WO2000043004A1 - Derives 1,4,8,11-tetraazacyclotetradecane utiles en tant qu'agents de radiodiagnostic et utilisation de ces derniers dans la determination de l'hypoxie et de la radioresistance des tumeurs - Google Patents

Derives 1,4,8,11-tetraazacyclotetradecane utiles en tant qu'agents de radiodiagnostic et utilisation de ces derniers dans la determination de l'hypoxie et de la radioresistance des tumeurs Download PDF

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Publication number
WO2000043004A1
WO2000043004A1 PCT/US2000/001754 US0001754W WO0043004A1 WO 2000043004 A1 WO2000043004 A1 WO 2000043004A1 US 0001754 W US0001754 W US 0001754W WO 0043004 A1 WO0043004 A1 WO 0043004A1
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Prior art keywords
complex
cyclam
derivative
group
tissue
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PCT/US2000/001754
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English (en)
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J. Donald Chapman
Richard F. Schneider
Edward L. Engelhardt
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Fox Chase Cancer Center
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Priority to CA002361115A priority Critical patent/CA2361115A1/fr
Priority to EP00908353A priority patent/EP1148878A4/fr
Publication of WO2000043004A1 publication Critical patent/WO2000043004A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage

Definitions

  • This invention relates to derivatives of 1,4,8,11- tetraazacyclotetradecane (cyclam) which demonstrate hypoxic cell selectivity and retention and which are useful as radiodiagnostic agents for assessing tissue oxygenation status non-invasively, as well as to methods for preparing such derivatives and radionuclide metal-containing complexes thereof and their use for imaging and non-invasively determining tissue hypoxia and radioresi stance of tumors.
  • Radiobiologic hypoxic fraction the fraction of clonogenic tumor cells that exhibit maximum radioresistance, has been shown to be an important parameter for predicting tumor treatment resistance and for the selection of aggressive and metastatic cell phenotypes. If this tumor property were known by clinicians at the time of diagnosis, it would be a useful predictor of tumor treatment response and would define subsets of patients for whom targeted therapies would produce improved cure rates.
  • hypoxic tissue A promising approach to the assessment of hypoxic tissue is suggested by the ability of certain classes of compounds to selectively localize in these tissues after intravenous administration.
  • the radiosensitizing drug, misonidazole (MISO) was shown to become selectively bound to the macromolecular fraction of EMT-6 murine tumor and V-79 hamster lung cells in hypoxic in vitro incubation studies (J.D. Chapman et al., Cancer Res., 43: 1523- 1528 (1983)) and to EMT-6 tumors in BALB/C mice (B.M. Garrecht et al., Brit. J. Radiol., 56: 745-753 (1983)).
  • MISO misonidazole
  • hypoxic tissue imaging agents incorporating ⁇ -emitting radionuclides have been investigated. These include 4- bromomisonidazole (D.C. Jette et al., Int. J. Nucl. Med. Biol, 10: 205-210 (1983); J.S. Rasey et al., Radiat. Rse., 91: 542-554 (1982)), l-(2-iodophenoxy)- ethyl)-2-nitroimidazole (L.I. Wiebe, Nucelartechnike, 23: 63-67 (1984)), a series of iodinated acetophenone derivatives of 2-nitroimidazole (J.R.
  • IAZA iodoazomycin arabinoside
  • IAZGP iodoazomycin galactopyranoside
  • IAZXP iodoazomycin xylopyranoside
  • IAZGP and IAZA have been found to be selectively toxic to hypoxic EMT-6 tumor cells and also sensitize these cells to the lethal effects of ionizing radiation.
  • IAZA is taken up preferentially in EMT-6 tumor tissue at a level useful for non-invasive imaging.
  • I-IAZA An imaging study using 125 I-IAZA showed EMT-6 tumor tissue to be clearly delineated from surrounding tissue. More recently, pilot clinical studies using 123 I-IAZA with single photon emission computed tomography (SPECT) and 18 F-FMISO with positron emission tomography (PET) have been reported. These data were recently reviewed and it appears unlikely that either marker is optimal for routinely determining the HF of individual human tumors (J.D. Chapman et al., Radiother. Oncol., 46: 229-37 (1998)). Among the azomycin-nucleoside markers, IAZXP and IAZGP have been shown to exhibit the most favorable properties for marking the HF of solid rodent tumors in vivo (J.D. Chapman et al. (1988), supra).
  • azomycin nucleosides and particularly IAZGP, have been found to have useful hypoxic marking properties, an extensive research effort is ongoing to identify hypoxic markers which exhibit good bioavailability to all tissues, low lipophilicity to promote rapid renal excretion, are amenable to detection at optimal times after administration and can be convenientily labelled with the preferred nuclear medicine isotopes.
