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Hexadentate ligands useful in radiographic imaging agents

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Publication number
WO1994015647A1
WO1994015647A1 PCT/US1994/000281 US9400281W WO1994015647A1 WO 1994015647 A1 WO1994015647 A1 WO 1994015647A1 US 9400281 W US9400281 W US 9400281W WO 1994015647 A1 WO1994015647 A1 WO 1994015647A1
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Patent type
Prior art keywords
group
same
imaging
selected
consisting
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Application number
PCT/US1994/000281
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French (fr)
Inventor
William L. Neumann
Raghavan Rajagopalan
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Mallinckrodt Medical, Inc.
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/28Phosphorus compounds with one or more P—C bonds
    • C07F9/50Organo-phosphines
    • C07F9/5027Polyphosphines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K51/00Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02Preparations 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
    • A61K51/04Organic compounds
    • A61K51/0474Organic 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
    • A61K51/0478Organic 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

Abstract

The present invention relates particularly to novel preorganized hexadentate ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes.

Description

HEXADENTATE LIGANDS USEFUL IN RADIOGRAPHIC IMAGING AGENTS

This is a continuation-in-part application of United States application serial number 07/627,176 filed December 14, 1990.

Background of the Invention

The present invention relates to novel ligands for forming radionuclide complexes, new complexes incorporating such ligands, processes for preparing such complexes, imaging agents incorporating such complexes, and methods of imaging using such imaging agents.

The use of radiographic imaging agents for visualizing skeletal structures, organs, or tissues, is well known in the area of biological and medical research and diagnostic procedures. The procedure whereby such imaging is accomplished, generally involves the preparation of radioactive agents, which, when introduced to the biological subject, are localized in the specific skeletal structures, organs or tissues to be studied. The localized radioactive agents may then be traced, plotted or scintiphotographed by radiation detectors, such as, traversing scanners or scintillation cameras. The distribution and relative intensity of the detected radioactive agents indicates the position of the tissue in which the agent is localized, and also shows the presence of aberrations, pathological conditions or the like.

In general, the radiographic imaging agents comprise radionuclide-labelled compounds; such as complexes of technetium 99m, rhenium 186 or rhenium 188, or other applicable radionuclides; with appropriate carriers, and auxiliary agents, such as delivery vehicles suitable fcr injection into, or aspiration by, the patient, physiological buffers and salts, and the like.

Detailed Description of the Invention

The present invention relates particularly to novel preorganized hexadentate ligands that are suitable for complexing with a radionuclide, and are useful as general imaging agents for diagnostic purposes. In particular the present invention relates to novel ligands having the general formula:

Formula I

wherein Rx, R2 and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl and carbarr.oyl; 1 and m may be the same or different and are from 1 to 6; Q and Z may be the same or different and are an 0, N or S atom; X and Y may be the same or different and are selected from the group consisting of -OH R4 COOH COSH

wherein R4, R5 and R6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, a ino, alkylamino, aminoalkyl, and carba oyl.

In a preferred embodiment, ligands according to the present invention have the general formula I above, wherein R: is hydrogen; R2 and R3 are methyl groups; 1 and are 3; Q and Z are oxygen atoms; and X and Y are the same and are as defined above. In a further preferred embodiment, X and Y are the same and are

The novel ligands described above, may be incorporated into radionuclide complexes used as radiographic imaging agents. The complexes of the present invention are prepared by reacting one of the aforementioned ligands with a radionuclide containing solution under radionuclide complex forming reaction conditions. In particular, if a technetium agent is desired, the reaction is carried out with a pertechnetate solution under technetium 99m complex forming reaction conditions. The solvent may then be removed by any appropriate means, such as evaporation. The complexes are then prepared for administration to the patient by dissolution or suspension in a pharmaceutically acceptable vehicle.

The ligands of the present invention may be prepared from commercially available starting materials such as 2-nitrobenzylbromide, hydroxyethylethylenedia ine, etc. by standard synthetic methods as described in the following Examples.

Radionuclide complexes according to the present invention may have the general formula:

Formula II

wherein M is an appropriate radionuclide such as technetium or rhenium, and wherein Rlf R2, R3, 1, m, X, Y, Q, and Z are as defined above in formula I. In a preferred embodiment a technetium radionuclide complex having the general formula II may be formed from a pertechnetate solution and a ligand having the general formula I above, wherein Rt is a methyl group, R2 is hydrogen, R3 is a methyl group, l = 3, m = 3, Q = 0, Z = 0, and wherein X and Y are the same and are as defined above.

