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DZ-1-Lys-DOTA conjugate compounded with radioactive metal and application of DZ-1-Lys-DOTA conjugate

A metal composite and radioactive technology, applied in radioactive carriers, in vivo radioactive preparations, drug combinations, etc., can solve the problems of high dissociation rate of radioactive metals and complexes, insufficient biodistribution, insufficient tumor accumulation rate, etc., and achieve high practical value and generalization value, improved image-guided therapy, effects of improved serum stability

Pending Publication Date: 2021-06-01
DEZHEN (CHINA) MEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Radionuclide complexes may also encounter reabsorption of renal proximal tubules and / or unfavorable prolonged retention of radioactive metabolites in cells, especially in renal cells or cells of other organs, which may result in undesired persistent radioactivity
[0012] Other problems with radioactive chemicals may include one or more of the following: lack of suitability for treatment of one or more cancers, insufficient sensitivity, insufficient selectivity for cancer cells, changes over time between tumor and non-cancerous tissue Insufficient contrast, insufficient biodistribution, insufficient tumor targeting, insufficient tissue and / or tumor penetration, uneven distribution in tumor tissue, insufficient tumor accumulation rate, insufficient retention in tumor, and clearance from blood after administration Slow, low radiation exposure of tissues and organs, low clearance rate of vital organs such as kidney, liver, heart, etc., non-target tissues or organs, especially cystic tissues, such as organs and dense tissues, including tumor tissues, especially calcified Tumor tissue that slowly establishes a steady-state distribution in the body and organs including the heart, liver, lungs, and kidneys, with persistent radioactivity in one or more organs, including the kidney and / or liver, that does not form with one or more radioactive metals Stable complexes or difficult to form stable complexes, low rate of complex formation, low labeling efficiency with one or more radioactive metals, insufficient solubility in aqueous solutions, low stability in aqueous solutions, at physiological pH Low stability in the environment, low stability in vivo, high dissociation rate of radioactive metals and complexes, especially high dissociation rate in vivo, slow tumor-specific targeting, high organ accumulation (such as
Such as kidney, spleen, liver, heart), slow clearance (such as clearance from blood, liver, kidney and other organs), difficult synthesis or high cost

Method used

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  • DZ-1-Lys-DOTA conjugate compounded with radioactive metal and application of DZ-1-Lys-DOTA conjugate
  • DZ-1-Lys-DOTA conjugate compounded with radioactive metal and application of DZ-1-Lys-DOTA conjugate
  • DZ-1-Lys-DOTA conjugate compounded with radioactive metal and application of DZ-1-Lys-DOTA conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1 Synthesis of DZ-1-Lys-DOTA coupled reflective metal complex

[0097] 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. DOTA, also known as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA tris(tert-butyl ester), also known as 1,4,7, 10-Tetraazacyclododecane-1,4,7-tri-tert-butylacetic acid-10-acetic acid, commercially available from Macrocyclics (Arlington Heights, IL). DOTA and all other chemicals mentioned herein, for example in the reaction schemes as shown, are also commercially available from various standard sources such as VWR International (Radnor, PA) or Thermo Fisher Scientific (Waltham, PA). MA), which is obvious to a person of ordinary skill. Deioniz...

example 1

[0098] The synthesis of example 1a DZ-1-Lys-DOTA conjugate

[0099] Scheme 1 shown below illustrates the formation of the DZ-1-Lys-DOTA conjugate, the first step in the coupling of compound 4, also referred to herein as "DZ-1"; other synthetic routes to It is obvious. DZ-1 can then be coupled with a lysine crosslinker (shown in Scheme 2 below) and further coupled with DOTA (shown in Scheme 3 and 4 below (or alternatively in Scheme 5) Option 4).

[0100] Scheme 1, the synthesis of compound 4 (DZ-1):

[0101]

[0102] Synthesis of Compound 1a (compare Scheme 1 above): A mixture of 2,3,3-trimethylindole (5 g, 31.4 mmol) and 1,4-butane sultone (5.1 g, 37.7 mmol) can be Stir and heat at 120°C for 5 hours under the protection of argon. The resulting reaction mixture is cooled to room temperature (eg, about 20° C.), and the solid can be dissolved in a sufficient volume of solvent, eg, an organic solvent, eg, about 50 mL of methanol. About 200 ml of diethyl ether is added to m...

example 1

[0118] Example 1b - Labeling of DZ-1-Lys-DOTA conjugates to form DZ-1-Lys-DOTA-M (here: Lu-177)

[0119] The DZ-1-Lys-DOTA conjugate can be labeled, i.e., chelated, with a radiometal ("M") in any convenient manner apparent to those of ordinary skill; for example, the radiometal M can be introduced in ionic form, and the cationic radiometal (M For example, selected from but not limited to: 177 Lu 3+ , 90 Y 3+ , 68 Gd 3+ ) with anionic reagents such as chloride (ie M n+ Cl n ) paired, as shown in Scheme 6 below, forming such as but not limited to: 177 LuCl 3 , 90 YCl 3 , 68 GaCl 3 .

[0120] Protocol 6: Labeling Formation DZ-1-Lys-DOTA-M

[0121]

[0122] M = 177 Lu 3+ , 90 Y 3+ , 68 Ga 3+

[0123] For radiolabelling, an appropriate amount of radioactive metal can be added to the DZ1-Lys-DOTA conjugate, for example at about 2 to about 200 MBq / μg (radiometal:conjugate), about 4 to about 100 MBq / μg or about 8 to about 50 MBq / μg, for example about 20 MBq / μg...

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Abstract

The invention discloses a DZ-1-Lys-DOTA conjugate compounded with radioactive metal. The DZ-1-Lys-DOTA conjugate comprises a heptamethyl cyanine dye group coupled with a DOTA group through a lysine cross-linking agent, wherein the DOTA group is compounded with the radioactive metal M; the radioactive metal M adopts one or more radioactive metal groups of lutetium -177, yttrium -90 and gallium- 68; the invention also discloses application of the DZ-1-Lys-DOTA conjugate compounded with the radioactive metal. The DZ-1-Lys-DOTA conjugate comprises improved imaging, improved treatment, improved image-guided treatment, improved serum stability, improved penetrability of tumors (especially solid tumors) and / or affinity of therapeutic and diagnostic pairs. Through the scheme, the DZ-1-Lys-DOTA conjugate has very high practical value and popularization value in the technical field of the DZ-1-Lys-DOTA conjugate.

Description

technical field [0001] The invention relates to the technical field of DZ-1-Lys-DOTA conjugates, in particular to a DZ-1-Lys-DOTA conjugate compounded with radioactive metal and its application. Background technique [0002] A limited number of diagnostic or therapeutic radiopharmaceuticals are available for imaging or treating cancer or tumors. Imaging utilizes the very low concentrations required for detection, for example, of positron emitters with positron emission tomography (PET). Internal radiation therapy is a type of treatment in which a radioactive source is placed inside the subject to treat cancer. Internal radiation therapy can be systemic, that is, the treatment is carried out with the blood into the tissues of the body, and the radiation to the cells near the radioactive metal is used to kill cancer cells. Radiometals can be delivered by chelation or complexation with a variety of chelating compounds and coupling to targeting ligands. [0003] Various combi...

Claims

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Application Information

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IPC IPC(8): A61K51/04A61P35/00A61P35/04A61K103/30A61K103/32A61K103/00
CPCA61K51/0482A61K51/0446A61P35/00A61P35/04A61K51/0497
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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