WO1999056791A1 - Complexes de radionucleide et de s3n - Google Patents

Complexes de radionucleide et de s3n Download PDF

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Publication number
WO1999056791A1
WO1999056791A1 PCT/US1999/009631 US9909631W WO9956791A1 WO 1999056791 A1 WO1999056791 A1 WO 1999056791A1 US 9909631 W US9909631 W US 9909631W WO 9956791 A1 WO9956791 A1 WO 9956791A1
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WO
WIPO (PCT)
Prior art keywords
complex
tris
brain
amine
use according
Prior art date
Application number
PCT/US1999/009631
Other languages
English (en)
Inventor
Stephen A. Koch
Michael J. Welch
Cathy S. Cutler
Duncan A. Quarless, Jr.
Original Assignee
The Research Foundation Of State University Of New York
Washington University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Research Foundation Of State University Of New York, Washington University filed Critical The Research Foundation Of State University Of New York
Priority to AU50790/99A priority Critical patent/AU5079099A/en
Publication of WO1999056791A1 publication Critical patent/WO1999056791A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic 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
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton

Definitions

  • Ga agents have been developed that show myocardial uptake.
  • Green and coworkers developed a series of uncharged lipophilic Ga(III) complexes of 1,1,1- tris-(5-methoxysalicylaldiminomethyl)ethane[(sal) 3 tame] and 1,1,1 ,-tris- (alkoxysalicylaldiminomethyl)ethane[ROsal) 3 tame] as 68 Ga myocardial imaging agents.
  • PET Gallium for positron emission tomography
  • radionuclide labeled compounds which can be of use in pharmaceuticals and for imaging of internal organs, particularly in brain and heart, with good uptake and retention.
  • R 1-15 can be independently selected from the group consisting of hydrocarbyl such as alkyl, aryl, alkylaryl or aryl- alkyl or heterohydrocarbyl which also includes oxygen, sulfur and/or nitrogen atoms in addition to carbon atoms; S-R ⁇ ; OR), ; NRJRj,; where R,, and R b are independently H or alkyl of one to 10 carbons; or halo (F, Cl, Br, I).
  • An alkyl may include one to 10 carbons or carbon-sized heteroatoms, such as oxygen, sulfur or nitrogen.
  • Aryl substituents include five to ten carbons or heteroatoms such as oxygen, sulfur or nitrogen.
  • R M5 is hydrogen.
  • Emission tomography is used to measure physiological functions of organs and related biochemical processes.
  • the two modes of emission tomography are single-photon emission computed tomography (SPECT) and positron emission tomography (PET).
  • SPECT uses radionuclides that emit a single photon of a given energy and these include gamma ray emitters such as 67 Ga, 97 Ru, 99m Tc, U 1 ln, 123 1, 131 I, 203 Pb, and others.
  • PET uses radionuclides known as positron emitters such as n C, ,5 0,
  • a thiol-protected benzylamine is reacted with 2 equivalents of the corresponding benzyl bromide in CH 3 CN with K 2 CO 3 to give the tertiary amine.
  • Removal of the thiol protecting groups can be accomplished by reaction with sodium in liquid ammonia to give the ligand tris (2- mercaptobenzyl)amine (S 3 N).
  • a tetradentate amine trithiolate ligand, tris (2-mercaptobenzyl)amine (S 3 N) was prepared by reacting thiol-protected benzylamine with 2 equivalents of the corresponding benzyl bromide in CH 3 CN with K 2 CO 3 to give the tertiary amine. Removal of the thiol-protecting groups by reaction with Na in liquid ammonia gave the ligand S 3 N which was isolated as the hydrochloride salt.
  • Tris-(2-bromobenzyl)amine, (NBr 3 ), (15.0g, 28.6 mmol) was partially dissolved in 100 mL of di ethyl ether cooled in a dry ice/acetone bath (-78°C). A volume of 38.0
  • the aqueous phase was washed with three 40mL portions of methylene chloride and then acidified to pH 1 with aqueous hydrochloric acid.
  • the copious white solid was filtered, washed with two 10 mL portions of cold methanol and 15 mL portion of cold methylene chloride and dried under vacuum (9.6g, 80% Yield).
  • Tris(mercaptobenzyl) amine hydrochloride (0.55 g 1.3 mmol) as prepared in Example 1 and lithium wire (0 036g, 5.2 mmol) were reacted in 20 mL of methanol.
  • the solution mixture immediately produced a fine precipitate.
  • Ga-S 3 N had a distorted tetrahedral coordination with average S-Ga-S angles of 115.5(7)° and the average N- Ga-S angles of 102.4(2)°.
  • the average Ga-S bond distance was 2.234(5) A and Ga-N bond distance was 2.053(6) A.
  • the ligand solution was prepared by dissolving ⁇ 1 mg of ligand in 1 mL of ethanol that had been degassed for 15 min with argon.
  • 68 Ga-Cl 3 (15-20 mCi) was eluted from a 68 Ge/ 68 Ga generator with 3 mL of IN HCl.
  • the 68 Ga-Cl 3 was evaporated to dryness with a heat gun under a stream of nitrogen, redissolved in 1 mL of ethanol and degassed for 10 min with argon. 100 ⁇ g (80-120 ⁇ L) of the ligand solution was then added to the dried 68 GaCl 3 and incubated at room temperature for 10 min. Quality control was determined by radio-TLC (thin layer chromatography) on C-l 8 plates developed in 90% methanol: 10% water, and by radio-TLC on silica plates
  • the octanol-water partition coefficient or log P of 68 Ga-S 3 N was determined to be 1.8 ⁇ 0.1.
  • a hamster biodistribution was carried out in the same manner as the rat biodistribution, the only difference being 14 ⁇ Ci of 68 Ga-S 3 N in lOO ⁇ L of 85% saline; 15% ethanol were injected intracardially.
  • the Ga(III) complex was predicted to be 4-coordinate in a tetrahedral geometry, thus fulfilling the coordination requirements of the metal. This prediction was later confirmed by x-ray crystallography. In(III) prefers to be 5 coordinate.
  • In(III) complex was shown to form predominantly a five coordinate complex in equilibrium with a four coordinate complex.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un complexe radiomarqué à base de tris(2-mercaptobenzyl)amine, ainsi que des complexes contenant des analogues du ligand de la tris(2-mercaptobenzyl)amine. Ce complexe est utile pour des applications diagnostiques et thérapeutiques qui impliquent la localisation et la détection du complexe radiomarqué dans les organes internes. Un complexe à base de gallium peut être localisé dans le cerveau.
PCT/US1999/009631 1998-05-07 1999-05-03 Complexes de radionucleide et de s3n WO1999056791A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU50790/99A AU5079099A (en) 1998-05-07 1999-05-03 S3n radionuclide complexes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7419298A 1998-05-07 1998-05-07
US09/074,192 1998-05-07

