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Radiometal-binding analogues of luteinizing hormone releasing hormone

a technology of luteinizing hormone and radiometal, which is applied in the field of derivatives of leutenizing hormone releasing hormone, can solve the problems of limiting the radiometal which can be used, altering the receptor binding properties of the compound, and being unstable and unstabl

Inactive Publication Date: 2002-05-21
IMMUNOMEDICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Complexes of this type tend, however, to be heterogeneous and unstable and, moreover, the use of free sulfhydryls in this manner limits the radiometals which can be used to label the peptide to those that tightly bind free S--H groups.
This methods also suffers from the problem that direct binding of the metal to an amino acid side chain can greatly influence the peptide conformation, thereby deleteriously altering the receptor binding properties of the compound.
This method is inherently limited by the lack of selectivity available when more than one side chain can potentially react with the chelator, or when the peptide sequence does not contain an amino acid that can be derivatized in this way.
Once again, however, application of this method is limited to those circumstances in which the N-terminus of the peptide can accommodate the presence of a (usually bulky) chelator without deleteriously affecting the binding properties of the peptide.

Method used

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  • Radiometal-binding analogues of luteinizing hormone releasing hormone
  • Radiometal-binding analogues of luteinizing hormone releasing hormone
  • Radiometal-binding analogues of luteinizing hormone releasing hormone

Examples

Experimental program
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Effect test

example 1

Synthesis of N.sup..alpha. Alloc-Ne-Fmoc-L-Lycine

N.sup.e -Fmoc-L-Lysine (10.00 g, 27.1 mmol, 100 mol %, Bachem Biosciences, Inc.) was suspended in dioxane (100 ml) and Na.sub.2 CO.sub.3 (1M, 33 ml) to form a milky suspension. Allyl chloroformate (3.2 ml, 30.2 mmol, 111 mol %) was added to dioxane (10 ml) and this solution was added dropwise to the suspension of N.sup.e -Fmoc-L-Lysine over 10 min. Sodium carbonate, (1M, 20 ml) was added in two portions and an additional quantity of allyl chloroformate (0.3 ml) was added. The reaction was stirred at room temperature for 16 hours. The volatile solvents were removed under reduced pressure and the residue was washed with diethyl ether (50 ml). The residual liquid was then acidified with HCl (1M) and extracted with ethyl acetate (2.times.150 ml). The organic layers were combined, washed with saturated NaCl (50 ml), dried over Na.sub.2 SO.sub.4, evaporated under reduced pressure to obtain a crude oily product (16 g). The crude product was ...

example 2

Synthesis of 2-(triphenylmethylmercapto)acetyl hydrazide

2-(triphenylmethylmercapto) acetic acid (20.35 g, 60.9 mmol, 100 mol %) was dissolved in anhydrous THF (150 ml) and cooled in an ice water bath. t-Butylcarbazate (8.61 g, 65.1 mmol, 107 mol %) was added to the reaction solution followed by diisopropylcarbodiimide (10.0 ml, 63.9 mmol, 105 mol %). The reaction was allowed to warm slowly to room temperature and stirred for 28 hours. The reaction mixture was filtered to remove the white precipitate that had formed and the filtrate was concentrated to a white foam by removal of the solvent under reduced pressure. This material was dissolved in chloroform (75 ml). Then acetic acid (75 ml) was added followed by the addition of borontrifluoride etherate (10.0 ml, 81 mmol, 134 mol %). The reaction was stirred at room temperature for 6 hours and then quenched by pouring the reaction mixture into water (200 ml) containing sodium acetate (30 g). This mixture was extracted with chloroform (...

example 3

Synthesis of N.sup..beta. -[2-(triphenylmethylthio) acetyl]azaglycine

Glyoxylic acid monohydrate (0.59 g, 6.41 mmol, 110 mol %) was dissolved in methanol (20 ml) and 2-(triphenylmethylmercapto)acetyl hydrazide (2.03 g, 5.82 mmol, 100 mol %) was added. Dioxane (20 ml) was added to the cloudy reaction mixture and the reaction was stirred at room temperature for 18 hours. Sodium borohydride (1.76 g) was added to the reaction mixture and after 30 minutes, another quantity of sodium borohydride (0.60 g) was added. The reaction was stirred for 3 hours at room temperature, then quenched by pouring the reaction mixture into HCl (1M, 60 ml). The mixture was extracted with ethyl acetate (2.times.50 ml). The organic layers were combined, washed with saturated NaCl solution (40 ml), dried over Na.sub.2 SO.sub.4, filtered, and concentrated under reduced pressure on the rotary evaporator to afford a solid (2.5 g) having ESMS MH.sup.+ calculated 407, found 407.

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Abstract

Peptide, derivatives of leutenizing hormone releasing hormone that are capable of binding radionuclides are provided. The peptide derivatives are readily labeled with isotopes of rhenium or technetium, while retaining their ability to tightly bind LHRH receptors. Methods for preparing the labeled peptides and their use in methods of radiodiagnosis and radiotherapy are described.

Description

BACKGROUND OF THE INVENTIONThis invention relates to derivatives of leutenizing hormone releasing hormones (LHRH) in which one or more of the amino acid side chains contain chelating moieties that can tightly bind radionuclides.Luteinizing hormone-releasing hormone (LHRH) is a decapeptide having the structure (<G)HWSYGLRPG-NH.sub.2, (SEQ ID NO:1) where <G is pyroglutamic acid. LHRH controls pituitary synthesis of the gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH). LH and FSH control the synthesis of sex steroids in the gonads. It has been shown that analogues of LHRH, when substituted in position 6, 10, or both, display both greater and more sustained bioactivity than native LHRH. More than 3000 LHRH peptides have been evaluated both in vitro and in vivo. See, for example, Schally et al., BASIC ASPECTS; GNRH ANALOGUES IN CANCER AND IN HUMAN REPRODUCTION, Vickery & Lunenfeld eds. Vol. 1, pp. 5-31, (Kluwer Academic Publishers, Dordecht, 1989); Scha...

Claims

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Application Information

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IPC IPC(8): A61K51/08A61K51/02A61K51/00A61K38/00C07K7/23C07K14/575
CPCA61K38/00A61K51/088C07K7/23
Inventor MCBRIDE, WILLIAM J.KARACAY, HABIBEGRIFFITHS, GARY L.
Owner IMMUNOMEDICS INC
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