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Radioiodinated phospholipid ether analogs and methods of using the same

a technology of phospholipid ether and radioiodination, which is applied in the field of radiolabelled analogs of phospholipid ether, can solve the problems of tumor-specific radiopharmaceuticals which are tissue-destructive by more than on

Inactive Publication Date: 2002-05-30
RGT UNIV OF MICHIGAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the inclusion of a long-lived radioactive isotope of iodine, for example, yields tumor-specific radiopharmaceuticals which are tissue-destructive by more than one mode.

Method used

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  • Radioiodinated phospholipid ether analogs and methods of using the same
  • Radioiodinated phospholipid ether analogs and methods of using the same
  • Radioiodinated phospholipid ether analogs and methods of using the same

Examples

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example 1

[0031] The synthesis of 18-(p-Iodophenyl)octadecanol (Compound VI), which is a preliminary compound for the illustrative preparatory schemes for the phospholipid ether analogs discussed in detail in Examples 2 through 4 below, was accomplished from commercially-available 15-(p-iodophenyl) pentadecanoic acid (Compound I) in accordance with the illustrative preparatory scheme shown in FIG. 1.

[0032] In general terms, aliphatic chain elongation from C-15 to C-18 was achieved by Li.sub.2CuCl.sub.4-catalyzed cross-coupling between Grignard reagent (Compound IV) prepared from benzyl 3-bromopropyl ether and 15-(p-iodophenyl) pentadecyl tosylate (Compound III). See, e.g., Fouquet and Schlosser. "Improved carbon-carbon linking by controlled copper catalysis," Angew. Chem. Int. Ed. 13:82-83 (1974); Schlosser and Bossert. "The two-fold reaction benchmark applied to the copper catalyzed assembling of 1, .omega.-difunctional hydrocarbon chains," Tetrahedron 47:6287-92 (1991). Cleavage of the benz...

example 2

[0039] Further conversion of 18-(p-iodophenyl) octadecanol into the desired phosphocholines was performed as described in detail for the C-12 analogs in Rampy et al., "Synthesis and biological evaluation of radio-iodinated phospholipid ether analogs," Nuci. Med. Biol. 22, 505-512 (1995). In one preferred embodiment, the improved phospholipid ether analog contemplated by the present invention is a simple straight chain alkyl phospholipid. 18-(p-iodophenyl)octadecyl phosphocholine (Compound XVI). The synthesis of Compound XVI was accomplished according to the illustrative preparatory scheme shown in FIG. 2.

[0040] As illustrated in FIG. 2, 2-chloro-2-oxo-1,3.2-dioxaphospholane (0.025 ml; 0.27 mmol) was added to the stirred solution of 18-(p-iodophenyl)octadecanol (Compound VI) (115 mg; 0.24 mmol) in dry benzene (3 ml) containing triethylamine (0.042 ml; 0.29 mmol). Stirring was continued overnight. The precipitated triethylamine hydrochloride was filtered off and the solvent was remove...

example 3

[0041] In another preferred embodiment, the improved phospholipid ether analogs contemplated by the present invention are constructed using a propanediol backbone. In this example, the synthesis of 1-O-[18-(p-Iodophenyl)octadecyl]-1,3-propanediol-3-phosphocholine (Compound XIV) was accomplished according to the illustrative preparatory scheme shown in FIG. 3.

[0042] To a solution of 18-(p-iodophenyl)octadecanol (Compound VI) (150 mg; 0.317 mmol) and triethylamine (0.07 ml; 0.475 mmol) in dry methylene chloride (2 ml) was added methane sulfonyl chloride (0.03 ml; 0.38 mmol) at 0.degree. C. Stirring was continued for 40 min and the reaction was quenched by addition of water. The reaction mixture was diluted with chloroform and washed several times with water. The chloroform layer was dried (Na.sub.2SO.sub.4) and evaporated. The residue was chromatographed in hexane-ethyl acetate (9:1). This afforded pure Compound VII, 18-(p-Iodophenyl)octadecyl methanesulfonate (142 mg; 82% yield).

[004...

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Abstract

The present invention provides improved radioiodinated phospholipid ether analogs which demonstrate significant tumor avidity and longer plasma half-life than shorter-chain analogs. The radioiodinated phospholipid ether analogs of the present invention provide superior imaging and visualization of neoplastic lesions and tumor-specific cytotoxic cancer therapy.

Description

FIELD OF THE INVENTION[0001] The present invention relates generally to the field of radiopharmaceuticals and biological probes, and more specifically to radiolabelled analogs of phospholipid ethers useful in cancer diagnosis and treatment.BACKGROUND OF THE INVENTION[0002] The early detection of cancer has been one of the primary goals of modern imaging technology, since the identification of a suspected tumor in a localized stage significantly improves the chances for successful treatment and elimination of the cancerous tissue. A large number of imaging strategies have therefore been designed, using a variety of techniques and modalities, to aid the physician in making an accurate diagnosis as early as possible.[0003] Unfortunately, conventional imaging techniques such as computerized tomography (CT) and MRI (magnetic resonance imaging) are limited in their ability to afford a conclusive diagnosis of a suspected lesion, since they are only capable of observing differences in the d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K51/04C07B59/00C07F9/09
CPCA61K51/0408A61K2123/00C07B59/004C07F9/091C07F9/094
Inventor COUNSELL, RAYMOND E.LONGINO, MARC A.PINCHUK, ANATOLY N.RAMPY, MARK A.WEICHERT, JAMEY P.
Owner RGT UNIV OF MICHIGAN
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