular contrast agents must be rigid enough to ensure good inteimolecular contact between interacting surfaces and also must overcome the loss of translational entropy of the monomers upon aggregation.
- Contrast agents can be plagued by the in vivo release of free metal ions from the complex, which can result in metal toxicity subject.
- the toxicity of paramagnetic metal complexes can be affected by the nature of the complexing ligands. Principal factors involved in the design of ligands for paramagnetic metal complexes include the thermodynamic stability constant of the metal-ligand complex (the affinity of the totally unprotonated ligand for the metal); the conditional stability constant (which is pH dependent and is important when considering stability under physiological pH); the selectivity of the ligand for the paramagnetic metal over other endogenous metal ions (e.g., zinc, iron, magnesium and calcium); and the structural features that make in vivo transmetallation reactions much slower than the clearance rate of the complex.
- This invention is based in part on the discovery of metal complexing podate ligands which are capable of forming rigid, stable, supramolecular structures.
- Podate ligands are acyclic analogues of coronand and crown ether compounds and form complexes with metal ions through nitrogen and oxygen coordination.
- These metal-ligand complexes are useful as MRI contrast agents, diagnostic agents in X-ray, ultrasound or scintigraphic image analysis, as radiotherapy agents, and as luminescent probes. Because these compounds have an unexpectedly high relaxivity, much less ofthe complex is required to be administered to the subject relative to commonly used image enhancing agents.
- a podate ligand according to the invention contains a central benzene anchor with three (e.g., l,3,5-tris(pyrazol-l-ylmethyl-3-carboxylic acid) benzene; Formula III), four (e.g., l ,2,4,5-tetrakis(pyrazol-l-ylmethyl-3-carboxylic acid) benzene; Formula II); or six pyrazole- containing arms.
- the ligand further contains carboxylated poly-pyrazole groups, which are a modification of pyrazole ligands previously described for ruthenium(II) complexation. Hartsom and Steel, Aust. J. Chem., 1995, 48, 1587; Hartsom and Steel, Angew.
- H 4 L' tetra-protonated tetra-substituted ligand
- the invention also provides a method of magnetic resonance imaging by administering to a human or non-human animal subject a contrast medium that includes a physiologically compatible paramagnetic metal complex of the herein desc ⁇ bed podate ligands and a non- toxic, pharmaceutically acceptable earner, adjuvant or vehicle in an amount sufficient to allow for the generation of a magnetic resonance image of at least a part of the subject
- a method of diagnostic imaging comprises administering to a human or non-human animal subject a diagnostic agent comprising a physiologically compatible heavy metal complex ofthe present invention and a non- toxic, pharmaceutically acceptable carrier, adjuvant or vehicle, and generating an X-ray, ultrasound or scintigraphic image of at least a part of the subject
- a method of radiotherapy practiced on a human or non-human animal subject comprises administering to the subject a radioactive agent comprising a physiologically compatible radioactive metal complex of the present invention and a non-toxic, pharmaceutically acceptable earner, adjuvant or vehicle
- FIG. IB depicts the calculated spectra of pure species at various protonation states
- FIG. 3A shows the titration of [HL 1 ] 3" by La + .
- Spectrum 1 0 eq. of La 3+ ;
- Spectmm 20 1.9 eq of La 3+ .
- FIG. 3B depicts the variation in absorbance at 285nm.
- [L'] 0 3.55 x 10- 5 M;
- FIG. 5A shows low resolution emission spectra in water.
- FIG. 7 depicts the titration of [TbL 1 ] (5 x 10-6 M in H O) by ⁇ CD.
- FIG. 9A depicts a graph of the T /Z/j ratio of pyrene fluorescence vs. the calculated concentration of [Gd(L') 2 j° " (arrows point to the observed breaks).
- FIG. 10 shows the determination of critical aggregation concentrations.
- FIG. 10A shows the first part of the curve, while FIG. 10B shows the entire curve.
- the present invention provides a novel class of podate ligands falling within formula I, as set forth below:
- R,, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are, independently, hydrogen, lower alkyl, or two R groups on any one pyrazole ring are fused to form an aromatic or non-aromatic ring; and Z,, Z 2 , Z 3 , Z 4 , are, independently, hydrogen, lower alkyl, or a functionality suitable for coupling with a biological material (e.g. a thiocyanate group).
