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WO2006082108A2 - Procede d'imagerie et composition permettant d'obtenir des images de maladies vasculaires - Google Patents

Procede d'imagerie et composition permettant d'obtenir des images de maladies vasculaires Download PDF

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Publication number
WO2006082108A2
WO2006082108A2 PCT/EP2006/001054 EP2006001054W WO2006082108A2 WO 2006082108 A2 WO2006082108 A2 WO 2006082108A2 EP 2006001054 W EP2006001054 W EP 2006001054W WO 2006082108 A2 WO2006082108 A2 WO 2006082108A2
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Prior art keywords
choline
sch
och
label
derivative
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WO2006082108A3 (fr
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Philip Kaufmann
Bruno Weber
Alfred Buck
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Bayer Pharma AG
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Schering AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • 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
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0408—Phospholipids

Definitions

  • the present invention relates to methods of using labeled choline or labeled choline derivatives as imaging agents for the detection and localization of vascular diseases or vascular lesions.
  • the invention also relates to the use of labeled choline or labeled choline derivatives for the preparation of radiopharmaceutical compositions for the detection and localization of vascular diseases or vascular lesions.
  • Cardiovascular disease is a major health problem throughout the world, having a particularly high incidence in the United States, where during each year approximately 1,500,000 persons suffer a heart attack, approximately 400,000 to 500,000 persons suffer a stroke, and approximately 5,600,000 persons suffer angina.
  • heart attack i.e., myocardial infarction
  • stroke is the third leading cause of death.
  • Unstable angina i.e., severe constricting pain of coronary origin that occurs in response to less exercise than usually required to induce angina, may be associated with sudden cardiac death.
  • Heart attack, angina, and stroke are caused by stenosis, or narrowing, of arteries, which is closely related to formation of atherosclerotic plaque, or atherogenesis.
  • cardiovascular lesions were believed to form gradually, and acute clinical episodes were believed to occur only when the stenosis exceeds 40% of the cross-sectional area of the original blood vessel's lumen.
  • improved therapeutic methods such as thrombolytic therapy during acute myocardial infarction have revealed that atherosclerotic lesions most likely to precipitate a heart attack often were not associated with a high degree of stenosis.
  • unstable or vulnerable plaque which is associated with acute myocardial infarction and which is particularly susceptible to rupture.
  • a large proportion of cardiovascular disease is now believed to progress through one or more subclinical episodes in which an unstable plaque is disrupted with local thrombin activation and subsequent healing.
  • Acute myocardial infarction is now believed to result from formation of an occluding thrombus, or blood clot, at the site of a ruptured atherosclerotic plaque.
  • Unstable angina is also believed to be associated with thrombus formation, while other forms of angina are believed to be associated with stenoses that are not associated with thrombosis.
  • Atherogenesis is believed to begin with an initial lesion that appears as a fatty streak on the inner surface of an artery, consisting of two to five layers of lipid filled macrophages known as foam cells. Subsequently an intermediate fibrofatty lesion forms, consisting of twenty to thirty alternating layers of foam cells together with T lymphocytes and smooth muscle cells that separate the layers. Ultimately a fibrous plaque forms, in which a fibrous cap covers a central necrotic zone that may contain lipid, cells, and necrotic debris. A region containing numerous smooth muscle cells may also lay beneath the central necrotic lesion.
  • the fibrous cap of an atherosclerotic plaque consists of layers of smooth muscle cells surrounded by a dense connective tissue matrix containing basement membrane, collagen fibers, and proteoglycan dispersed throughout the matrix.
  • Some fibrous caps are inherently weaker than others, and these weak fibrous caps are rupture-prone, hi addition a plaque may be relatively stable or vulnerable. It is mostly the latter kind which harbors danger.
  • Currently available methods for diagnosing cardiovascular diseases employ a variety of imaging technologies, including conventional x-ray imaging, computerized tomography (CT), magnetic resonance imaging (MRI), ultrasound, and nuclear medicine imaging. Contrast agents and radiopharmaceuticals capable of accumulating at the site of a lesion are commercially available for use in imaging cardiovascular disease, for example in angiography and venography.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • ultrasound and nuclear medicine imaging.
  • Contrast agents and radiopharmaceuticals capable of accumulating at the site of a lesion are commercially available for use in imaging cardiovascular disease, for example in angiography and venography.
  • angiograms only detect stenosis and, thus, do not detect or measure the degree of atherosclerosis accurately, since they do not detect plaques that cause no stenosis.
