SSTR2-Targeting Compounds With Stable Amide Linkers
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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 containing 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.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a thiosuccinimide bond is used to couple EB and TATE portions, then the coupling has high selectivity and fast reaction kinetics, but the bond is easily eliminated through retro-Michael reaction or thiol exchange reaction under physiological conditions, resulting in poor in vivo stability
Solution Approach 1:
The patent changes the chemical nature of the coupling bond from thiosuccinimide bond to amide bond. This parameter change transforms the bond's stability characteristics, making it resistant to retro-Michael reaction and thiol exchange reaction under physiological conditions, thereby solving the in vivo stability problem while maintaining coupling efficiency
Solution Approach 2:
The patent creates a composite molecular structure combining EB portion, TATE portion, and amide bond connecting arm. This composite design integrates the high affinity binding capability of TATE with the stability of amide bonds, achieving both manufacturing efficiency and in vivo stability simultaneously
2Reliability
If Lutathera is used for SSTR2 targeting, then it can bind to receptors highly expressed in tumor cells, but rapid clearance in the blood (mainly through the kidney) reduces the dose entering tumor tissues and increases kidney toxicity
Solution Approach 1:
The patent modifies the pharmacokinetic parameters of the drug by changing the coupling bond type and adding a flexible connecting arm. This changes the molecular properties to reduce renal clearance and extend blood circulation time, thereby increasing the dose available for tumor uptake while maintaining receptor binding specificity
Solution Approach 2:
The flexible connecting arm acts as an intermediary structure between the EB portion and TATE portion. This intermediary element optimizes the spatial arrangement and pharmacokinetic properties, reducing rapid clearance and enhancing tumor accumulation without compromising the specific binding capability
3Duration of action of moving object
If a longer blood circulation time is achieved through albumin binding, then more time is available for binding to highly expressed receptors at tumor sites, but higher in vivo stability is required to ensure full binding, and existing coupling bonds fail to provide sufficient stability
Solution Approach 1:
The patent changes the chemical stability parameter of the coupling bond from unstable (thiosuccinimide) to stable (amide bond). This parameter change enables the drug to maintain structural integrity during extended blood circulation and ensures reliable binding to tumor receptors without degradation
Solution Approach 2:
The amide bond provides beforehand structural stability that prevents bond degradation during blood circulation. This pre-established stability cushion allows the drug to survive long circulation times and reach tumor sites intact, ensuring full binding capability
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, making it suitable for diagnosis and treatment of diseases with SSTR2 over-expression.
Implementation Method 1
the SSTR2 binding ligand and the truncated Evans blue are linked by a flexible connecting arm containing an amide bond
Implementation Method 2
a compound capable of targeting SSTR2... the SSTR2 binding ligand and the truncated Evans blue are linked by a flexible connecting arm
Implementation Method 3
causing damage to the tumor cells through α rays or β rays released by nuclide decay
Data Source
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.