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Symmetrical difunctional coupling agent and coupled molecular imaging agents thereof

A technology of molecules and names, which is applied in the application field of preparing imaging agent drugs, can solve problems such as shortage, achieve the effects of low toxicity and side effects, easy purification, and increase reaction yield

Inactive Publication Date: 2012-03-28
THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the biggest problem at present is the lack of effective symmetric bifunctional coupling agents to link the relevant small molecule ligand pharmacophore

Method used

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  • Symmetrical difunctional coupling agent and coupled molecular imaging agents thereof
  • Symmetrical difunctional coupling agent and coupled molecular imaging agents thereof
  • Symmetrical difunctional coupling agent and coupled molecular imaging agents thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] [Example 1] Symmetrical bifunctional coupling agent N-fluorenylmethoxycarbonyl-L-beta-glutamic acid-two-N-succinimide (Fmoc-beta-Glu(OSu)-OSu, I) Synthesis

[0107] Synthetic Route 1 Symmetrical bifunctional coupling agent N-(9-fluorenylmethoxycarbonyl)-L-beta-glutamic acid-di-N-succinimide (Fmoc-beta-Glu(OSu)-OSu, I) Synthesis.

[0108] ① The compound Fmoc-beta-Glu(OtBu)-OH is used as the raw material, and the compound Fmoc-beta-Glu(OH)-OH is obtained after the tert-butyl group (tBu) is removed by TFA (trifluoroacetic acid) hydrolysis.

[0109]

[0110] ②Fmoc-beta-Glu(OH)-OH reacts with HOSu (N-hydroxysuccinimide) under the action of DCC (dicyclohexylcarbodiimide) to form a symmetrical bifunctional coupling agent Fmoc-beta-Glu( OSu)-OSu(I).

[0111]

[0112] Specific steps are as follows:

[0113]Organic synthesis of coupling group N-(9-fluorenylmethoxycarbonyl)-L-beta-glutamic acid-di-N-succinimide (Fmoc-beta-Glu(OSu)-OSu, I).

[0114] Fmoc-beta-Glu(OSu)-OS...

Embodiment 2

[0115] [Example 2] Synthesis of precursor-coupled bivalent peptide molecule beta-Glu-E(RGDyk)2 and coupled hybrid molecule RGD-beta-Glu-BBN

[0116] Synthetic Route 3 Solid phase synthesis of precursor bivalent peptide molecule beta-Glu-E(RGDyk)2.

[0117] ① Connect 9-fluorenylmethoxycarbonyl-aspartic acid-allyl (Fmoc-Asp-Oall) to wang resin (Wang's resin) to generate resinized product (5).

[0118]

[0119] ② Connect glycine (Gly), 2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl (pbf)-protected arginine (Arg), 1 -(4,4-dimethyl-2,6-dioxocyclohexyl-1-ylidene)ethane (Dde) protected lysine (Lys), and tert-butyl (tBu) protected D- Tyrosine (Tyr), remove allyl group (Oall),

[0120] Cyclization to obtain the resin cyclization product (6). cyclic(RGDyk(Dde)) is a cyclic monomer RGD protected by Dde group.

[0121]

[0122] ③ The resin cyclization product (6) is reduced by hydrazine to remove the Dde group to obtain the cyclization RGD product (7). .

[0123]

[0124] ④The ...

Embodiment 3

[0142] [Example 3] 18 F labeled prosthetic group N-succinimide-4- 18 F-fluorobenzoate ( 18 F-SFB) radiosynthesis and its use to label beta-Glu conjugated molecules.

[0143] Synthetic Route 5 Reporter Signal Group Nuclide Labeled Prosthetic Group (S): N-Succinimide-4- 18 F-fluorobenzoate ( 18 F-SFB) radiosynthesis.

[0144] ① Using ethyl 4-(trimethylammonium trifluoromethanesulfonate) benzoate (9) as raw material, compound (10) was obtained through fluorination.

[0145]

[0146] ② Compound 10 reacts with tetrapropylammonium hydroxide to generate 4- 18 F-Ammonium benzoate (11).

[0147]

[0148] ③Compound 11 reacts with N,N,N',N'-tetramethyl-0-(N-succinimide) hexafluorophosphate urea salt (HSTU) under the action of tetrapropylammonium hydroxide to generate 18 F-SFB.

[0149]

[0150] Synthetic Route 6 Bivalent Peptide Molecular Imaging Agent 18 Radiosynthesis of F-FB-beta-Glu-E(RGDyk)2. beta-Glu-(RGDyK)2 dissolved in Na 2 HPO 4 or borate buffer, add a smal...

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Abstract

The invention provides a symmetrical difunctional coupling agent compound (I), i.e. N-fluorenylmethyloxycarbonyl-L-beta-glutamate-di-N-succinimide (Fmoc-beta-Glu(OSu)-OSu), and a production method thereof. Based on the compound, a series of novel coupling compounds which respectively contain a symmetrical difunctional coupling base, i.e. beta-Glu (beta-glutamate) are prepared through being coupled to ligand molecules; the structural formula of the series of coupling compounds is shown as (II), wherein M1 is a -NH2-contained ligand of a target molecule T1, M2 is a -NH2-contained ligand of a target molecule T2, L is a linking group, and S is a report signal group. The compound (1) provided by the invention has been used in coupling a targeted integrin alphavbeta3 receptor ligands, gastrin-releasing peptide receptor ligands, telomerase inhibitor pharmacophores and epidermal growth factor receptor ligands, and thus, a plurality of coupled bi-ligand molecular imaging agents and coupled tri-ligand molecular imaging agents are synthesized. The invention further relates to the use of the compound (I) and the series of novel coupling compounds (II) in the preparation of imaging agent drugs.

Description

【Technical field】 [0001] The invention relates to a symmetrical bifunctional coupling agent, a coupled compound, a preparation method thereof, and an application thereof in the preparation of imaging agent medicines. 【Background technique】 [0002] Multi-target molecular imaging (MMI) is a molecular imaging technique for imaging two or more target molecules in certain diseased tissue cells, including multiple imaging agents-multi-target imaging, fusion molecule multi-target Imaging, coupled molecular multi-target imaging and multi-target multifunctional molecular imaging [1] , among them, coupled molecular multi-target imaging is one of the most promising multi-target molecular imaging techniques, including multivalent molecular imaging and hybrid molecular imaging. Coupled molecule multi-target imaging is to design and synthesize a specific coupling molecule imaging agent for multiple (one) target molecules in a diseased tissue cell, selectively act on multiple targets, an...

Claims

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Application Information

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IPC IPC(8): C07D207/46C07D401/12C07D239/74C07D401/14C07K7/64C07K19/00A61K51/00A61K101/02
Inventor 唐刚华
Owner THE FIRST AFFILIATED HOSPITAL OF SUN YAT SEN UNIV
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