  • the radiopharmaceuticals include nuclides such as 201 TI, " 111 Tc, 133 Xe; or nuclide labeled metabolic agents like ⁇ C-2-deoxy-D-glucose, 18 F-2-fluorodeoxy-D-glucose, [ 11 C]- and [ 123 I]-beta-methyl fatty acid analogs, 13 N-ammonia; or infarct avid agents such as 99m Tc-tetracycline, 99m Tc- pyrophosphate, 203 Hg-mercurials, 67 Ga-citrate, and the like. These imaging agents have not been suitable for diagnosis of cardiovascular lesions, especially for pre-acute event diagnosis of unstable atherosclerotic plaques.
  • Non-invasive methods of diagnosing atherosclerosis using radiodiagnostic tracers have been described before.
  • antibodies labeled with radioisotopes, or labeled low-density lipoproteins (LDL) were introduced that bond to atherosclerotic wall sections (Lees et al. (1983) J. Nucl. Med., 24: 154-156; Kaliman et al. (1985) Circulation, 72: 300; Virgolini et al. (1991) Sur. J. Nucl. Med., 18: 944-947).
  • LDL low-density lipoproteins
  • Endothelin peptides and derivatives have been proposed as biological carriers being able to target sites of vascular injury. Dinkelborg et al. describe in US 6,342,201 Bl radiolabeling of these endothelins and derivatives, and propose their use as imaging agents. Radiolabeled somatostatin peptides have also been proposed for radiodiagnosis of atherosclerotic lesions (Dean et al. US 5,976,496). The small (36 kDa) protein annexin V radiolabeled with 99m Tc has been shown to image apoptosis in human tumors (Mochizuke et al. (2003) J. Nucl.
  • Atherosclerosis would be of great importance for monitoring the therapeutic effect of diets, calcium antagonists, lipid and hypertension depressants, for monitoring restenosis after angioplastic surgery, for diagnosing coronary heart diseases, and for detecting thrombotic deposits in the vessels.
  • Yet another object of the present invention is to provide means to prepare pharmaceutical compositions for detection of a lesion in a vascular system.
  • FDG PET has been found to have less sensitivity and/or specificity for some types of cancer, motivating efforts to develop new tracers for tumor imaging.
  • Carbon-11 min) labeled choline (CH, [ 11 C]trimethyl-2-hydroxyethylammonium) has shown potential improved utility relative to FDG in two oncological imaging applications: brain tumors (Hara et al (1997) J. Nucl.
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and KM, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • labeled choline or choline derivatives show a propensity to accumulate at sites of vascular lesions and, thus, can be employed to image vascular, preferably cardiovascular lesions.
  • labeled choline or choline derivatives can be used to image unstable atherosclerotic plaques and, thus, allow addressing a previously unmet need.
  • the incidence of acute cardiovascular illness may be reduced through detection of unstable plaques in a patient and administration of appropriate treatment prior to the occurrence of a potentially debilitating or fatal myocardial infarction. Prior to the present invention, detection of unstable plaques has not been possible.
  • the present invention provides a method for detection of a lesion in a vascular system of a subject, comprising the steps of:
  • the labeled choline or choline derivative or salt thereof, used in the methods according to the invention are particularly appropriate for detection purposes as they do not additionally and non- specifically accumulate at levels in other tissues or organs in the vicinity of the vascular lesion, which would interfere with the distinction between diseased and healthy tissue. This is decisive for their suitability as agents for diagnosis.
  • the labeled choline or choline derivative or salt thereof, used in the methods according to the present invention shows both higher accumulation in pathological vascular areas and better contrast characteristics due to more favorable pharmacokinetics than many of the agents for diagnosis that have previously been described for detecting vascular diseases.
  • the label comprised in the choline or derivative thereof can be any label known to someone of skill in the art, which allows its detection due to chemical or physical phenomenons, e.g. fluorescence; phosphorescence; ⁇ - 5 ⁇ -, ⁇ -, or positron emission; or absorption.
  • the labeled choline or choline derivative comprises a label selected from the group consisting of a fluorescent label, an electron dense label, a radioactive label, and a paramagnetic label.
  • the skilled person is capable of coupling the label to choline using standard techniques.
  • Labels capable of forming covalent bonds can be linked directly to the choline or derivative thereof or through a spacer while labels, which comprise a metal or metal ion can be complexed through a metal chelating moiety, which in turn can be covalently linked directly or indirectly to the choline or derivative thereof.