- a biological material e.g. a thiocyanate group
- ring stmcture can be an aromatic ring such as benzene or naphthalene:
- the pyrazole ring is replaced by a 1,3,5-triazine ring:
- the invention also provides a base or acid addition salt, hydrate, ester, solvate, prodmg, metabolite, stereoisomer, or mixture thereof.
- a salt of the ligand-metal complex is administered to a living animal.
- a pharmaceutically acceptable salt is desired.
- the invention further comprises compounds of formula I complexed with a metal atom or cation.
- the invention also includes pharmaceutical formulations comprising a compound of Formula I and a metal atom or anion in association with a pharmaceutically acceptable carrier, diluent, or excipient.
- the podate ligand has the stmcture as set out in formula II, which is complexed with the Gd(III) ion.
- the base or acid addition salt is a pharmaceutically acceptable salt.
- Salts encompassed within the term "pharmaceutically acceptable salt” are non-toxic salts of the compounds of this invention which are generally prepared by reacting an acidic complex with physiologically biocompatible cations of organic and/or inorganic bases or amino acids to produce “pharmaceutically-acceptable acid addition salts" of the compounds described herein. These compounds retain the biological effectiveness and properties of the free complexes.
- the lithium ion, the potassium ion and especially the sodium ion are suitable inorganic cations.
- Suitable cations of organic bases include, among others, those of primary, secondary or tertiary amines, for example, ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine or especially N-methylglucamine.
- Lysines, arginines or omithines are suitable cations of amino acids, as generally are those of other basic naturally occurring such acids.
- the metal atoms or cations, M which are suitable for use in the complexes of the invention as MRI contrast agents are paramagnetic metals h ⁇ ving atomic numbers 21-29, 42- 44 and 57-71.
- the complexes for use as MRI contrast agent > are those wherein the preferred metal is Eu, Gd, Dy, Ho, Cr, Mn or Fe, more preferably Mn(II)or Fe(III), and most preferably Gd(III).
- the metal atoms or cations which are suitable for use in the complexes of the invention as X-ray or ultrasound contrast agents are heavy metals having atomic numbers 20-32, 42-44, 49 and 57-83.
- the complexes for use as X-ray or ultrasound contrast agents are those wherein the preferred metal is a non-radioactive metal having atomic numbers 42-44, 49 and 57-83, most preferably Gd, Dy or Yb
- the metal atoms or cations of the complexes of the invention which are suitable for use in scintigraphic and radiotherapy are radioactive metals of any conventional complexable radioactive metal isotope, preferably those having atomic numbers 20-32, 42-44, 49 and 57-
- the metal atom or cations which ai e suitable for use as luminescence enhancers include, c g , Eu and Tb.
- the 1 1 and 1 :2 lanthanide-podate complexes of the present invention display good stability under physiological conditions
- the compounds of the invention can be to enhance images produced by method of magnetic resonance imaging ln one embodiment, a contrast medium made from a physiologically compatible complex of the invention and a nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle is administered to a human or non-human animal (subject), and a magnetic resonance image is generated of at least a part of the subject
- the compounds can similarly be used to enhance images produced by X-ray, ultrasound or scintigraphic imaging of a subject.
- diagnostic analysis of the present invention involve administering the compounds of the invention to a human or non-human animal subject or host, in an amount sufficient to effect the desired contrast (or shift) and then subjecting the host to diagnostic analysis
- diagnostic analysis is MRI analysis
- the complexes of the present invention are useful in diagnostic analysis by X-ray image analysis, ultrasonic analysis or scintigraphic analysis. While described primarily as contrast enhancing agents, the complexes of the invention can act as MRI shift reagents and such use is contemplated by the methods herein.
- the complexes of the invention used as contrast enhancing agents are administered in an amount sufficient to effect the desired contrast.
- this amount is an MRI signal effecting amount of the complex, i.e. any amount of said complex that will alter the spin- lattice (Tl ) or spin-spin or spin-echo (T2) relaxation times of an MRI signal.
- Tl spin- lattice
- T2 spin-spin or spin-echo
- a shift reagent a sufficient amount of said complex will selectively shift the spectral position of a resonance nucleus relative to other similar nuclei. This alteration is effected in a manner in order to enhance the signals received from the subject under analysis either by reducing the aforementioned relaxation times or by increasing them with respect to an area of the host or the host per se which has had the complex administered to it.