  • the linking group comprises a chain of 2 to 7 atoms selected from the group of carbon or nitrogen, wherein the moiety connecting the cyclam nitrogen and the 1-imidazole nitrogen to the remainder of the linking group is a -CH 2 - moiety, the carbons in the remainder of the linking moiety being optionally substituted with a hydroxyl group, and two adjacent carbons in the linking groups being optionally replaceable by an amide group.
  • Stereoisomers including both enantiomers, meso forms and diastereomers of the cyclam derivatives of the above general formula, as well as the pharmaceutically acceptable salts of such cyclam derivatives and their isomers, are included within the present invention.
  • the present invention also provides radiodiagnostic complexes comprising a cyclam derivative, as described above, and various complex- forming radionuclide metals.
  • a process for preparation of the cyclam derivatives of the invention. Briefly, this method involves the nucleophilic displacement by cyclam of a suitable leaving group on a moiety containing azomycin.
  • the present invention provides radiodiagnostic compositions comprising the above-mentioned radionuclide metal-containing complexes and a biologically compatible carrier medium for use in determining tumor hypoxia and radioresistance, as well as in imaging body tissue of a living test subject.
  • kits for carrying out such method.
  • the kit contains
  • a novel non-invasive method for the detection and measurement of tissue hypoxia in a mammal comprising the steps of:
  • a method for imaging body tissue of a living test subject by administering to the test subject a radionuclide metal-containing complex, as described herein, and detecting the localization of the complex in the body tissue using a suitable radiation detector.
  • a suitable radiation detector include, without limitation, SPECT and PET cameras.
  • the cyclam derivatives of the present invention are considered superior to previously reported radiodiagnostic agents for measuring hypoxia and predicting tumor radioresistance because of their high specific activity and the large differential labelling of experimental tumors having a an HF of 15-20%, as compared to tumor tissue that exhibits no detectable HF.
  • the ability to define one type of tumor resistance in advance of therapy is important, since various modalities of targeted cancer treatment, such as chemical radiosensitizers, chemopotentiation agents and bioreductive drugs, can now be directed towards treatment-resistant hypoxic cells.
  • a radiodiagnostic agent for oxygenation status will be useful in detecting and defining other disease states, including myocardial infarct and cerebrovascular hemorrhage, in which ischemia and/or infarct play a role and in infections which involve anaerobic foci.
  • FIGURES 2A-D show collimated, gamma-camera planar images of two pair of R 3327-AT (left; hypoxic) and R 3327-H (right; non-hypoxic) tumor-bearing rats six hours after i.v. administration of Tc-99m-labelled
  • FIGURE 3 is a graphical representation of data showing the binding rate (dpm/10 6 cells/hr) of a Cu-64 containing tetra-[2-hydroxy-3-(2- nitroimidazol-l-yl)propyl]-substituted cyclam to tumor cells in vitro, as a function of oxygen concentration.
  • FIGURES 4A and B show collimated, gamma camera planar images of a pair of R3327-AT (left; hypoxic) and R3327-H (right; non-hypoxic) tumor bearing rats 5-7 hours after administration of a Cu-64 containing tetra-[2- hydroxy-3-(2-nitroimidazol-l-yl)propyl]-substituted cyclam.
  • cyclam derivatives of formula I can be prepared from known starting materials and the syntheses of specific embodiments of such derivatives that are within the scope of the invention are exemplified below. Certain of these derivatives have been used for radiodiagnostic imaging of animal tumor models and for evaluating their ability to determine tissue hypoxia and assess their hypoxic marking properties, as reported below.
  • Suitable linking groups for linking the 2-nitro-imidazolyl moiety to the cyclam nucleus are those of the formula
  • At least one of the cyclam ring nitrogens is linked to a nitroimidazolyl moiety of the above formula through an unsubstituted or hydroxyl-substituted divalent alkylene linking moiety of 2 to 7 carbon atoms, which may optionally be interrupted by at least one group containing the amide moiety.
  • the cyclam derivatives of this invention can form soluble salts with pharmaceutically acceptable acids, such as hydrochloric, phosphoric, tartaric and citric acids, and these salts are also within the scope of the present invention.
  • pharmaceutically acceptable salts of the cyclam derivatives described herein can be prepared following procedures that are familiar to those skilled in the art.
  • the cyclam derivatives described herein form a complex with various radionuclide metals selected from the group of the radioactive isotopes of
