WO2006026855A1 - Synthesis of radiolabeled sugar metal complexes - Google Patents
Synthesis of radiolabeled sugar metal complexes Download PDFInfo
- Publication number
- WO2006026855A1 WO2006026855A1 PCT/CA2005/001361 CA2005001361W WO2006026855A1 WO 2006026855 A1 WO2006026855 A1 WO 2006026855A1 CA 2005001361 W CA2005001361 W CA 2005001361W WO 2006026855 A1 WO2006026855 A1 WO 2006026855A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sugar
- radiolabeled
- synthesis
- complex
- complexes
- Prior art date
Links
- 235000000346 sugar Nutrition 0.000 title claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 title claims description 16
- 239000002184 metal Substances 0.000 title claims description 16
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 29
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- 229910052713 technetium Inorganic materials 0.000 claims abstract description 10
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- 239000002243 precursor Substances 0.000 claims description 3
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
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- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 102000005548 Hexokinase Human genes 0.000 description 2
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
-
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
-
- 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
- C07F17/00—Metallocenes
Definitions
- the invention relates to methods for producing radiolabeled sugar metal complexes and the resulting radiolabeled materials.
- Radiolabeled carbohydrates have been of increasing interest in nuclear medicine applications due, in part, to the success of 2- 18 F-fluoro-2-deoxy-glucose (FDG) as an imaging agent in positron emission tomography (PET).
- FDG 2- 18 F-fluoro-2-deoxy-glucose
- PET positron emission tomography
- the success of FDG is attributable, in part, to its utility for imaging both cardiac viability and tumors due to the fact that it undergoes glucose metabolism and is a substrate for hexokinase.
- This success has raised the question of whether a single-photon emitting glucose analog with properties and utility similar to FDG can be developed for use with single-photon emission computed tomography (SPECT).
- SPECT single-photon emission computed tomography
- SPECT applications may be produced as Na" m Tc0 4 from a 99 Mo generator making it widely available and relatively inexpensive.
- the third row transition metal analogue of technetium, rhenium has similar chemistry to that of technetium and has particle emitting radioisotopes with physical properties applicable to therapeutic nuclear medicine.
- a 99m Tc SPECT tracer that will mimic the biodistribution of FDG and the therapeutic potential of the analogous rhenium compounds may be particularly useful.
- 99m Tc is widely used in imaging applications, one complication to address in preparing a tracer is that this isotope must be attached to the molecule via a chelate or organometal conjugate, which may perturb the system being studied.
- a SPECT analog based on a widely available isotope such as 99m Tc would make these agents available to the broader medical community.
- the isotopes 1867188 Re also show promise in the development of therapeutic strategies.
- a half-life of between 12 hours and 5 days is preferred.
- the depth of penetration into tissue is approximately 5 mm.
- the behavior of the radioelement can be conveniently followed by using a gamma camera.
- the nuclear properties of 186/188 R e are well suited for these purposes.
- the invention provides a method for manufacturing or preparing neutral, low molecular weight 99m Tc-labeled and 186 Re-labeled carbohydrate complexes with an improved radiochemical yield from a simple functionalized glucosamine.
- Rhenium carbonyl complexes of /3-estradiol derivatives in which a chromium-tricarbonyl moiety was either attached to the aromatic ring of the steroid or as a cyclopentadienyl chromium tricarbonyl pendant group to the 17 ⁇ position, have been shown to have high affinity for the estradiol receptors.
- the synthesis of a 5-HT 1A serotonin brain receptor ligand labelled with 99m Tc has also been achieved with the technetium-tricarbonyl moiety attached via chelation to the neutral bidentate amine ligand (N ⁇ N 1 ) portion of the molecule.
- radiopharmaceuticals are inorganic complexes with the metal in the +5 oxidation state.
- the DLT and SLT reactions opens up the possibility of forming (cyclopentadienyi)tricarbonyl- technetium and -rhenium organometallic radiopharmaceuticals from the perrhenate and pertechnetate forms of these isotopes. Due to the harsh conditions of the DLT reaction, more success has been achieved in synthesizing sugar-Cp complexes with Tc or Re using an indirect approach as shown below (synthesis IV).
