Gallium Indium Metal Complex Radiolabelling
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Solution Overview
Problem
Current methods for 18F radiolabelling of biological molecules, such as peptides, face challenges due to hydrogen bonding interactions with amino acids like lysine and arginine, which reduce nucleophilicity and require higher temperatures, causing degradation or structural disruption, and are not suitable for aqueous conditions, limiting their applicability and efficiency.
Innovation Solution
A method for radiolabelling using gallium and indium metal complexes, which form stable fluoride bonds at room temperature and in aqueous conditions, allowing for high affinity fluoride binding and conjugation to biological molecules, enabling efficient 18F labelling under mild conditions without the need for organic solvents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard nucleophilic substitution methods are used to label biological molecules with 18F, then the labeling can be achieved, but the hydrogen bonding interactions with amino acids reduce nucleophilicity and require higher temperatures causing degradation
Solution Approach 1:
The patent introduces a metal complex (such as aluminum, gallium, indium, lutetium, or thallium) as an intermediary carrier that binds to the biological molecule and facilitates 18F incorporation. The metal complex acts as a mediator between the 18F fluoride source and the biological molecule, enabling labeling under mild conditions without direct nucleophilic attack on the amino acid residues.
Solution Approach 2:
The patent changes the chemical parameters of the labeling system by introducing metal complexes with specific coordination chemistries. This allows the reaction to proceed at lower temperatures (room temperature to moderate heating) rather than requiring high temperatures, thereby avoiding peptide degradation while maintaining labeling efficiency.
2Reliability
If higher temperatures are used to overcome hydrogen bonding interactions, then nucleophilicity is improved, but peptide or protein structure is degraded or disrupted
Solution Approach 1:
The metal complex serves as an intermediary that enhances fluoride nucleophilicity without requiring high temperatures. The metal center coordinates with fluoride and facilitates its transfer to the biological molecule through a mechanism that preserves peptide structure, avoiding thermal degradation.
Solution Approach 2:
The patent replaces the thermal activation mechanism (heating to increase nucleophilicity) with a chemical mechanism involving metal complex coordination. This substitution allows fluoride activation without the mechanical/thermal stress that would disrupt peptide hydrogen bonding and overall structure.
3Reliability
If traditional radiolabelling methods are used, then labeling can be achieved, but the process requires organic solvents and multiple steps increasing complexity and time
Solution Approach 1:
The metal complex serves multiple functions simultaneously: it acts as a carrier for the biological molecule, provides a coordination site for fluoride binding, and facilitates the transfer of 18F to the molecule. This multi-functionality reduces the need for separate reagents and steps, simplifying the overall radiolabelling process.
Solution Approach 2:
The patent changes the solvent system parameter by enabling the reaction to proceed in aqueous or mixed aqueous-organic conditions rather than requiring purely organic solvents. This allows for simpler workup procedures and reduces the number of purification steps needed.
4Reliability
If conventional methods are used for 18F labelling, then labeling can be performed, but radioactive decay causes yield loss over time
Solution Approach 1:
The patent replaces multi-step sequential operations with a more direct one-pot or near-one-pot procedure. By combining the metal complex formation, fluoride binding, and transfer steps into a single operational sequence, the time window for radioactive decay is minimized, thereby reducing yield loss.
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 efficient 18F radiolabelling of peptides and other biological molecules at room temperature and in aqueous conditions, ensuring high in vivo stability and reducing the complexity and time of the radiolabelling process, thereby minimizing yield loss due to radioactive decay.
Implementation Method 1
gallium and indium metal complexes, which form stable fluoride bonds at room temperature and in aqueous conditions, allowing for high affinity fluoride binding
Implementation Method 2
reacting the 18F with a metal to form an 18F metal complex; and attaching the 18F metal complex to a molecule
Data Source
AI summary
The present invention relates to a method of labelling biological molecules with 18F, via attachment to fluorine to a macrocyclic metal complex of a non-radioactive metal, where the metal complex is conjugated to the biological molecule. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.