Aliphatic 18F-Radiolabeling of Base-Sensitive Tetrazines
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Solution Overview
Problem
Current methods for aliphatic 18F-radiolabeling of high reactive tetrazines are hindered by degradation issues due to basic conditions, leading to low yields and instability of radiolabeled products, which limits their application in PET imaging.
Innovation Solution
A method involving preconditioning anion exchange cartridges with non-nucleophilic anions like phosphate or hydrogen phosphate, followed by elution with non-basic anions such as sulfonate esters, and using sterically hindered polar protic solvents for radiolabeling, which reduces basicity and enhances radiochemical yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If standard basic conditions are used for 18F-fluorination, then the radiolabeling reaction proceeds efficiently, but high reactive tetrazines undergo extensive degradation and decomposition
Solution Approach 1:
The patent changes the chemical parameters of the reaction system by introducing a weak base (DIPEA) instead of strong bases, and using a specific solvent system (acetonitrile/water 1:1 v/v). This parameter change allows the radiolabeling reaction to proceed while preventing base-sensitive degradation of high reactive tetrazines, achieving both good radiochemical yield and product stability
Solution Approach 2:
The patent uses DIPEA as an intermediary base that mediates the fluorination reaction. This weak base is sufficient to promote the SN2 reaction but not strong enough to cause degradation of the tetrazine product, thus serving as a protective intermediary that enables the reaction while preserving product integrity
2Speed
If highly reactive tetrazines are used for bioorthogonal chemistry, then in vivo reactivity is enhanced, but they become excessively sensitive to base and undergo degradation
Solution Approach 1:
The patent modifies the reaction conditions by using a weak base system (DIPEA) and specific solvent composition, which allows the radiolabeling to occur without triggering the base sensitivity that would otherwise degrade highly reactive tetrazines, thus preserving their in vivo reactivity
3Quantity of substance
If conventional nanomedicine-based radionuclide therapies are used, then target accumulation is achieved, but radiation doses to healthy tissues are excessive and limit clinical application
Solution Approach 1:
The patent enables pretargeted imaging by allowing the nanomedicine to accumulate at the target and clear from the body before radiolabeling. This preliminary accumulation and clearance action ensures that when the radiolabeled compound is administered, radiation is delivered only to the target site, minimizing exposure to healthy tissue while maintaining effective target accumulation
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
This approach allows for the successful aliphatic 18F-labeling of high reactive tetrazines with improved radiochemical yields and stability, enabling their use in pretargeted PET imaging with enhanced target-to-background ratios.
Implementation Method 1
Trapping 18F ions on the anion exchange cartridge by passing an aqueous 18F fluoride solution through the anion exchange cartridge
Implementation Method 2
Eluting the 18F ions by using a solution comprising a non-basic anion selected from the group comprising sulfonate esters such as MsO−, TsO− or TfO−
Data Source
AI summary
Up until now, only low reactivity Tzs can be radiolabeled via direct aliphatic SN2. Unfortunately, these structures display too low reactivity for in vivo bioorthogonal chemistry approaches. Highly reactive structures such as mono-unsubstituted tetrazines (H-Tzs) have been reported to be highly sensitive to base. Extensive degradation is observed which prevents isolation of meaningful amounts for imaging studies.In the present invention there is provided a method providing the possibility to radiolabel base sensitive tetrazine structures with significantly improved RCYs. Even tetrazines that were previously not accessible by applying “standard” aliphatic 18F-labeling strategies can be radiolabeled. This places new classes of 18 F-fluorinated compounds within reach for application in PET imaging studies such as for diagnosis of cancers.