- the MRI signal effecting amount of the complex is that amount which in addition to changing the relaxation times of the MRI signals in the host, will also change such relaxation times sufficiently so that sharper lines of definition or higher contrast is obtained between those parts of the host that have and have not been administered the complex.
- the complexes of the invention may be administered to a host as a pharmaceutical composition in a contrast-enhancing amount.
- the pharmaceutical compositions contain a contrast-enhancing dosage of the contrast agents according to the invention together with a nontoxic pharmaceutically acceptable carrier, adjuvant or vehicle.
- the compositions can be administered by well-known routes including oral, intravenous, intramuscular, intranasal, intradermal, subcutaneous, parenteral, enteral and the like. Depending on the route of administration, the pharmaceutical composition may require protective coatings.
- the pharmaceutical forms suitable for injectable use includes sterile solutions, suspensions, emulsions symps or dispersions in oily or aqueous media and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the ultimate solution form must be sterile and fluid.
- Typical carriers include a solvent or dispersion medium containing, for example, water, buffered aqueous solutions (i.e. biocompatable buffers), ethanol, polyol (glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, surfactants or vegetable oils.
- Sterilization can be accomplished by any art recognized technique, including but not limited to, addition of antibacterial or antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. Further, isotonic agents, such as sugars or sodium chloride may be incorporated in the subject compositions.
- antibacterial or antifungal agents for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents such as sugars or sodium chloride may be incorporated in the subject compositions.
- sterile injectable solutions containing the subject contrast agent is accomplished by incorporating these agents in the required amount in the appropriate solvent with various ingredients enumerated above, as required, followed by sterilization, preferably filter sterilization. To obtain a sterile powder, the above solutions are vacuum-dried or freeze- dried as necessary.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluent, e.g. lubricating agents such as magnesium stearate.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, symps, and elixirs containing inert diluent commonly used in the art, such as water.
- Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- contrast agents of the inventions are thus compounded for convenient and effective administration in pharmaceutically effective amounts with a suitable pharmaceutically acceptable carrier, adjuvant or vehicle in a dosage which effects contrast enhancement. These amounts are preferably about 1 ⁇ mol to 1 mol of the contrast agent per liter and/or administered in doses of about 0.001 to 5 mmol/kg body weight.
- compositions provide effective-dosages of contrast agents in the range of about 0.001 -5 mmol/kg for MRI diagnostics, preferably about 0.005-0.5 mmol/kg; in the range of about 0.1-5 mmol/kg for X- ray diagnostics, and in the range of ibout 0 1 -5 mmol/kg for ultrasound diagnostics
- the dose of the contrast agent should generally be lower than for MRI diagnostics
- conventional doses known to those of ordinary skill in the art can be used
- a pharmaceutically acceptable carrier, adjuvant or vehicle includes any and all solvents, dispersion media, coatings, antibacte ⁇ al and antifungal agents, isotonic agents, and the like. The use of such media and agents are well known in the art
- ligand of Formula I is coupled to a biological molecule prior to formation of the metal- ligand complex
- a ligand of Formula I is coupled to a biological molecule after formation of the metal-hgand complex has been accomplished
- conjugates are particularly useful as image enhancing agents
- Useful biological molecules are those known to concentrate in a particular organ or the part of an organ to be examined These biomolecules include, for example, hormones (e g , insulin), prostaglandins, steroid hormones, amino sugars, peptides, proteins, lipids, etc Conjugates with albumins (e g , human serum albumin) or antibodies, (e g , monoclonal antibodies specific for tumor associated antigens or proteins such as myosin, etc ) are especially notable
- the diagnostic agents formed therefrom are suitable, for example, for use in tumor and infarct diagnosis Conjugates with liposomes, or inclusion of salts of the contrast agent in liposomes, (e g unilamella
- the advantages ofthe new system described herein include applications in various fields of medicine, including angyology and in vivo temperature mapping Furthermore, control of the aggregation of the spherical particles by changing the mass, size, shape and number of nanoparticles in solution may lead to further improvement of properties of the supramolecular aggregates, for instance the ability to reversibly control their relaxivity Lin, et al , Nature, 1989, 339, 360 Thus, the molecules of the present invention are useful as both contrast agents for MRI and luminescent stains for medical mapping applications
- ⁇ - and ⁇ -cyclodextrins (CD) enhances the luminescence intensity of the 1 : 1 metal: ligand complexes.
- the association is strong (logA ' / y « 5-6), and is primarily through interaction with the phenyl anchor.