  • metal chelating moieties are known in the art and are described in, for example, US 5,654,272, US 5,681,541, US 5,788,960, US 5,811,394, US 5,720,934, US 5,776,428, US 5,780,007, US 5,922,303, US 6,093,383, US 6,086,849, US 5,965,107, US 5,300,278, US 5,350,837, US 5,589,576, US 5,679,778 and US 5,879,659.
  • the respectively described metal chelating residues are specifically referenced herewith and can all equally be used as metal chelating residues in the context of the choline or choline derivatives of the present invention.
  • direct link means a covalent bond to a residue of the choline or choline derivative, preferably to a backbone carbon
  • indirect link means that one or more additional chemical residues which are connected by covalent or non-covalent bonds, preferentially by covalent bonds, are located between the choline or choline derivative and the label.
  • additional chemical residues can also be termed “spacer” and can decrease the interaction between the choline or choline derivative and the label, which might interfere with the specific interaction between the choline or the derivative thereof and the vascular lesion.
  • Photons of this wavelength are comparatively little absorbed by tissue and can therefore penetrate several centimeters into the tissue before the absorption process (primarily by oxyhemoglobin and deoxyhemoglobin) ends the light transport. Absorption can take place, moreover, by the fluorescence dyes that are introduced into the tissue, but that emit the absorbed energy in the form of longer-wave fluorescence radiation.
  • This fluorescence radiation can be detected spectrally separated and makes possible the localization of dyes and the correlation with molecular structures to which the dye or a targeting residue attached thereto has bonded (see in this respect also Licha, K. (2002) In: Topics in Current Chemistry - Contrast Agents II (Editor: W. Krause), Volume 222, Springer Heidelberg, pp. 1 — 31.).
  • fluorescent labels In the context of the method of the present invention a wide variety of fluorescent labels can be used. Particularly suitable fluorescent labels show absorption and/or emission in the near infrared, since light with a wavelength in the range of 700 to 900 run allows for an efficient photon migration through the tissues and has minimal autofiuorescence. Fluorescent labels are preferably used, if vascular lesions are detected in extremities, e.g. in the vascular system of arms, legs or the neck.
  • a particular suitable vessel for performing the method of the present invention is the carotid artery, which can be penetrated by near infrared light.
  • fluorescent labels which are excited and/or emit light in a wavelength, which does not easily penetrate the skin and tissue can still be used in connection with endoscopic or arteriographic techniques.
  • Preferred fluorescent labels which can be used in a method of the present invention are selected from the group consisting of polymethine dyes, like dicarbocyanine, tricarbocyanine, indotricarbocyanine, merocyanine, styryl, squarilium, holopolar cyanine, hemicyanine, oxonol and hemioxanole dyes; rhodamine dyes, phenoxazin dyes; or phenothiazin dyes.
  • polymethine dyes like dicarbocyanine, tricarbocyanine, indotricarbocyanine, merocyanine, styryl, squarilium, holopolar cyanine, hemicyanine, oxonol and hemioxanole dyes
  • rhodamine dyes phenoxazin dyes
  • phenothiazin dyes phenothiazin
  • carbocyanines with indocarbocyanine, indodicarbocyanine and indotricarbocyanine skeletons have high extinction coefficients and good fluorescence quantum yields (Licha, K. (2002) supra, and the references cited therein).
  • the synthesis of cyanine dyes useable according to the present invention can be carried out using the methods known in the state of the art and which are exemplified in, e.g. Hamer F.M. The Cyanine Dyes and Related Compounds, John Wiley and Sons, New York 1964; Ernst LA, et al.
  • the coupling of fluorescent labels to the choline or choline derivative can be effected by art known methods involving, e.g. activated fluorescent labels.
  • activated fluorescent labels carry a leaving group, which allows reaction with, for example, a hydroxyl residue on the choline or choline derivative.
  • Suitable leaving groups include without limitation maleinimide (maleimide), bromoacetyl, chloroacetyl, iodoacetyl, chloroacetamido, bromoacetamido, iodoacetamido, chloroalkyl, bromoalkyl, iodoalkyl, pyridyl disulfide and vinyl sulfonamide.
  • CT and X-ray imaging is based on the principle that various substances effect different degrees of attenuation of an X-ray beam.
  • Contrast agents useful for CT or X-ray imaging usually contain atoms which are electron dense, such as bromine or iodine, and are efficient attenuators of X-ray radiation.
