Radiolabeled Oligonucleotides Post-Synthesis Labeling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for radiolabeling oligonucleotides suffer from low radiochemical yield, dilution problems leading to lower specific activity, and stringent storage and transportation requirements due to the use of reactive and prone-to-degradation phosphoramidite species.
Innovation Solution
A novel radiolabeled oligonucleotide with a specific structure and a process for its preparation, involving the use of radiolabeled C1-6-alkyl groups and a receptor targeting moiety, such as a GalNAc moiety, to enhance biodistribution and pharmacokinetic studies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If phosphoramidite chemistry is used for radiolabeling oligonucleotides, then radiolabeled oligonucleotides can be synthesized, but the radiochemical yield is limited and the specific activity is reduced due to dilution with natural abundance isotopes
Solution Approach 1:
The patent extracts the radioisotope labeling step from the conventional phosphoramidite coupling sequence. Instead of incorporating the radioisotope during oligonucleotide synthesis, the method introduces the radiolabeled nucleoside after synthesis is complete, thereby avoiding dilution with natural abundance isotopes and achieving high specific activity without sacrificing radiochemical yield
Solution Approach 2:
The patent performs preliminary actions by first synthesizing the oligonucleotide sequence without the radiolabel, then subsequently introducing the radiolabeled nucleoside. This preliminary synthesis allows for complete incorporation of the radioisotope without competition from natural abundance isotopes, resolving the contradiction between yield and specific activity
2Ease of manufacture
If phosphoramidite species are used for radiolabeling, then radiolabeled oligonucleotides can be prepared, but stringent storage and transportation requirements are needed due to reactive and prone-to-degradation nature of phosphoramidite
Solution Approach 1:
The patent extracts the unstable phosphoramidite species from the final product formulation. By introducing the radiolabeled nucleoside as a stable post-synthesis add-on rather than incorporating it during synthesis via phosphoramidite chemistry, the method eliminates the need for stringent storage and transportation conditions while maintaining ease of manufacture
Solution Approach 2:
The patent replaces the unstable phosphoramidite intermediate with a stable radiolabeled nucleoside that can be stored and transported under normal conditions. This substitution of a stable component for an unstable one resolves the contradiction between ease of manufacture and reliability during storage and transportation
Data Source
AI summary
The invention comprises radiolabeled oligonucleotide of the formula Iwherein n, X1, X2, the linker 1, the linker 2, Q and the receptor targeting moiety are as defined I the description. The radiolabeled oligonucleotides of the formula I can be used for the determination of the biodistribution and pharmacokinetics of the oligonucleotide in the tissue or body fluid.