  • the radionuclide metal-containing complexes are prepared by causing a salt or chelate of a suitable radionuclide metal to undergo a complex-forming reaction with a cyclam derivative of the invention.
  • Complex formation is effected by contacting the cyclam derivative with the desired metal in the form of a salt or in the form of a chelate wherein the metal is bound to a relatively weak chelator.
  • the desired complex is formed via the principle of ligand exchange.
  • a reducing agent may be required for the above reaction, as in cases where technetium metal is used.
  • Suitable reducing agents for this purpose include Sn(LI) compounds, dithionites, sodium borohydride, and the like.
  • the desired radionuclide may be contacted with cyclam derivative in the form of a chelate, bound to a relatively weak chelator, such as a glucoheptonate, pyrophosphate, a polyphosphate, a phosphonate or polyphosphonate, an oxinate, a carboxylate, a hydroxycarboxylate, an aminocarboxylate, an enolate or a mixture thereof, such reaction being carried out under moderate conditions.
  • a relatively weak chelator such as a glucoheptonate, pyrophosphate, a polyphosphate, a phosphonate or polyphosphonate, an oxinate, a carboxylate, a hydroxycarboxylate, an aminocarboxylate, an enolate or a mixture thereof, such reaction being carried out under moderate conditions.
  • the kit embodiment of this invention may optionally comprise a solution of the radionuclide metal. Because such solutions have a limited shelf life, however, they may be made available separately.
  • Radiodiagnostic compositions comprising a radionuclide metal- containing complex, as described above, may be conveniently formulated for administration with a biologically acceptable carrier medium.
  • the carrier medium is sterile, pyrogen-free phosphate buffered sale (PBS).
  • the radiodiagnostic agents of the invention should be delivered to tissue in trace amounts, on the order of 10 "12 M.
  • Nuclear medicine markers are usually administered according to their biodistribution, with isotope dose up to 40 mCi in the case of Tc-99m, for example.
  • any substance used in formulating a radiodiagnostic composition in accordance with this invention should be virus-free, pharmaceutically pure and substantially non- toxic in the amount used.
  • biologically acceptable carrier medium is intended to include any and all solvents, dispersion media and the like which may be appropriate for the desired route of administration of the composition.
  • radiodiagnostic agents of the invention are administered parenterally, intravenous administration being the preferred route.
  • radiodiagnostic composition After administration of the radiodiagnostic composition to a test subject, an image is obtained to detect accumulated radioactivity and thus to determine the location thereof in the body tissue of the test subject.
  • the radionuclide metal-containing complexes of the invention may be utilized in a number of different clinical and research imaging techniques, including without limitation, SPECT and PET.
  • PET has been gaining increasing acceptance in the field of oncology.
  • One of the principal advantages of positron imaging currently is its high detection efficiency and higher resolution, as compared to prior gamma- detectors. This technique is particularly well suited to the detection of tumor oxygen levels, providing results that are consistent with those obtained through invasive polarographic electrode measurements.
  • Cu-64 is the preferred radionuclide for PET applications. It can be obtained from the Mallinckrodt Institute of Radiology, or may be prepared as described in U.S. Patent 6,001,825. PET imaging systems are available from commercial sources. See also, U.S. Patent 5,451,789 to Wong et al. ("High Performance Positron Camera").
  • Examples 1-4 describe the synthesis and purification of representative cyclam derivatives of the invention, as well as the preparation of complexes of such derivatives with suitable ⁇ -emitting radionuclides. In the examples, all temperatures are given in degrees Centigrade, unless otherwise indicated.
  • This material was dissolved in 300 ⁇ l of 1 N HCl.
  • the flask was placed in a beaker containing 25 ml of abs. ethanol in a dessicator. After 2 days, a large portion of the white crystals was removed and the remaining crystals combined with the 190 mg fraction.
  • the combined products were dissolved in 2 ml of water, the solution rendered basic with 3.0 ml of 1 N NaOH and extracted with 5 x 2 ml of methylene chloride. The solvent was evaporated from the combined extracts and the residue dried to give 184.6 mg of partially crystalline yellow material.
  • This product was dissolved in 300 ⁇ L of abs. ethanol and applied to a 20 x 153 mm column of E. Merck silica gel 60 (230-400 mesh). The column was developed with: chloroform 175 ml; abs. ethanol 275 ml; cone. NH 4 OH 50 ml.