  • CT agents are monomeric or dimeric iodinated benzene rings with various pendent groups such as ORAGRAFIN, CHOLOGRAFIN and RENOGRAFIN (Squibb Diagnostics, Princeton, NJ.).
  • One important advance in the use of iodine-containing CT agents has been the development of non-ionic contrast agents, such as the ones described by M. T. Rneller et al., PCT Application Ser.
  • the electron dense label is selected from the group consisting of Ag, Au, Br, Fe, and I.
  • Particularly preferred electron dense labels comprised in the labeled choline or derivative thereof are Br and I, which can replace one or more hydrogens within the choline molecule or can be comprised in a further molecule, like iodinated benzene rings, which are directly or indirectly linked to the choline or derivative thereof.
  • metals or metal ions are used as electron dense labels, e.g. Ag, Au or Fe, they can be attached to choline or a derivative thereof using metal chelating moieties as outlined above.
  • Nuclear imaging is based on the detection of radioactive isotopes.
  • a wide variety of radioactive isotopes is known in the art, which can be used for imaging and/or therapeutic purposes.
  • Isotopes, which can be used to label the choline or derivative thereof include without limitation 225 Ac, 211 At, 212 Bi, 213 Bi, 76 Br 5 11 C, 34m Cl, 67 Cu, 18 F, 68 Ga, 166 Ho, 123 I, 124 I, 125 I, 131 I, 13 N 5 223 Ra, 186 Re, 188 Re, 47 Sc, 153 Sm, 94m Tc, 99m Tc, and 90 Y.
  • the isotopes 11 C, 34m Cl, 76 Br, 68 Ga, 18 F, 123 I, 124 I, 131 I, and 13 N are particularly suitable for imaging and are, thus, particular preferred labels within the context of the present invention.
  • Radioactive metals or metal ions are preferably attached to the choline or derivative thereof through a chelating residue, which is directly or indirectly linked to the choline.
  • Radioactive isotopes capable of forming a covalent bond like, for example, 11 C, 34m Cl, 96 Br, 18 F, 123 I, 124 I 5 131 I, and 13 N can be directly or indirectly linked to the choline or derivative thereof or in case of 11 C and 13 N replace one or more of the carbon or nitrogen moieties in the backbone of choline.
  • 11 C and 13 N can also be comprised in a separate molecule, which is directly or indirectly linked to the choline or choline derivative.
  • Methods of synthesizing molecules labeled with a radioactive isotope are known in the art. For example, US 6,630,125 B2 discloses methods of synthesizing 18 F labeled choline and choline derivatives.
  • the amount or radioactivity comprised within the choline or derivative thereof is within the range of about 0.1 to about 100 mCi and more preferably in the range of between about 1 and about 15 mCi, even more preferably between about 3 and about 10 mCi.
  • the preferred and more preferred ranges of radioactivity are particular suitable in the context of 11 C, 34m Cl, 18 F, 76 Br, 123 1, 124 1, 131 I, and 13 N labels, in particular 11 C, and 18 F labels.
  • paramagnetic label means a metal ion which is magnetized parallel or antiparallel to a magnetic field to an extent proportional to the field.
  • these are metal ions which have unpaired electrons; this is a term understood in the art.
  • suitable paramagnetic metal ions include, but are not limited to, gadolinium III (Gd 3+ or Gd(III)), iron III (Fe 3+ or Fe(III)), manganese II (Mn 2+ or Mn(II)), yttrium III (Yt 3+ or Yt(III)), dysprosium (Dy 3+ or Dy(III)), and chromium (Cr(III) or Cr 3+ ).
  • the paramagnetic ion is the lanthanide atom Gd(III), due to its high magnetic moment, a symmetric electronic ground state (S8), and its current approval for diagnostic use in humans.
  • the methods of the present invention also comprise the simultaneous use of two labels of different categories, e.g. of a radioactive PET label like, e.g. 18 F, and an electron dense label like, e.g. Br or I.
  • a radioactive PET label like, e.g. 18 F
  • an electron dense label like, e.g. Br or I.
  • the present invention also comprises labeled choline or choline derivatives, which comprise two labels each detectable by a different imaging or detection technique.
  • the two labels are selected from the group of labels comprising fluorescent labels, electron dense labels, radioactive labels, and paramagnetic labels.
  • two or more different cholines or choline derivatives are administered simultaneously or subsequently (within an interval of a few minutes to a few hours), wherein each choline or derivative thereof carries a different label, preferably from categories of labels, which are detectable by different imaging or detection methods.
  • pharmaceutically acceptable salt refers to a salt of a choline or derivative thereof.