The radionuclide containing solution may be obtained from radionuclide generators in a known manner. For example, when forming a technetium complex, the pertechnetate solution may be obtained from a technetium generator in a known manner. The radionuclide complex forming reaction is then carried out under appropriate reaction conditions. For example, the technetium 99m complex forming reaction is carried out under technetium complex forming temperatures, e.g. 20° C to 100°C for 10 minutes to several hours. A large excess of the appropriate ligands over the radionuclide complex forming amounts is preferably used. For example, when forming a technetium complex, at least a ten fold excess of the ligands over the pertechnetate solution is used. The pertechnetate is used in technetium complex forming amounts, e.g. about IO6 to IO12 molar amounts.

The present invention also relates to imaging agents containing a radionuclide complex as described above, in an amount sufficient for imaging, together with a pharmaceutically acceptable radiological vehicle. The radiological vehicle should be suitable for injection or aspiration, such as human serum albumin; aqueous buffer solutions, e.g tris (hydromethyl) aminomethane (and its salts) , phosphate, citrate, bicarbonate, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as Ca*2, Na*, K*, and Mg*2. The concentration of the imaging agent according to the present invention in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries. The imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 ml of aqueous solution may be prepared.

Imaging may be carried out in the normal manner, for example by injecting a sufficient amount of the imaging composition to provide adequate imaging and then scanning with a suitable machine, such as a gamma camera.

The complexes according to the present invention may be prepared in accordance with the examples set forth below.

7 Example 1

Preparation of

Acetylacetone (1.51 g, 15.1 mmol) was added to a solution of 4,5-diamino-l,8-bis(dephenylphosphoro) -octane (3.40 g, 7.50 mmol) in methanol (20 ml) and the mixture was heated to reflux for 5 minutes, allowed to cool and stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with hexanes (5 X 50 ml) . The combined hexane extracts were evaporated to yield a viscous oil. This crude material was purified by radial chromatography (Ξi02, 3:1 hexanes - ethylacetate) to furnish the desired ligand as a yellow viscous oil.

H- MR (toluene-d8) : 5 11.22 (d,2H), 6.95 - 7.55 (m, 20H) , 4.40 (S, 2H) , 2,10 (m, 2H) , 1.95 - 2.05 (multiple singlets, 12H) , .95 - 2.05 (m, 12H) . nC- MR (toluene-d8) : 5 195.5 (S) , 162.4 (S) , 140.5 (S) , 140.3 (S), 140.2 (S), 134.0 (d) , 133.8 (d) , 133.7 (d) , 133.6 (d), 133.4 (d) , 132.5 (d) , 132.4 (d) , 131.4 (d) , 131.3 (d), 95.9 (d) , 58.5 (d) , 54.8 (d) , 38.3 (-CH2-, JPCCC = 12.3 Hz), 35.0 (-CH2-, JPCCC = 12.3 Hz), 29.0 (q) , 28.6 (-CHj-, JPCC = 12.6 Hz), 28.5 (-CH2-, J?cc = 7.5 Hz), 23.0 (-CH2-P-, JPC = 16.9 Hz), 19.2 (q) . 31P-NMR (toluene-d8) : 5 -18.0. Example 2

Preparation of

4-Methoxysalicylaldehyde (2.43 g, 16.0 mmol) was added to a solution of 4, 5-diamino-l, 8-bis (diphenylphosphine) octane (3.60 g, 7.99 mmol) in methanol (25 ml) and the resulting yellow mixture was heated to reflux for 5 minutes, allowed to cool and stirred for 1 hour at ambient temperature. The solvent was removed under reduced pressure and the yellow residue was triturated with hexanes (3 X 50 ml) to provide 5.77 g (93%) or the ligand as an amorphous yellow solid. 13C-NMR (benzene-d6) : δ 165.6 (d) , 165.5 (S) , 164.6 (S) ,

140.3 (S), 140.2 (S) 140.0 (S), 135.7 (S), 135.0 (d) , 134.8 (d), 134.0 (d) 133.9 (d), 133.8 (d) , 133.7 (d) , 133.6 (d), 133.4 (d) 131.6 (d), 131.5 (d) , 113.2 (d) ,

107.4 (d), 101.8 (d) 73.3 (d), 55.1 (q) , 34.3 (-CH2-, J PCCC = 12.2 Hz), 28.4 (-CH2-, JPCC = 12.7 Hz) , 23.1

(-CH2-P-, JPC = 17.0 Hz) 31 P-NMR (benzene-d6) : δ -17

The foregoing has been a discussion of the preferred embodiments of the present invention, but is not intended to limit the invention in any way. Rather, many modifications, variations and changes in detail may be made within the scope of the present invention.