- Ferrocene can be synthesized with a wide variety of functionality on one or both of its cyclopentadienyl rings. As a result, ferrocenyl-sugar conjugates, including, for example, the dozen conjugates illustrated below, may be successfully prepared giving the SLT reaction significant potential.
- Ferrocene may then be linked to these sugars through thio, amino and/or alcohol functionalities present on the sugars.
- the sugars were either fully protected, yielding organic soluble ferrocene derivatives, or were unprotected, resulting in water soluble conjugates. Tc- and Re-sugars via metal chelates
- the facially coordinated carbonyl ligands stabilize the Tc +1 oxidation state, obviating the elaborate, often macrocyclic, polydentate structures required to stabilize other intermediate oxidation states of Tc and Re.
- the/ ⁇ c- (M(CO) 3 ) core possesses intermediate lipophilicity, an advantage in living systems.
- Glucosamine (2-amino-2-deoxy-D-glucose) is a highly attractive scaffold for a glucosyl ligand, because the amine acts both as a potential coordination site and as a useful target for further functionalization. Furthermore, there is much evidence in the literature to suggest that N-functionalized glucosamines show activity with GLUTs (glucose transporters) and hexokinases - the enzymes that are most closely associated with the metabolism of FDGs even when the functional group is large.
- HL 2 N-(2'-Hydroxybenzyl)-2-amino-2-deoxy-D-glucose
- HL 1 (1.00 g, 3.53 mmol) was dissolved in MeOH (60 niL), and 10% Pd/C w/w (50 mg) was added to the solution to form a reaction mixture.
- the reaction mixture was stirred under a pressurized H 2 atmosphere (50 bar) for 24 hours and then clarified by filtration and the solvent evaporated to give HL 2 (0.98 g, 98%) as illustrated below.
- Tricarbonyl (N-(2'-Hydroxybenzyl)-2-amino-2-deoxy-D-glucose) rhenium(I) (ReL 2 (CO) 3 ), illustrated below, was prepared by dissolving [NEt 4 J 2 [Re(CO) 3 Br 3 ] (200 mg, 0.26 mmol), HL 2 (74 mg, 0.26 mmol) and sodium acetate trihydrate (40 mg, 0.32 mmol) in H 2 O (7 niL) and heated with stirring to 50 °C for 2 hours. The solvent was then removed under vacuum and the residue dissolved in CH 2 Cl 2 (10 mL) for 30 minutes. On standing, a brown residue was recovered by decanting the solvent.
- [ 186 Re(CO) 3 (H 2 O) 3 ] + was prepared by addition 4.5 ⁇ L of 85% H 3 PO 4 to a saline solution of Na[ 186 ReO 4 ] (0.5 mL, 100 MBq), followed by addition of this solution to 3 mg of borane ammonia complex that had been flushed with CO for 10 min. The mixture was heated at 60 °C for 15 minutes and then cooled to room temperature. Labeling was achieved by mixing an aliquot of one of the above final solutions (0.5 mL) with a 1 mM solution of HL 2 in PBS (pH 7.4, 1 mL) and incubating at 75 °C for 30 min.
- the molecular ion was identified as [((L 2 )Re(CO) 3 ) + H] + by ESIMS, and the formulation of the bulk sample was confirmed by elemental analysis. Comparison of the anomeric ratio (a/ ⁇ ) observed in the 1 H NMR spectrum (CD 3 OD) showed a change from 1.9 for HL 2 to 1.1 for the complex, indicating that complexation has decreased the difference in thermodynamic stability between the two anomers.
- the complex instability may be due to the relatively weak binding ability of the donor atoms, especially the secondary amino group and the carbohydrate hydroxyl.
- the fortuitous tridentate binding has directed us to investigate purposely tridentate ligands, and those containing binding groups with higher affinities for the soft (M(CO) 3 ) center.