  • Fractious 8-11 gave 60.5 mg of a yellow syrup from which a few needle-like crystals separated.
  • This product was dissolved in 820 ⁇ L of 1 N HCl.
  • the flask was placed in a beaker of abs. ethanol in a dessicator at atmospheric pressure for 4 days. At this time, there was a small area of crystaline material in the neck. There were numerous small globules of clear yellow liquid on the walls.
  • the slightly cloudy mother liquor was transferred to another flask that was placed in a beaker of alcohol for 4 days. Cream colored crystals were deposited.
  • the solution was passed through a 0.8 X 4 cm BioRad Poly-Prep Chromatography Column (cat #731-1550) containing 0.31 g BioRad Ag 1-X8 ion exchange resin, chloride form, 200-400 mesh (cat # 140-1451).
  • the column was rinsed with 1.0 ml deareated distilled water. At this point, the radiolabeled ligand in the eluant was ready as a radiodiagnostic agent.
  • the solution was allowed to incubate at room temperature for one- half hour.
  • the solution was filtered through a 0.22 ⁇ filter, which renders it ready for use as a radiodiagnostic agent.
  • Figure 2 shows two pairs of Fischer X Copenhagen rats in which R3327-AT and R3327-H tumors of approximately equal volume were growing and to which Ceretec®, radiolabeled with Tc-99m, and the complex of this example were administered i.v.. Ceretec® is a commercial tumor perfusion marker.
  • Planar images using a collimated gamma camera were acquired six to seven hours after marker administration. After the imaging procedure, animals were sacrificed and the specific activity of hypoxic marker in blood, muscle and tumor tissue was measured. The tumor specific activity of these markers is presented in Example 5, below.
  • Figure 4 shows the uptake of the radiodiagnostic complex of this example in a pair of Fischer X Copenhagen rats in which R3327-AT (Fig. 4A) and R3327-H (Fig. 4B) tumors of approximately equal volume were growing.
  • the tumors of 8-10 gm. weight, are indicated by a black circle in each figure. Tumor specific activity was determined to be about 2.2.
  • T/B-maximal tumor/blood ratio of tissue-specific radioactivity T/M-maximal tumor/muscle ratio of tissue-specific radioactivity %ID/g AT - percentage of injected dose of marker/g in anaplastic tumor tissue assessed 6 hours following injection. Specific activities were corrected to a standard rat weight of 400 g. Anaplastic tumors formed following injection of cells from the Dunning rat prostate carcinoma, R3327-AT.
  • %ID/g H - percentage of injected dose of marker/g in well-differentiated tumor tissue assessed 6 hours following injection. Specific activities were corrected to a standard rat weight of 400 g.
  • the radiodiagnostic agent of Example 4b was recovered from the hypoxic tumors at a level of about three times higher than the non-hypoxic, well oxygenated tumors. It is also noteworthy that up to six-fold higher levels were observed in individual pairs of animals.
  • Tc-99m labelled Ceretec® distributed to the well oxygenated tumors at a level of about 1.7 times higher than hypoxia tumors.
  • the following example describes PET imaging, using Cu-64- labelled cyclam derivatives of the present invention to detect and quantify tumor hypoxic microenvironments in prostate carcinomas of laboratory animal test subjects.
  • a micro-PET imaging system using luetium oxyorthosilicate detector elements (Concord Microsystems, Knoxville, TN) with an 8-cm field of view, a spatial resolution of 2 mm at the center of the field of view and a volumetric resolution of about 8 ⁇ l may be used to image and quantitate rat tumor metabolism and viable hypoxic cells.
  • the animals, bearing implanted hypoxic and non-hypoxic prostate carcinomas, are anesthetized with Avertin (Aldridge, Milwaukee, WI) before the imaging procedure.
  • the long access of the rats is parallel to the long access of the scanner.
  • each rat is injected i.v.
  • each rat is reanesthesized and repositioned so as to acquire PET images from the tumor region.
  • the rat is then injected with 2 mCi of optimal Cu-64-labelled cyclam derivative. Sequential scans are obtained from each rat using 5 minute aquisitions at 6 different times up to 8 hours after marker administration.
  • Attenuation correction is determined with a 1 mCi Ge-68 ring transmission source and rat images are reconstructed using the 3-dimensional filtered back projection algorithm with the appropriate ramp filtered cutoff.
  • Time activity curves are established for each organ in the field, including tumor, and the relative distribution of FDG and labelled cyclam derivative are determined.
  • the standardized unit value (SUV) of metabolic activity and HF are calculated for each tumor at various times and statistical analysis of data are performed to assess differences in metabolism and hypoxic fraction of the two tumor types.