  • Suitable pharmaceutically acceptable salts of choline or derivative thereof for compounds bearing a basic moiety include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • compositions include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, fo ⁇ nate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorc
  • a “choline derivate” is an organic compound with a choline derived structure, i.e. it comprises a N or P heteroatom substituted with at least one lower alkyl (C 1 to C 5 ) side chain, which bears a terminal hydroxyl group and a short hydrocarbon chain (C 1 to C 5 ), preferably a lower alkyl chain (C 1 to C 5 ), having a propensity to accumulate at a site of vascular lesions, which is at least 10% of the propensity of choline at the same molar concentration.
  • the heteroatom of the choline derivative is further substituted with hydrogen or a short hydrocarbon chain (C 1 to C 5 ) optionally interspersed with a O or S residue, preferably a lower alkyl chain (C 1 to C 5 ).
  • the propensity of a given derivative can be measured, for example, using an ApoE -/- mouse-model as outlined in Example 2 below.
  • Fig. 1 shows the accumulation of a labeled choline derivative in areas of vascular lesions, while almost no label is detectable between the lesions.
  • the ratio of the amount of label detected in healthy vascular tissue and diseased vascular tissue is a measure of the propensity of a labeled choline derivative to accumulate in vascular lesions.
  • the choline derivative has at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 200%, 250%, 300%, 400%, 500% or more of the propensity of choline to accumulate at the site of vascular lesions.
  • a cardiovascular lesion includes atherosclerotic plaques at any stage of atherogenesis, e.g., initial fatty streaks, intermediate fibrofatty lesions, and fibrous plaque are all considered to be cardiovascular lesions which are detectable by the methods of the present invention.
  • Any cardiovascular lesion may be detected using a labeled form of a choline or a choline derivative in accordance with the present invention.
  • highly stenotic plaques i.e., plaques that occlude more than about 40% of the blood vessel luminal cross-section, are detectable using the methods of the invention.
  • non-critically stenotic plaques i.e., plaques that occlude less than about 40%, preferably less than about 30%, less than about 20% of the blood vessel luminal cross-section
  • unstable atherosclerotic plaques are detected using the methods and kits of the invention.
  • a useful histopathologic definition of the term "unstable plaques" has been provided by the American Heart Association (AHA) on the basis of work by Herbert Stary (Stary HC, et al. (1992) Circulation, 85: 391; Stary HC, (1994) Circulation, 89: 2462-2478; Stary HC, et al.
  • This layer is composed of preexisting intima in type IV plaques, whereas in type V plaques, the intima has been replaced by pathological fibromuscular tissue.
  • plaques of lesion type II or III are detected using the method of the present invention, i.e. at a stage at which a life style change or medication has the potential of reversing the disease.
  • Cardiovascular lesions are detected in accordance with the invention by administering an amount of labeled choline or choline derivatives which is sufficient for later detection. As used herein, this amount is defined as an amount sufficient to yield an acceptable image using equipment that is available for clinical use.
  • An effective amount of the labeled choline or choline derivative may be administered in more than one dose, but is preferably administered in a single dose.
  • Effective amounts of the labeled choline or choline derivative may vary according to factors such as the degree of susceptibility of the individual; the age, sex, and weight of the individual; idiosyncratic responses of the individual; and in case of radioactively labeled cholines and derivatives thereof dosimetry. Effective amounts of the labeled choline or choline derivative may also vary with the particular instrument employed and film- and/or detector-related factors and can be determined by the physician. For example, assuming a medium body weight of 70 kg, the amount of radioactivity for diagnostic applications is preferably between 1 and 15 mCi, more preferably 3 and 10 mCi per application. Normally, a solution of the agent according to the invention is applied as an intravenous injection of 5 to 10 ml of the agent according to the invention.
  • the labeled choline or choline derivative or pharmaceutically acceptable salt of the choline or choline derivative is of the following formula (I):
  • a + is N + or P + ,
  • R 1 and R 2 independent of each other are H; a direct or indirect link to a label; or a C 1-5 straight or branched alkyl, e.g. C 1 , C 2 , C 3 , C 4 , or C 5 alkyl, in particular methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1- dimethylpropyl, or 1,2-dimethylpropyl; C 2-5 straight or branched alkenyl, e.g.
  • C 2 , C 3 , C 4 , or C 5 alkenyl in particular ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, pentenyl, 1- methylbutenyl, 2-methylbutenyl, 3-methylbutenyl, 1,1-dimethylpropyl, or 1,2-dimethylpropyl; C 2-5 straight or branched alkynyl, e.g.