- Fmoc Boo reaction conditions: (i) benzaldehyde, NaBH(OAc) 3 , DCE or Fmoc-CI, NaHC ⁇ 3, dioxane or BocaO, Et 3 N, DCM; (ii) SC>3-pyrid ⁇ ne complex, Et 3 N, DMSO or Dess-Martin periodinane, DCM
- reaction conditions (i) 3a/3b/3c, NaBH(OAc) 3 , MeOH; (ii) H 2 , Pd(OH) 2 , EtOH or TFA, DGM or piperidine, DMF; (iii) 5a/5b/5c, DCC, HOBT, DMF
- reaction conditions (i) 2-pyridinecarboxaldehyde/1 -benzyl-2-imidazolecarboxaldehye/i -methyl-2-imidazole- carboxaldehyde/imidazolecarboxaldehyde/salicylaldehyde/ 17/18/19/20, NaBH(OAc) 3 , MeOH; (ii) 2-pyridine- carboxaldehyde/i-benzyl ⁇ -imidazolecarboxaldehye/i-methyl ⁇ -imidazole-carboxaldehyde/imidasole- ⁇ - carboxaldehyde/salicylaldehyde/ 17/18/19/20/3b-1, NaBH(OAc) 3 , MeOH or BrCH 2 CO 2 Et, Na 2 CO 3 , CH 3 CN; (iii) a. KOH, H 2 O; b. piperidine, DMF for 3b-1 derivatives.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Optics & Photonics (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Saccharide Compounds (AREA)
Abstract
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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CA002579355A CA2579355A1 (en) | 2004-09-07 | 2005-09-07 | Synthesis of radiolabeled sugar metal complexes |
JP2007529307A JP2008512360A (en) | 2004-09-07 | 2005-09-07 | Method for synthesizing sugar-metal complexes labeled with radioisotopes |
EP05784198A EP1797106A1 (en) | 2004-09-07 | 2005-09-07 | Synthesis of radiolabeled sugar metal complexes |
AU2005282160A AU2005282160A1 (en) | 2004-09-07 | 2005-09-07 | Synthesis of radiolabeled sugar metal complexes |
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US60729504P | 2004-09-07 | 2004-09-07 | |
US60/607,295 | 2004-09-07 |
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WO2006026855A1 true WO2006026855A1 (en) | 2006-03-16 |
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PCT/CA2005/001361 WO2006026855A1 (en) | 2004-09-07 | 2005-09-07 | Synthesis of radiolabeled sugar metal complexes |
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US (1) | US20060051291A1 (en) |
EP (1) | EP1797106A1 (en) |
JP (1) | JP2008512360A (en) |
KR (1) | KR20070053739A (en) |
AU (1) | AU2005282160A1 (en) |
CA (1) | CA2579355A1 (en) |
WO (1) | WO2006026855A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010039609A2 (en) * | 2008-09-30 | 2010-04-08 | Mallinckrodt Inc. | A version of fdg detectable by single-photon emission computed tomography |
CN102146098A (en) * | 2011-03-02 | 2011-08-10 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1917041A4 (en) * | 2005-08-24 | 2010-09-29 | Cedars Sinai Medical Center | Use of fructose-based therapies for the treatment of cancer |
DE102010042517A1 (en) * | 2010-10-15 | 2012-04-19 | Siemens Aktiengesellschaft | Improved SPECT procedure |
DE202011050033U1 (en) * | 2011-05-04 | 2012-08-06 | Wik Far East Ltd. | Holder for a personal care device |
DK2721045T3 (en) | 2011-06-20 | 2017-07-24 | Radiomedix Inc | COMPOSITIONS, METHODS OF SYNTHESIS AND USE OF CARBOHYDRATE TARGETED AGENTS |
JP6188660B2 (en) * | 2014-09-29 | 2017-08-30 | 株式会社ダステック | Chelate compound and method for producing the same |
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CA2160979A1 (en) * | 1993-04-22 | 1994-10-27 | Martin Wenzel | Use of cyclopentadienylcarbonyl transition metal carboxylic acids and their derivatives for labeling proteins |
US5538712A (en) * | 1990-06-01 | 1996-07-23 | Institut Fur Diagnostikforschung Gmbh/An Der Freien Universitat Berlin | Cyclopentadienylcarbonyl 99MTC complexes, process for their production as well as their use in diagnostics |
WO1998048848A1 (en) * | 1997-04-25 | 1998-11-05 | Mallinckrodt Inc. | Method for the preparation of facial metal tricarbonyl compounds and their use in the labelling of biologically active substrates |