Publications (1)

Publication Number Publication Date
WO1999056791A1 true WO1999056791A1 (fr) 1999-11-11

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/009631 WO1999056791A1 (fr) 1998-05-07 1999-05-03 Complexes de radionucleide et de s3n

Country Status (2)

Country Link
AU (1) AU5079099A (fr)
WO (1) WO1999056791A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089425A1 (fr) * 2003-04-11 2004-10-21 Ge Healthcare Limited Procede d'activation micro-onde permettant de preparer des complexes de gallium radiomarques
WO2008026051A3 (fr) * 2006-08-29 2008-05-22 Ge Healthcare Ltd Marquage par 68ga d'un chélateur macrocyclique libre et conjugué à une macromolécule à la température ambiante

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861140A (en) * 1996-11-20 1999-01-19 Hoechst Celanese Corp. Tripodal paramagnetic contrast agents for MR imaging

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5861140A (en) * 1996-11-20 1999-01-19 Hoechst Celanese Corp. Tripodal paramagnetic contrast agents for MR imaging

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE STN CAPLUS 1 January 1900 (1900-01-01), XP002919410, Database accession no. 1998-141326 *
MOTCHAIRIS R J, MARTELL A E, WELCH M J: "THE GA(III) AND IN(III) COMPLEXES OF TRIS(2-MERCAPTOBENZYL)AMINE", BOOK OF ABSTRACTS. ACS NATIONAL MEETING., XX, XX, no. 783, 1 April 1997 (1997-04-01), XX, pages COMPLETE, XP002919411 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089425A1 (fr) * 2003-04-11 2004-10-21 Ge Healthcare Limited Procede d'activation micro-onde permettant de preparer des complexes de gallium radiomarques
JP2006522783A (ja) * 2003-04-11 2006-10-05 ジーイー・ヘルスケア・リミテッド 放射標識ガリウム錯体を合成するためのマイクロ波法
AU2004228746B2 (en) * 2003-04-11 2009-11-12 Ge Healthcare Limited Microwave method for preparing radiolabelled gallium complexes
CN1771058B (zh) * 2003-04-11 2010-05-26 通用电气健康护理有限公司 制备放射性标记的镓络合物的微波方法
US8007766B2 (en) 2003-04-11 2011-08-30 Ge Healthcare Limited Microwave method for preparing radiolabelled gallium complexes
JP4814785B2 (ja) * 2003-04-11 2011-11-16 ジーイー・ヘルスケア・リミテッド 放射標識ガリウム錯体を合成するためのマイクロ波法
KR101108420B1 (ko) * 2003-04-11 2012-01-30 지이 헬쓰케어 리미티드 방사성표지된 갈륨 착물의 마이크로파 제조 방법
WO2008026051A3 (fr) * 2006-08-29 2008-05-22 Ge Healthcare Ltd Marquage par 68ga d'un chélateur macrocyclique libre et conjugué à une macromolécule à la température ambiante

Also Published As

Publication number Publication date
AU5079099A (en) 1999-11-23

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