Tetrazine Compounds for Pretargeted Imaging
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Solution Overview
Problem
Current methods for labeling tetrazine compounds with radionuclides like 18F, 123I, 124I, 131I, and 211At are not highly reactive and stable enough for clinical applications, particularly due to issues with aromatic nucleophilic substitution reactions and the rapid plasma isomerization of trans-cyclooctene derivatives, limiting their use in pretargeted PET and SPECT imaging and therapy.
Innovation Solution
Development of tetrazine compounds with specific polar groups that provide a lipophilicity of c log D7.4<ā3, allowing for direct and scalable labeling with these radionuclides using tin- or boronic species precursors, enabling faster reaction kinetics and improved metabolic stability for bioorthogonal chemistry applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If aromatic nucleophilic substitution reactions are used for labeling tetrazine compounds with radionuclides, then labeling can be achieved, but the reaction rates are not fast enough and metabolic stability is insufficient for clinical applications
Solution Approach 1:
The patent modifies the chemical structure of tetrazine compounds by introducing specific polar groups (carboxyl, hydroxyl, amino, or carbonyl groups) at defined positions (R2 or R4) in the tetrazine ring. This structural parameter change enhances both the reaction rate and metabolic stability, resolving the contradiction between productivity and reliability in the labeling process.
Solution Approach 2:
The patent creates composite tetrazine compounds combining the core tetrazine structure with specific polar functional groups and radionuclide labels (18F, 123I, 124I, 131I, or 211At). This composite approach integrates multiple functional requirements into a single molecule that achieves both fast reaction kinetics and metabolic stability.
2Reliability
If trans-cyclooctene derivatives are used for pretargeted imaging, then bioorthogonal chemistry can be achieved, but rapid plasma isomerization occurs limiting their utility
Solution Approach 1:
The patent employs highly reactive tetrazine compounds that are designed to be consumed in the bioorthogonal reaction. The tetrazine compounds are so reactive that they quickly react with the TCO derivative before plasma isomerization can occur, effectively using their short half-life advantage to complete the labeling process rapidly.
Solution Approach 2:
The patent introduces the tetrazine compound with specific polar groups before the actual imaging or therapy step. The compound is pre-activated and ready to react immediately upon contact with the TCO derivative, performing the bioorthogonal chemistry action before plasma isomerization can interfere.
3Productivity
If tetrazine compounds with high reactivity are used, then reaction kinetics improve, but cell membrane penetration increases which is undesirable for non-internalizing vectors
Solution Approach 1:
The patent carefully adjusts the lipophilicity parameter of the tetrazine compound by selecting specific polar groups and their positions. The compounds are designed to have optimal lipophilicity that maintains high reaction kinetics while preventing excessive cell membrane penetration, thus avoiding the harmful effect of intracellular accumulation.
Solution Approach 2:
The patent introduces polar groups at specific local positions (R2 or R4) in the tetrazine ring structure. This localized modification provides the necessary polarity to reduce membrane penetration while maintaining the overall reactivity of the tetrazine core, achieving a balance between productivity and harmful effects.
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 tetrazine compounds achieve high reaction rates and metabolic stability, resulting in excellent imaging results and therapeutic potential, particularly in cancer diagnostics and therapy, with enhanced target-to-background ratios and reduced radiation burden.
Implementation Method 1
The tetrazine ligation itself is based on an Inverse-Electron-Demand Diels-Alder (IEDDA) cycloaddition reaction followed by a retro-Diels-Alder elimination of nitrogen between an electron-deficient tetrazine (Tz) and often a strained trans-cyclooctene (TCO) derivative.
Implementation Method 2
Fluorine-18 (18F) is considered as the 'gold standard' PET radionuclide for clinical applications as it provides almost ideal physical characteristics for PET molecular imaging. A relatively short positron range (2.4 mm max. range in water), a good branching ratio (96.7% positron decay) and a half-life of approx. 110 min results in good resolution
Implementation Method 3
Iodine-123 (123I) is a standardly used radionuclide for SPECT and is as such useful for SPECT imaging
Implementation Method 4
The compounds comprise a covalently bound radionuclide of F, I or At and are high polar compounds that will not enter cell membranes and are thus particularly useful in relation to cancer diagnostics and cancer therapy using non-internalizing pretargeting vectors.
Data Source
AI summary
The present invention relates to novel tetrazine compounds for use in pretargeted in vivo imaging and in therapy and to the precursors of the tetrazine compounds. The compounds are suitable for use in click chemistry. i.e. reactions that join a targeting molecule and a reporter molecule. The compounds comprise a radionuclide of F, I or At and on or more polar groups providing that the compounds can efficiently react with extracellularly located pretargeting vectors and as such used for example for pretargeted cancer diagnostics and cancer therapy.