SSTR2-Targeting Compounds With Amide-Linked Evans Blue
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Solution Overview
Problem
Existing peptide receptor radionuclide therapeutic drugs for SSTR2 targeting suffer from poor in vivo stability and reduced tumor uptake due to rapid clearance in the blood, necessitating improved coupling bonds to enhance stability and increase tumor uptake.
Innovation Solution
A novel SSTR2-targeting compound is developed with a structure incorporating an SSTR2 binding ligand and truncated Evans blue linked by a flexible connecting arm via an amide bond, allowing for radionuclide labeling and improved stability, synthesized through a combination of solid and liquid phase synthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional peptide receptor radionuclide therapeutic drugs are used for SSTR2 targeting, then tumor targeting is achieved, but in vivo stability is poor and tumor uptake is reduced due to rapid blood clearance
Solution Approach 1:
The patent applies composite material design by combining the SSTR2 binding ligand (TATE) with Evans blue (a plasma protein binding agent) through an amide bond connection. This creates a hybrid molecule that leverages both components: the TATE portion provides SSTR2 targeting specificity while the Evans blue portion enhances plasma protein binding, thereby extending blood circulation time and improving in vivo stability. The composite structure resolves the contradiction by integrating two functional elements into a single therapeutic agent.
Solution Approach 2:
The amide bond serves as an intermediary connection between the TATE ligand and Evans blue molecule. This chemical bridge allows the two components to function together as a unified therapeutic agent while maintaining the ability to undergo metabolic cleavage, providing both extended circulation and tumor targeting capabilities.
2Quantity of substance
If conventional peptide receptor radionuclide therapeutic drugs are used for SSTR2 targeting, then receptor binding is achieved, but tumor uptake dose is reduced due to rapid clearance
Solution Approach 1:
The composite structure of TATE-Evans blue conjugate increases blood circulation time through plasma protein binding, which directly enables higher tumor uptake dose by providing more time for the radioligand to accumulate in tumor tissue through the enhanced permeability and retention effect and receptor-mediated endocytosis.
Solution Approach 2:
The Evans blue component enables continuous plasma protein binding and extended circulation, maintaining a sustained presence of the radioligand in the bloodstream. This continuous availability increases the probability of tumor cell encounter and binding, thereby increasing the cumulative tumor uptake dose over time.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compound exhibits higher in vivo stability, long blood circulation time, and enhanced tumor uptake, suitable for diagnosis and treatment of diseases with SSTR2 over-expression, with excellent metabolic kinetics and long tumor retention.
Implementation Method 1
coupling an EB portion and a TATE portion through an amide bond
Implementation Method 2
causing damage to the tumor cells through α rays or β rays released by nuclide decay
Data Source
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Figure 3A~4B
Figure 5A~6B
AI summary
The present invention provides a compound targeting SSTR2, a preparation method therefor and a use thereof, and relates to the fields of nuclear medicine and molecular imaging. The compound targeting SSTR2 has a structure shown in a formula (I) below, and a compound targeting SSTR2 and capable of being labeled with a radionuclide has a structure shown in a formula (II) below. The present invention further provides a radionuclide labeled compound targeting SSTR2 that is obtained by labeling the compound shown in the formula (II) with a radionuclide. The present invention further provides methods for preparing the compounds shown in the formula (I) and the formula (II) and a use of the compounds in preparation of drugs for diagnosis and/or treatment of diseases characterized by over-expression of SSTR2.