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Abstract

Du 1,4,8,11-tétraazaclyclotétradécane qui est chimiquement lié à un ou plusieurs groupes nitroimidazole dont le nombre peut varier entre un et quatre constitue un agent de radiodiagnostic efficace permettant de déterminer l'hypoxie tissulaire et la radiorésistance de tissus tumoraux.
PCT/US2000/001754 1999-01-26 2000-01-26 Derives 1,4,8,11-tetraazacyclotetradecane utiles en tant qu'agents de radiodiagnostic et utilisation de ces derniers dans la determination de l'hypoxie et de la radioresistance des tumeurs WO2000043004A1 (fr)

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CA002361115A CA2361115A1 (fr) 1999-01-26 2000-01-26 Derives 1,4,8,11-tetraazacyclotetradecane utiles en tant qu'agents de radiodiagnostic et utilisation de ces derniers dans la determination de l'hypoxie et de la radioresistance des tumeurs
EP00908353A EP1148878A4 (fr) 1999-01-26 2000-01-26 Derives 1,4,8,11-tetraazacyclotetradecane utiles en tant qu'agents de radiodiagnostic et utilisation de ces derniers dans la determination de l'hypoxie et de la radioresistance des tumeurs

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US60/117,253 1999-01-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6627176B2 (en) 2000-09-25 2003-09-30 Procter & Gamble Company Metal complexes for use in medical and therapeutic applications
WO2005087275A2 (fr) * 2004-03-11 2005-09-22 Board Of Regents, The University Of Texas System Agents d'imagerie tep radiomarques metalliques
JP2010508292A (ja) * 2006-10-27 2010-03-18 ナチュラル ファーマシア インターナショナル インコーポレイティッド 低酸素症選択性の弱塩基性２−ニトロイミダゾール送達薬剤およびその使用方法
CN101486708B (zh) * 2009-02-27 2012-08-29 北京师范大学 一类锝-99m标记的肿瘤乏氧显像剂及其制备方法和应用
CN101486707B (zh) * 2009-02-27 2012-08-29 北京师范大学 亲乏氧肿瘤的硝基咪唑类配合物及其制备方法和应用
JP2013539469A (ja) * 2010-08-26 2013-10-24 ツイ，クンユァン 巨大環状脂肪族化合物及びその応用
WO2019056098A1 (fr) * 2017-09-19 2019-03-28 The Governors Of The University Of Alberta Composés activés par bioréduction, leurs promédicaments, produits radiopharmaceutiques, les compositions et leurs applications dans la gestion théranostique multimodale de l'hypoxie, dont le cancer
CN111356698A (zh) * 2017-09-19 2020-06-30 阿尔伯塔大学理事会 用于低氧成像、映射和治疗的标记物、缀合物、组合物和方法

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6627176B2 (en) 2000-09-25 2003-09-30 Procter & Gamble Company Metal complexes for use in medical and therapeutic applications
WO2005087275A2 (fr) * 2004-03-11 2005-09-22 Board Of Regents, The University Of Texas System Agents d'imagerie tep radiomarques metalliques
WO2005087275A3 (fr) * 2004-03-11 2006-06-08 Univ Texas Agents d'imagerie tep radiomarques metalliques
JP2010508292A (ja) * 2006-10-27 2010-03-18 ナチュラル ファーマシア インターナショナル インコーポレイティッド 低酸素症選択性の弱塩基性２−ニトロイミダゾール送達薬剤およびその使用方法
CN101486708B (zh) * 2009-02-27 2012-08-29 北京师范大学 一类锝-99m标记的肿瘤乏氧显像剂及其制备方法和应用
CN101486707B (zh) * 2009-02-27 2012-08-29 北京师范大学 亲乏氧肿瘤的硝基咪唑类配合物及其制备方法和应用
JP2013539469A (ja) * 2010-08-26 2013-10-24 ツイ，クンユァン 巨大環状脂肪族化合物及びその応用
WO2019056098A1 (fr) * 2017-09-19 2019-03-28 The Governors Of The University Of Alberta Composés activés par bioréduction, leurs promédicaments, produits radiopharmaceutiques, les compositions et leurs applications dans la gestion théranostique multimodale de l'hypoxie, dont le cancer
CN111356698A (zh) * 2017-09-19 2020-06-30 阿尔伯塔大学理事会 用于低氧成像、映射和治疗的标记物、缀合物、组合物和方法

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