- the association of cyclodextrins with the Tb-L' complex results in a large increase in luminescence intensity at physiological pH.
- the synthesis of the H 4 L' podand is modified so as to improve the antenna effect of the pyrazole arms by increasing its molar absorbance and lowering the ⁇ * state.
- the increase in absorbance can be achieved, for example, by adding chromophores at the 4, 5 (or 4 and 5) positions of the pyrazole amis.
- Typical chromophores include benzene and naphthalene.
- One feature of the present invention is the ability of the L' -metal complexes to self- aggregate into nanometric, rigid, porous and spherical particles in a controlled way (mean diameter: 10, 60, and « 300 nm). Formation of these aggregates significantly enhances the relaxivity of the complexed metal ion. For example, an unprecedented high relaxivity (r,) of 53 mM " ' s ' is observed for aggregated particles of the 1 :2 Gd-podate (20 MHz, 25 °C). The [Ln(L') : ] entities aggregate into spherical nanoparticles of low dispersivity, with diameters of
- nanosized spherical particles arc obtained instead of microcrystals because, under the growth conditions used in the present invention, the formation of nanometric supramolecular structures is too fast to generate a regular stacking between the hydrophobic surfaces. Instead, the complex allows free circulation of solvent molecules inside the structure. The diffusion of these solvent molecules may contribute to the high relaxivity of the Gadolinium-Ligand complexes.
- the Ln-L' nanoparticles further coagulate into larger, non-symmetrical stmctures (about 10- 15 particles, 280-300 nm).
- Generation of aggregates at « 10 "3 M is fast (t m in the range of seconds at 20 °C) and solutions are stable over weeks at room temperature, with no evidence of sedimentation.
- the formation of supramolecular stmctures explain the large relaxivity of solutions of the Gd 1 :2 podate, which is more than one order of magnitude larger than the relaxivity of the first generation contrast agents.
- concentrations of lanthanide stocks were determined by complexometric titrations using a standardized NaAEDTA solution in urotropine buffered medium with xylene orange as indicator.
- concentrations of stock solutions of cyclodextrins (CDs) were calculated from the optical rotation (°) of sodium light at
- the average number of water molecules coordinated to the Eu(III) ion (as determined by lifetime measurements) is 2.6 for the 1 : 1 complex and 1 .2 for the 1 :2 complex.
- [M,L ) H k ]/[M]'[L]'[H ' ] .
- the ester was made under nitrogen flow by refluxing for 5 h 1.02 g of the dried acid (9.1 ⁇ 10 "3 mol) in 20 mL of absolute ethanol and 1.5 mL of concentrated sulfuric acid. The solvent was then evaporated and a yellow oil was obtained. 50 mL of water were added to dissolve the substance and the solution was neutralized with NaHCO,. The product was extracted with ethyl acetate, the solvent was partially evaporated and addition of a few milliliters of petroleum ether started crystallization of a white material (85 % yield).
- the tetraester was hydrolyzed overnight with KOH ( 1.2 eq.) in 40 mL of water at 50 C.
- the yellow solution was washed with ether (4 x 50 mL) and the aqueous phase was transferred into centrifugation tubes, adjusted to pH ⁇ 2 (cone. HCl), cooled to 0 °C and the precipitate was collected by centrifugation. This procedure was repeated several times.
- the isolated ligand was washed successively with cold water ( 100 mL), ether (80 mL), methylene dichloride (50 ml) and acetone (50 mL).Yield : 47 %.
- the methanol wash, sonication and centrifugation steps were repeated three times.
- the solid was dried and washed with 20 mL of acetone on a sintered-glass filter.
- the product was dried for 1 .5 days at 65°C and 0.01 torr. Typical yields were ca. 60 %.
- the pH was adjusted to 8.0 with 0.1 M KOH, and the solution was dried with N,.
- the collected material was washed on a sintered-glass filter with acetone (ca. 1 00 mL) and then methanol (ca. 10 mL). The washed solid was dried for 1 .5 days at 65 °C and 0.01 torr. Typical yields were ca. 70 %.