  • C 2 , C 3 , C 4 , or C 5 alkynyl in particular ethynyl, propynyl, butynyl, iso-butynyl, pentynyl, 1-methylbutynyl, 2-methylbutynyl, 3-methylbutynyl, or 1,1- dimethylpropynyl; C 1-5 straight or branched oxyalkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , or C 5 oxyalkyl wherein the O residue can be interspersed at any position between the carbon residues, in particular methoxy, ethyoxy, propoxy, butoxy, pentoxy, methylmethoxy, methylethoxy, methylpropoxy, methylbutoxy, ethylmetl ⁇ oxy, or ethylethoxy; C 2-5 straight or branched oxyalkenyl, e.g. C 2 , C 3 , C 4 , or C 5 oxyalkenyl, wherein the O residue can be interspersed at any position between the carbon residues; C 1-5 straight or branched thioalkyl, e.g.
  • C 1 , C 2 , C 3 , C 4 , or C 5 thioalkyl wherein the S residue can be interspersed at any position between the carbon residues, in particular thiomethyl, thioethyl, thiopropyl, thiopentyl; or C 2-5 straight or branched tliioalkenyl e.g.
  • alky, alkenyl, alynyl, oxyalkyl, oxyalkenyl, thioalkyl or thioalkenyl is optionally substituted with one or more OH, aryl, heteroaryl or halogen, e.g. F, Cl, Br, I, and/or comprises at least one direct or indirect link to a label, preferably R 1 and R 2 independent of each other are H or substituted or unsubstituted C 1-5 straight or branched alkyl, e.g. C 1 , C 2 , C 3 , C 4 , or C 5 alkyl,
  • R 3 is a C 1-3 straight or branched alkyl, e.g. C 1 , C 2 , or C 3 alkyl, in particular methyl, ethyl, propyl, iso-propyl, or alkenyl, e.g. C 2 , or C 3 alkenyl, in particular ethenyl, propyl, iso-propenyl, optionally substituted with one or more OH or halogen, e.g. F, Cl, Br, I, and/or comprises at least one direct or indirect link to a label,
  • OH or halogen e.g. F, Cl, Br, I
  • X 1 and X 2 independent of each other are H, deuterium or halogen, e.g. F, Cl, Br, I,
  • n 1, 2 or 3, preferably 2 or 3;
  • At least one label is comprised within R 1 , R 2 or R 3 , or that at least one carbon moiety within the choline or derivative is 11 C, or that at least one nitrogen moiety is 13 N.
  • R 3 is (CX 3 X 4 ) m X 5 , wherein
  • X 3 and X 4 independent of each other are H, deuterium or halogen, e. g. F, Cl, Br, or I, preferably X 3 and X 4 are H,
  • X 5 is H or a direct or indirect link to a label
  • m 1, 2 or 3, preferably 2 or 3.
  • the counteranion is preferably selected from the group consisting of OH " , acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydro chloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorc
  • the labeled choline or choline derivative is chosen form the group consisting of [ 18 F] N,N-dimethyl-N- fluoroethylethanolamine ( 18 F-fluoroethylcholine), [ 18 F] N,N-dimethyl-N-fluoromethyl- ethanolamine ( 18 F-fluorocholine), [ 18 F] fluoromethyl-methylethyl-2-hydroxyethyllammonium, [ 18 F] fluoropropyl-dimethyl-2-hydroxyethyl-ammonium, N,N-dimethyl-N-[ ⁇ C] methyl- ethanolamine ( 1 ⁇ -choline).
  • Administration may be accomplished by arterial or venous injection.
  • analogs of the invention are preferably administered as an intravenous (IV) bolus.
  • IV intravenous
  • the patient is fasted at least 4 hours prior to administration of the analogue.
  • the imaging or detection method in a time interval of between 5 min and 20 hours after administration of the labeled choline of derivative thereof, preferably in a time interval of between 10 min and 10 hours, more preferably 20 min to 2 hours and even more preferably 30 min to 1 hour.
  • the time required in each case will depend on the respective choline or choline derivative used and patient parameters and will ultimately be determined by the attending physician.
  • the method according to the invention can further comprise a step of imaging of a region of said vascular system at which said labeled choline or choline derivative has accumulated.