WO2001025243A1 (en) * | 1999-10-05 | 2001-04-12 | Mallinckrodt Inc. | Carbon monoxide source for preparation of transition-metal-carbonyl-complexes |
WO2001040239A2 (en) * | 1999-12-03 | 2001-06-07 | Yale University | Transition metal-cyclopentadienyl-tropane conjugates |
US6669925B1 (en) * | 2000-04-27 | 2003-12-30 | Wake Forest University | Sigma-2 receptors as biomarkers of tumor cell proliferation |
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US5968477A (en) * | 1994-01-24 | 1999-10-19 | Neorx Corporation | Radiolabeled annexin conjugates with hexose and a chelator |
-
2005
- 2005-09-07 WO PCT/CA2005/001361 patent/WO2006026855A1/en active Application Filing
- 2005-09-07 JP JP2007529307A patent/JP2008512360A/en active Pending
- 2005-09-07 KR KR1020077005378A patent/KR20070053739A/en not_active Application Discontinuation
- 2005-09-07 CA CA002579355A patent/CA2579355A1/en not_active Abandoned
- 2005-09-07 US US11/219,846 patent/US20060051291A1/en not_active Abandoned
- 2005-09-07 AU AU2005282160A patent/AU2005282160A1/en not_active Abandoned
- 2005-09-07 EP EP05784198A patent/EP1797106A1/en not_active Withdrawn
Patent Citations (6)
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US5538712A (en) * | 1990-06-01 | 1996-07-23 | Institut Fur Diagnostikforschung Gmbh/An Der Freien Universitat Berlin | Cyclopentadienylcarbonyl 99MTC complexes, process for their production as well as their use in diagnostics |
CA2160979A1 (en) * | 1993-04-22 | 1994-10-27 | Martin Wenzel | Use of cyclopentadienylcarbonyl transition metal carboxylic acids and their derivatives for labeling proteins |
WO1998048848A1 (en) * | 1997-04-25 | 1998-11-05 | Mallinckrodt Inc. | Method for the preparation of facial metal tricarbonyl compounds and their use in the labelling of biologically active substrates |
WO2001025243A1 (en) * | 1999-10-05 | 2001-04-12 | Mallinckrodt Inc. | Carbon monoxide source for preparation of transition-metal-carbonyl-complexes |
WO2001040239A2 (en) * | 1999-12-03 | 2001-06-07 | Yale University | Transition metal-cyclopentadienyl-tropane conjugates |
US6669925B1 (en) * | 2000-04-27 | 2003-12-30 | Wake Forest University | Sigma-2 receptors as biomarkers of tumor cell proliferation |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010039609A2 (en) * | 2008-09-30 | 2010-04-08 | Mallinckrodt Inc. | A version of fdg detectable by single-photon emission computed tomography |
WO2010039609A3 (en) * | 2008-09-30 | 2010-09-10 | Mallinckrodt Inc. | Conjugates of hexose and metal coordinating compounds for imaging purposes |
US20110177004A1 (en) * | 2008-09-30 | 2011-07-21 | Moore Dennis A | Version of FDG Detectable by Single-Photon Emission Computed Tomography |
US8858916B2 (en) * | 2008-09-30 | 2014-10-14 | Mallinckrodt Llc | Metal chelate linked to a hexose carrier for use as a metallopharmaceutical diagnostic or therapeutic agent |
US9217009B2 (en) | 2008-09-30 | 2015-12-22 | Mallinckrodt Llc | Version of FDG detectable by single-photon emission computed tomography |
CN102146098A (en) * | 2011-03-02 | 2011-08-10 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
CN102146098B (en) * | 2011-03-02 | 2013-08-07 | 北京师范大学 | Preparation method and application of 99mTc labeled D-glucose coordination compound |
Also Published As
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US20060051291A1 (en) | 2006-03-09 |
KR20070053739A (en) | 2007-05-25 |
AU2005282160A2 (en) | 2009-03-12 |
AU2005282160A1 (en) | 2006-03-16 |
CA2579355A1 (en) | 2006-03-16 |
JP2008512360A (en) | 2008-04-24 |
EP1797106A1 (en) | 2007-06-20 |
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