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Heptamethyl carbonyanine dye-crosslinked tetracyclic amine chelating agent conjugate, and compound and application thereof

A technology of heptamethyl carbocyanine and chelating agent is applied in the field of heptamethyl carbocyanine dye-cross-linked tetracyclic amine chelating agent conjugate, and can solve the problems of unwanted radioactivity and the like

Pending Publication Date: 2021-07-13
DEZHEN (CHINA) MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Radionuclide complexes may also experience unfavorable prolonged cellular retention of radionuclide metabolites in renal proximal tubules, especially in renal cells or cells of other organs, which may result in undesired persistent radioactivity

Method used

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  • Heptamethyl carbonyanine dye-crosslinked tetracyclic amine chelating agent conjugate, and compound and application thereof
  • Heptamethyl carbonyanine dye-crosslinked tetracyclic amine chelating agent conjugate, and compound and application thereof
  • Heptamethyl carbonyanine dye-crosslinked tetracyclic amine chelating agent conjugate, and compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Synthesis of DZ-1-(L)-CTC Chelator-Coupled Radiometal Complex

[0109] The synthesis of DZ-1 dye and its derivatives has been described previously, for example in US 10307489, which is hereby incorporated in its entirety, and can be performed as detailed in Example 1a below. The conjugate can then be complexed with a radiometal as described in Example 1b. The following chemicals and reagents can be used.

[0110] CTC chelators CB-TE2A and DiAmSar are commercially available from Macrocyclics (Plano, Texas). All other chemicals mentioned herein, can be purchased from various standard sources such as VWR International (Radnor, PA) or Thermo Fisher Scientific (Waltham, MA), as will be apparent to those of ordinary skill . Deionized ultrapure water (18.2 MQ) was used to prepare the solution, which is available from Milli-Q Direct Ultrapure Water Systems from Millipore Corporation (Billerica, MA, USA). Analytical Reverse Phase (RP) High Performance Liquid Chrom...

Embodiment 2

[0122] Embodiment 2: the synthesis of DZ-1-L-CTC conjugate

[0123] Scheme 3 below illustrates one option for the synthesis of DZ-1-L-CTC, here DZ-1-lysine-CB-TE2A8:

[0124]

[0125] Synthesis and radiolabelling of DZ-1-(L)-CTC, here DZ-1-lysine-CB-TE2A 8 (compare Scheme 3). An appropriate form of carbon tetrachloride (here CB-TE2A), such as one of its salts, such as hydrochloride, can be mixed with appropriate amounts of diisopropylcarbodiimide (DIC) and diisopropylethyl amine (DIEA), or triethylamine (Et 3N) mix. For example, CB-TE2A-4HCl salt 7 (50 mg, 0.11 mmol), diisopropylcarbodiimide (DIC) (14 mg, 0.11 mmol) and diisopropylethylamine (DIEA) (14 mg, 0.11 mmol ) is dissolved in an appropriate volume of DMF, for example 2ml of dimethylformamide (DMF). The mixture may be stirred for an appropriate amount of time to ensure complete dissolution and / or mixing, for example about 30 minutes. DZ-1-L (a conjugate with terminal aminocarboxyl group), such as DZ-1-lysine 6 (...

Embodiment 3

[0129] Embodiment 3: the synthesis of the DZ-1-CTC conjugate that does not contain cross-linking agent

[0130] Scheme 5 below illustrates the synthesis of DZ1-CTC without crosslinker, here DZ-1-DiAmSar:

[0131]

[0132] Synthesis of DZ-1-DiAmSar (comparison scheme 5): an appropriate amount of DZ-14 (for example about 50mg, 0.071mmol), diisopropylcarbodiimide (DIC) (for example about 13.5mg, 0.11mmol) and hydroxyl A mixture of benzotriazoles (HOBt) (eg about 11.5 mg, 0.085 mmol) was dissolved in an appropriate amount of DMF (eg about 2 ml DMF). The mixture was stirred well to completely dissolve and mix, for example about 30 minutes, then CTC (here DiAmSar 5H O 10 (29 mg, 0.071 mmol)) was added and stirred well to react, for example about 5 Hour. The product can be precipitated in an appropriate volume of medium, such as cold diethyl ether (e.g. about 40 ml), at a suitable low temperature. The precipitate is separated, e.g., centrifuged at a suitably high speed for a su...

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Abstract

The invention discloses a heptamethyl cyanine dye-crosslinked tetracyclic amine chelating agent conjugate. The conjugate comprises a heptamethyl cyanine dye (HMCD) group coupled by a crosslinking agent group L and a crosslinked tetracyclic amine (CTC) chelating agent residue R; the cross-linking agent group L is composed of zero or one or more amino acid residues; the residue R of the cross-linked tetracyclic amine (CTC) chelating agent is a group consisting of CB-TE2A or DiAmSar or a derivative of the CB-TE2A or DiAmSar; and the residue R of the cross-linked tetracyclic amine (CTC) chelating agent is combined with <64>Cu. According to the scheme, the copper compound containing DZ-1-(L)-CTC can provide improved serum stability compared with copper compounds known in the past, and meanwhile, the tumor targeting property is reserved, and good imaging quality is provided.

Description

technical field [0001] The invention relates to the technical field of heptamethylcarbocyanine dye-crosslinked tetracyclic amine chelating agent conjugates, in particular to heptamethylcarbocyanine dye-crosslinking tetracyclic amine chelating agent conjugates, complexes and applications thereof. Background technique [0002] Currently, only a limited number of diagnostic or therapeutic radiopharmaceuticals are available in the prior art for tumor imaging or cancer treatment. Imaging requires very low concentrations of radiopharmaceuticals, such as detection of positron emitters with positron emission tomography (PET). Internal radiation therapy is a method in which a radioactive source is placed inside a subject to treat cancer. Internal radiation therapy may be systemic, that is, the treatment is carried out with the blood into the tissues of the whole body, and the cancer cells are killed by the radiation received by the cells near the radioactive metal. Radiometals can ...

Claims

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Application Information

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IPC IPC(8): C07D487/08C07K5/078A61K51/04A61P35/00A61P35/04A61K103/00
CPCC07D487/08C07K5/06139A61K51/0482A61P35/00A61P35/04
Inventor 钟维国王若翔张驿程宇平余波
Owner DEZHEN (CHINA) MEDICAL TECH CO LTD
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