  • this is performed by extracorporeal monitoring, and in a more preferred embodiment, monitoring is performed with a fluorescent, CT, MRI, PET, fluorescent/PET, MRI/PET, CT/PET, ultrasound/PET, fluorescent/CT, fluorescent/MRI, fluorescent/ultrasound, CT/MRI, or CT/MRI/ultrasound scanner.
  • the combination of two or more imaging methods is particularly preferred, if the choline or derivative thereof, which is used comprises labels of two or more categories, i.e. which is detectable with two or more different imaging methods.
  • the PET imaging technique is particular preferred.
  • PET scanners are widely available for imaging of human subjects.
  • micro-PET scanners that have high spatial resolution can be used for imaging of small animals or extremities of larger animals.
  • positron emission radioactivity can also be monitored using one or more radiation detector probes.
  • the method according to the invention includes detection of the accumulation of radiolabled choline or choline derivative by PET/CT or
  • PET is a radiodiagnostic technique uniquely suited to image small disease features like atherosclerotic lesions owing to its superior resolution and sensitivity relative to single photon emission tomography (SPECT). Furthermore, image reconstruction and attenuation correction techniques are better-developed for PET as compared to SPECT, allowing for better quantification. Therefore, a more preferred embodiment of the method according to the invention includes detection of the accumulation of radiolabled choline or choline derivative by PET/CT. PET can be used to detect and stage vascular diseases or vascular lesions because of its unique strength in detecting and quantifying small regions of label uptake.
  • PET particular suitable to be used to monitor a patient's response to therapy.
  • the labeled choline or choline derivative is preferably administered intravenously, in combination with a pharmaceutically acceptable carrier, to the subject.
  • a pharmaceutically acceptable carrier may include any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
  • the labeled choline or choline derivative is formulated as a sterile, pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • the labeled choline or choline derivative may further be administered to the subject in an appropriate diluent or adjuvant or be co-administered with enzyme inhibitors or in a carrier such as species appropriate albumin.
  • Pharmaceutically acceptable diluents include solutions such as saline or aqueous buffer solutions. Many such diluents are known to those of skill in the art, such as, for example, Sodium Chloride Injection and Ringer's Injection.
  • labeled choline and choline derivatives of the invention can also be formulated with a chemical stabilizer.
  • Such stabilizers can reduce the likelihood for radiolysis-induced decomposition of the radiolabeled choline or choline derivative at high concentrations of radioactivity.
  • Suitable stabilizers include antioxidants such as the pharmaceutically acceptable antioxidant, sodium L-ascorbate or ⁇ -tocopherol.
  • the labeled choline or choline derivative may be administered in autologous serum or plasma.
  • Supplementary active compounds may also be co-administered with labeled choline or choline derivative in accordance with the invention.
  • the invention further relates to the use of labeled choline or a labeled choline derivative or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for detection of a lesion in a vascular system of a subject, as described hereabove.
  • the invention further relates to the labeled choline or choline derivatives, which are suitable for carrying out the method of the present invention.
  • Labeled choline or choline derivatives can also be used in the noninvasive assessment of the response of vascular lesions in a patient to therapeutic interventions using PET scanning or another external radiation detection technique.
  • the patient can be scanned at more than one time and the data from two or more scans are compared to determine potential differences in the uptake of the analogue at the site of said vascular lesion. Comparisons can involve either qualitative image comparison (e.g. contrast of vascular lesion uptake from background) or quantitative indices derived from the imaging or external radiation detection data (e.g. standardized uptake values (SUVs)).
  • qualitative image comparison e.g. contrast of vascular lesion uptake from background
  • quantitative indices derived from the imaging or external radiation detection data e.g. standardized uptake values (SUVs)
  • Fig. 1 Plaque imaging in atherosclerotic ApoE -/- mice using 18 F-Choline.
  • the accumulation of 18 F-Choline in the aorta of atherosclerotic mice is shown (ApoE ko #2 and ApoE ko #3), whereas no significant accumulation in the aorta of wild type mice (WT) has been observed (see left panel of the images for the respective animal).
  • the right panel of the images show oil red O stained aortas for the respective animal. This suggests that 18 F- Choline can be effectively used to perform PET scan of mammals in order to detect lesions in the vascular system, and particularly atherosclerotic vulnerable plaques.
  • [ 18 F]FCH was produced by the reaction of [ 18 F]fluoromethyltriflate with diaminoethanol.