- the K,[Ln(L') 2 ] complexes were analyzed by IR Spectroscopy and elemental analysis as follows:
- the Gd 1.2 podate was prepared by dissolving H 4 L' (15.1 mg , 2.61x10 5 mol) in 2 mL H 2 O, adjusting the pH to 6.8 (KOH 0.1M), adding GdCl 3 nH 2 O (0.57 ml, 0.0228 M, '/_ eq.) and heating the solution 15 min at 40°C The pH was then adjusted to 7.2 (KOH 0.1 M) and let 1 day at room temperature. The solution was transferred in a cent ⁇ fugation flask, methanol ( ⁇ 1 ml) was added and precipitation of the complex was started with a with few drops of ether.
- the critical aggregation concentration (cac) of the self- aggregation process was characterized by luminescence using a pyrene probe, light scatte ⁇ ng measurements and by transmission electron microscopy Self-aggregation of the H 4 L' podates was shown to occur at concentrations above 3x 10 ' M.
- Dynamic light scatte ⁇ ng measurements were performed at 22.0 ⁇ 0.1 °C in a toluene bath at a scatte ⁇ ng angle of 90°, using a He-Ne laser hght-scatte ⁇ ng instemper operating at 632 8 nm. The intensity of the light scattered by toluene was used as reference. Diffusion coefficients of particles in H 2 0 were determined from an exponential fit to the correlation curve. Hydrodynamic radii were calculated from measured diffusion coefficients by means of the Stokes-Einstein equation. 3 3 Transmission Electron Microscopy (TEM)
- Protonation constants for L' were determined by spectrophotometry (Fig. 1) and were compared with pH-potentiometry. Spectra were taken at various pH values in the range of 2 to 12 at 20 °C (Fig la). Because dramatic changes occur in the UV-spectra between pH 8 and 13 in the carboxylate chromophore zone (around 210 nm), the first protonation constant was easily obtained. Two other bands were followed during the titrations: the band at 230 nm ( ⁇ ⁇ 30 000 M 'cm ') was assigned to a ⁇ * transition in the pyrazole chromophore (Reeves, et al., J. Chem.
- FIG. 2a shows a ID spectmm of the unprotonated ligand at pD 12.9.
- Proton numbering was as shown in Formula II, where 3,6 corresponds to the phenyl protons; 7, T correspond to the benzyl protons; and 1 1 and 12 correspond to the pyrazole protons. Because a change in protonation status at one site is likely to influence the chemical shift of protons on neighboring atoms, the chemical shift of the four types of protons were monitored as a function of pD in the pD range of 2 to 12.9 (Fig. 2b).
- Ligand:metal stoichiometry used in the modeling of pH-potentiometric data were suggested from spectrophotometric titration and qualitative ESI-MS data.
- Titration of L' with Ln 3+ ions in D 2 O (pD 7), as monitored by 'H NMR, indicated that the largest chemical shift variations occurred when the stoichiometry changes from the 1 :2 to the 1 : 1 complexes, especially for benzyl(7, 7') and phenyl (3, 6) protons; indicating that the metal ion was closer to the anchor in the 1 : 1 podates.
- UV-excitation in the ⁇ * and n ⁇ * absorption bands ofthe pyrazole units resulted in ligand-centered emission from L', displaying two stmctured and overlapping bands assigned to emission from the ' ⁇ * and 3 ⁇ * states.
- the 0-phonon component of the singlet state emission was located at 33,750 cm " ' while the corresponding transition from the triplet state occurred at 27,740 cm " '.
- the overlap between the ligand ' ⁇ * and 3 ⁇ * states induced an efficient intersystem crossing process.
- the 3 ⁇ * transition was not much altered in the 1 :1 and 1 :2 La podates, but complexation to Gd 3+ and Lu 3+ induced a broadening of the 3 ⁇ * emission band.
- the lifetime ofthe ⁇ * state is relatively short (0.1 ms). The lifetime was shown to increase in complexes with heavier lanthanide ions, in agreement with the heavy atom effect, which facilitated the intersystem crossing. Fluorescence and Phosphorescence, Rendell, D.; Sheffield Polytechnic, Wiley & Sons. London, 1987.
- the Tb data is also consistent with the mle that the energy gap ⁇ E( 3 ⁇ *- 3 D 4 ) should be larger than 3,500 cm " ' for efficient and irreversible energy transfer. Steemers et al., J. Am. Chem. Soc, 1995, 777, 9408.
- Metal-centered luminescence was also shown to be pH dependent.
- Absolute quantum yields of 1 : 1 ⁇ u and Tb complexes were found to be 4.9 % and 5.0 %, respectively, indicating that energy transfer from the ligand to the ⁇ u( 5 D 0 ) level was significantly improved in aqueous solution compared to the frozen ethanol solutions (Fig. 5).