Claims

What is claimed is:
1. A ligand useful in forming radionuclide complexes, said ligand having the general formula:
wherein Rl t R2 and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and are from 2 to 5; Q and Z may be the same or different and are an 0, N or S atom; and X and Y may be the same or different and are selected from the group consisting of
-OH R4 COOH COSH
wherein R,, R5 and ?,6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl.
2. A ligand accroding to claim 1, wherein either Rx and R2, or R2 and R3 together may form a carbocyclic or heterocyclic ring of 5 to 7 members.
3. A ligand according to claim 1, wherein R1 and R3 are methyl groups; R2 is hydrogen; 1 and m are 3; and Q and Z are oxygen atoms.
4. A ligand according to claim 1, wherein Rl and R3 are methyl groups; R2 is hydrogen; 1 and m are 3; Q and Z are
oxygen atoms; and X and Y are p Λ wherein R4 and R5
\
R
are phenyl groups.
5. A ligand according to claim 1, wherein R: is hydrogen; R2 and R3 together form a carbocyclic ring; 1 and m are 3; Q and Z are oxygen atoms; and X and Y are
p wherein R4 and R5 are phenyl groups.
6. A ligand according to claim 5, wherein said carbocyclic ring is methoxybenzene. 11
7. A radionuclide complex having the general formula:
wherein M is a radionuclide; and wherein R:, R2 and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and are from 2 to 5; Q and Z may be the same or different and are an 0, N or S atom; X and Y may be the same or different and are selected from the group consisting of
-OH -COOH -COSH
/
-N—C—N i P Λ ' A s
\ \ \
R , < wherein R4 R5 and R6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl.
8. A complex according to claim 7, wherein either R, and R2, or R2 and R3 together may form a carbocyclic or heterocyclic ring of 5 to 7 members.
9. A complex according to claim 7, wherein M is technetium or rhenium.
10. A complex according to claim 7, wherein Rx is a methyl group, R2 is hydrogen, R3 is a methyl group, 1 = 3, m = 3, Q = 0, Z = 0, and wherein X and Y are the same.
11. A complex according to claim 7, wherein Rx and R3 are methyl groups; R2 is hydrogen; 1 and m are 3; Q and Z are
oxygen atoms; and X and Y are p wherein R4 and R5
\ R5
are phenyl groups.
12. A complex according to claim 7, wherein R: is hydrogen; R2 and R3 together form a carbocyclic ring; 1 and m are 3; Q and Z are oxygen atoms; and X and Y are
p wherein R4 and R5 are phenyl groups .
\ R«
13 . A complex according to claim 12 , wherein said carbocyclic ring is ethoxybenzene .
14. A method of making a radionuclide complex having the general formula:
wherein M is a radionuclide; and wherein R1# R2 and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and may be the same or different and are from 2 to 5; Q and Z may be the same or different and are an O, N or S atom; X and Y may be the same or different and are selected from the group consisting of
-OH -COOH -COSH
S
II / / /
-N—C- -As
I \ \ \ wherein R4, R5 and R6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl; said method comprising reacting a radionuclide containing solution and a ligand having the general formula:
wherein R1# R2, R3, 1, m, X, Y, Q, and Z are as defined above.
15. A method according to claim 14, wherein either R: and R2, or R2 and R3 together may form a carbocyclic or heterocyclic ring of 5 to 7 members.
16. A method according to claim 14, wherein M is technetium or rhenium, and said radionuclide containing solution is a pertechnetate or perrheneate solution respectively.
17. A radiographic imaging agent comprising a complex having the general formula:
wherein M is a radionuclide; and wherein R R-. and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkcxycarbonyl and carbamoyl; 1 and m may be the same or- different and are from 2 to 5; Q and Z may be the same or different and are an 0, N or S atom; X and Y may be the same or different and are selected from the group consisting of
-OH -COOH -COSH
S
II / / /
—N- -c- -As
\ \ \
R wherein R4, R5 and R6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl; and a pharmaceutically acceptable radiological vehicle.
18. An imaging agent according to claim 17, wherein either R: and R2, or R2 and R3 together may form a carbocyclic or heterocyclic ring of 5 to 7 members.
19. An imaging agent according to claim 17, wherein M is technetium or rhenium.
20. An imaging agent according to claim 17, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic solutions containing chloride salts, dicarbonate salts or blood plasma cations.
21. An imaging agent according to claim 17, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries.
22. A method of radiographic imaging, comprising injecting a sufficient amount of an imaging agent to provide adequate imaging and then scanning with a suitable scanning machine; said imaging agent comprising a complex having the general formula:
wherein M is a radionuclide; and wherein R:, R2 and R3 are the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or pcly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl and carbamoyl; 1 and m may be the same or different and are from 2 to 5; Q and Z may be the same or different and are an 0, N or S atom; X and Y may be the same or different and are selected from the group consisting of OH R. C00H COSH
S F II / / / / -N—C—N > -As I \ \ \ \ wherein R4, R5 and R6 may be the same or different and are selected from the group consisting of hydrogen, and organic compounds having 2 to 10 carbon atoms selected from the group consisting of alkyl, aryl, hydroxyl, alkoxyl, mono- or poly- hydroxyalkyl, mono- or poly- alkoxyalkyl, alkoxycarbonyl, amino, alkylamino, aminoalkyl, and carbamoyl; and a pharmaceutically acceptable radiological vehicle.
23. A method of imaging according to claim 22, wherein either R: and R2, or R2 and R3 together may form a carbocyclic or heterocyclic ring of 5 to 7 members .
24. A method of imaging according to claim 22, wherein M is technetium or rhenium.
25. A method of imaging according to claim 22, wherein said vehicle is suitable for injection or aspiration and is selected from the group consisting of human serum albumin, aqueous buffer solutions, sterile water, physiological saline, and balanced ionic soluticns containing chloride salts, dicarbonate salts or blood plasma cations.
26. A method of imaging according to claim 22, wherein the concentration of said complex in said vehicle is from about 1.0 to 50 millicuries.
PCT/US1994/000281 1993-01-06 1994-01-04 Hexadentate ligands useful in radiographic imaging agents WO1994015647A1 (en)