  • [ 18 F] fluoride (azeotropically dried with 2 x 0.7 ml acetonitrile) was reacted with dibromomethane in acetonitrile in the presence of Kryptofix(2.2.2) at HO 0 C to give [ 18 F]fluorobromomethane (Bergman J, et al. (2001) Appl Radiat Isot, 54: 927-933) which was purified over a series of 4 Sep-Pak Plus silica cartridges.
  • [ 18 F]fluoromethyltriflate was made by passing [ 18 F]bromofluoromethane over a silvertriflate/Graphpac GC column at 18O 0 C.
  • [ ls F]fluoromethyltriflate was then used for the N-alkylation of 2-dimethylaminoethanol immobilized on a Sep-Pak Plus C-18 cartridge (a solution of 2-dimethylaminoethanol in ethanol (200 ⁇ l in 600 ⁇ l) was put on the cartridge), to quantitatively yield the desired product.

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Abstract

Procédés d'utilisation de choline marquée ou de dérivés de choline marqués en tant qu'agents d'imagerie pour la détection et la localisation de maladies ou de lésions vasculaires. La présente invention concerne également l'utilisation de choline marquée ou de dérivés de choline marqués pour la préparation de compositions radiopharmaceutiques destinées à la détection et à la localisation de maladies ou lésions vasculaires.
PCT/EP2006/001054 2005-02-07 2006-02-07 Procede d'imagerie et composition permettant d'obtenir des images de maladies vasculaires Ceased WO2006082108A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031712A1 (fr) * 2007-09-07 2009-03-12 Kyoto University Composés, agent de diagnostic, procédé d'analyse par résonance magnétique nucléaire, procédé d'imagerie par résonance magnétique nucléaire, procédé de spectrométrie de masse et procédé d'imagerie par spectrométrie de masse
WO2011024156A1 (fr) * 2009-08-31 2011-03-03 Brain Watch Ltd. Agents neurochimiques marqués de manière isotopique et leurs utilisations pour le diagnostic d’états et de troubles
WO2012040151A3 (fr) * 2010-09-21 2012-05-03 Ge Healthcare Limited Analogues de la choline marqués par un isotope du carbone
WO2012040138A3 (fr) * 2010-09-21 2012-05-18 Ge Healthcare Limited Nouveau radiotraceur
US8787643B2 (en) 2009-02-17 2014-07-22 Koninklijke Philips B.V. Functional imaging
CN117800856A (zh) * 2021-08-25 2024-04-02 深圳鼎邦生物科技有限公司 一种稳定性同位素取代的胆碱化合物的制备方法及其应用

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* Cited by examiner, † Cited by third party
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US6630125B2 (en) * 2000-04-28 2003-10-07 Duke University 18F-labeled choline analogs

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009031712A1 (fr) * 2007-09-07 2009-03-12 Kyoto University Composés, agent de diagnostic, procédé d'analyse par résonance magnétique nucléaire, procédé d'imagerie par résonance magnétique nucléaire, procédé de spectrométrie de masse et procédé d'imagerie par spectrométrie de masse
JP2009079046A (ja) * 2007-09-07 2009-04-16 Kyoto Univ 化合物、診断薬、核磁気共鳴分析方法、核磁気共鳴イメージング方法、質量分析方法及び質量分析イメージング方法
US8787643B2 (en) 2009-02-17 2014-07-22 Koninklijke Philips B.V. Functional imaging
WO2011024156A1 (fr) * 2009-08-31 2011-03-03 Brain Watch Ltd. Agents neurochimiques marqués de manière isotopique et leurs utilisations pour le diagnostic d’états et de troubles
WO2012040151A3 (fr) * 2010-09-21 2012-05-03 Ge Healthcare Limited Analogues de la choline marqués par un isotope du carbone
WO2012040138A3 (fr) * 2010-09-21 2012-05-18 Ge Healthcare Limited Nouveau radiotraceur
CN103282343A (zh) * 2010-09-21 2013-09-04 通用电气健康护理有限公司 作为放射性示踪剂的胆碱类似物
CN103339100A (zh) * 2010-09-21 2013-10-02 通用电气健康护理有限公司 同位素碳胆碱类似物
JP2013538234A (ja) * 2010-09-21 2013-10-10 ジーイー・ヘルスケア・リミテッド 同位体炭素コリン類似体
JP2013542187A (ja) * 2010-09-21 2013-11-21 ジーイー・ヘルスケア・リミテッド 新規放射性トレーサー
CN117800856A (zh) * 2021-08-25 2024-04-02 深圳鼎邦生物科技有限公司 一种稳定性同位素取代的胆碱化合物的制备方法及其应用

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