- the quantum yields of the 1 :2 podates were about half the values found for the 1 : 1 complexes.
- EXAMPLE 7 Luminescence Enhancement of 1 :1 Podates by Association with
- Fig. 7 shows the change in emission spectra upon increasing CD concentration.
- Figure 7b graphically depicts the increase in phosphorescence intensity with increasing CD concentration. Cyclodextrin titrations conducted in phosphorescence mode (depicted in Fig. 7) facilitated the determination of the apparent association constants of the 1 : 1 podates with CDs.
- association constants K and the phosphorescence enhancement ratios (C u /C w ) upon CD complexation were introduced as fitting parameters in a non-linear regression of the experimental I 0 ( ⁇ )/I( ⁇ ) values as a function of CD concentration.
- the binding constants reported in Table 4 are about three orders of magnitude larger than association constants between ⁇ -CD and transition metal complexes with macrocycles (Raj and Ramaraj, Electrochemica Ada, 1999, 44, 2685) or cyclo-pentadienyl ligands (Wang et al., Inorg. Chem., 1998, 37, 317).
- Table 4 Association constants (Kj j) for 1 : 1 complexes between [L'Tb] " and CDs and phosphorescence enhancement ratio (Cj ]/C°jo) obtained from luminescence titrations.
- the large effect of CD association on Tb phosphorescence may be related to an increase in the rotational correlation time ofthe complex upon association and/or to a change of polarity in the micro-environment ofthe podate.
- C n /C strongly increased with the polarity of the CD, e.g. ⁇ -CD > ⁇ -CD.
- the magnitude of AT, increased with the hydrophobic character of CDs, indicating that an important factor in the driving force for the association of CDs with the podates were hydrophobic interactions and an entropically favorable release of solvent molecules.
- the critical aggregation concentrations were determined by measuring the concentration dependence of the light-scattering ratio I so '/7 loluene .
- a plot of the correlation curve baseline value, ⁇ (base) computed from these data is shown in Fig. 10b (close-up in Fig. 10a).
- Two discontinuities were apparent at 3.5 x 10 "3 M (cac-1) and at 10 "4 M (cac-2).
- the value of cac-1 was in good agreement with the data from fluorescence measurements.
- N Je The average aggregation number (N Je ) was estimated from a plot of ⁇ T-c/ ⁇ 7 90 as a function of the solute concentration c (Fig 1 1)
- A. is defined as follows for the vertically polarized incident light (Taboada et al , Langnn , 1999, 75, 2022)
- protons must induce some charge neutralization, as no other ion than Gd 3+ is present in the isolated Gd 1 :2 podates; (determined by EDS analysis of the 1 1 and 57 nm particles and by elemental analysis).
- the proton relaxivity of a solution of Gd 1 :2 podate at various temperatures is shown in Fig. 12.
- the high field peak in the range 20-60 MHz indicated a slow rotational correlation time and a highly rigid the system. These characteristics can only be explained by the formation of nanometric particles in solution through monomer aggregation.
- the proton relaxivity (measured at 10 MHz) slightly decreased (5- 10 %) upon decreasing the [Gd(L') 2 ] 5" concentration from 1.5 x 10 "3 to 1.5 x 10 "4 M. These data suggested that particle size was somewhat affected by a change in concentration, as was indicated by light-scattering measurements.
- Contrast agents formed from non-covalent association between proteins and Gd chelates usually have water relaxivity values lower than 40 mM 's " .
- one disadvantage to using these agents in for MRI spectroscopy is that the association constants of the adducts are not very high, indicating that the in vivo relaxivity is lower than that measured in vitro.
- the measured relaxivity of millimolar solutions of the Gd complexes is often overestimated by up to 25 % because their molality is in fact larger than expected.
- Gd 1 :2 podate Another interesting property of the Gd 1 :2 podate is that NMRD profiles were shown to be temperature dependent, yet the solutions always displayed a high relaxivity. Fig. 12. These results indicated that aggregation was temperature dependent. This feature may be useful for in vivo temperature mapping techniques. Finally, the relaxivity of a [Gd(L') 2 ] 5" solution equilibrated during 24h in presence of an equimolar amount of zinc(II) remained unaffected. These results suggest a resistance to metal exchange, which is important for agents used for in vivo experiments.
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