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JP51624694A JPH08505398A (en) 1993-01-06 1994-01-04 Hexadentate ligands that are useful in radiographic imaging agent
EP19940907172 EP0690727A4 (en) 1993-01-06 1994-01-04 Hexadentate ligands useful in radiographic imaging agents

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0649421A4 (en) * 1992-07-06 1995-03-13 Mallinckrodt Medical Inc Hexadentate ligands useful in radiographic imaging agents.

Citations (6)

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US3048480A (en) * 1959-06-09 1962-08-07 Gulf Research Development Co Aviation turbine fuels
US4795626A (en) * 1985-05-10 1989-01-03 University Of Cincinnati 99m Tc.sup.(III) myocardial imaging agents which are non-reducable in vivo
US4917879A (en) * 1989-05-19 1990-04-17 University Of Cincinnati 99MTC(III) myocardial imaging agents that are effective in humans
US5112594A (en) * 1991-04-04 1992-05-12 Mallinckrodt Medical, Inc. Kit for preparing a technetium-99m myocardial imaging agent
US5112595A (en) * 1990-12-21 1992-05-12 Mallinckrodt Medical, Inc. 99MTC(III) myocardial imaging agents and method of use
US5243073A (en) * 1990-12-14 1993-09-07 Mallinckrodt Medical, Inc. Hexadentate ligands useful in radiographic imaging agents

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3048480A (en) * 1959-06-09 1962-08-07 Gulf Research Development Co Aviation turbine fuels
US4795626A (en) * 1985-05-10 1989-01-03 University Of Cincinnati 99m Tc.sup.(III) myocardial imaging agents which are non-reducable in vivo
US4917879A (en) * 1989-05-19 1990-04-17 University Of Cincinnati 99MTC(III) myocardial imaging agents that are effective in humans
US5243073A (en) * 1990-12-14 1993-09-07 Mallinckrodt Medical, Inc. Hexadentate ligands useful in radiographic imaging agents
US5112595A (en) * 1990-12-21 1992-05-12 Mallinckrodt Medical, Inc. 99MTC(III) myocardial imaging agents and method of use
US5112594A (en) * 1991-04-04 1992-05-12 Mallinckrodt Medical, Inc. Kit for preparing a technetium-99m myocardial imaging agent

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* Cited by examiner, † Cited by third party
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See also references of EP0690727A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0649421A4 (en) * 1992-07-06 1995-03-13 Mallinckrodt Medical Inc Hexadentate ligands useful in radiographic imaging agents.
EP0649421A1 (en) * 1992-07-06 1995-04-26 Mallinckrodt Medical, Inc. Hexadentate ligands useful in radiographic imaging agents

Also Published As

Publication number Publication date Type
JPH08505398A (en) 1996-06-11 application
EP0690727A4 (en) 1996-03-06 application
EP0690727A1 (en) 1996-01-10 application

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