Bispidine Derivatives for Mild-Temperature Radiolabelling
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Solution Overview
Problem
Current ligands for radiolabelling with Lutetium-177 and Actinium-225, such as DOTA and DTPA, face challenges including high temperature requirements for radiolabelling, kinetic lability leading to in vivo decomplexation, and insufficient radiolabelling efficiency.
Innovation Solution
Development of bispidine derivatives as ligands that can complex large metal ions under mild conditions, offering high kinetic stability and allowing for quantitative radiolabelling of Lutetium and Actinium ions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If DOTA is used as a ligand for radiolabelling, then the complexation can be carried out under mild conditions, but high temperatures of 80°C are required to achieve complete radiolabelling
Solution Approach 1:
The patent modifies the ligand structure by introducing additional coordinating atoms (nitrogen and oxygen) in specific positions around the bispidine core, changing the coordination parameters to achieve complete radiolabelling at lower temperatures (20-25°C) while maintaining high efficiency
2Speed
If DTPA is used as a ligand, then fast complexation is achieved, but kinetic lability leads to in vivo decomplexation
Solution Approach 1:
The patent creates a composite ligand structure combining the fast-complexing ability of open-chain DTPA-like structures with the kinetic stability of cyclic macrocyclic frameworks, achieving both rapid complexation and high in vivo stability through the synergistic arrangement of coordinating atoms
Solution Approach 2:
The ligand design incorporates flexible side chains that can dynamically adjust during complexation to achieve rapid binding, while the rigid bispidine core provides the structural framework for high kinetic stability, combining dynamic and static properties in one molecule
3Productivity
If Macropa is used for radiolabelling with lanthanides, then complexation is achieved, but conversion is insufficient and requires prolonged heating
Solution Approach 1:
The patent introduces specific local coordinating groups (pyridine rings, carboxylic acid groups, hydroxyl groups) at strategic positions around the bispidine core, creating localized high-affinity binding sites that dramatically enhance lanthanide complexation efficiency and reduce required heating time
4Reliability
If existing ligands are used, then radiolabelling can be performed, but the compounds show insufficient stability to human serum albumin
Solution Approach 1:
The ligand is divided into distinct functional segments: a stable bispidine core for serum albumin binding, coordinating groups for metal complexation, and modular side chains for biomolecule conjugation, allowing each segment to independently optimize its function while maintaining overall stability
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 bispidine derivatives provide high radiolytic and chemical stability, enable fast and efficient radiolabelling at mild conditions with high radiochemical purity (>95%), and maintain stability in human serum, preventing transmetalation.
Implementation Method 1
the compounds according to the invention have shown a high stability to human serum albumin as well as faster radiolabeling at mild conditions with radiochemical purities of >95%
Data Source
AI summary
The invention relates to a compound of general formula (I) in which X is selected from consisting of a first group, a second group or a third group, wherein the first group consists of and, the second group consists of and, and the third group consists of and; Y is a group of general formula II or of general formula (III) if X is selected from the first group, Z is selected from a first group consisting of if X is selected from the second group, Z is selected from a second group consisting of and; if X is selected from the third group, Z is selected from a third group consisting of and, R1 and R2 independently are selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, -C(O)-O-Ra, -C(O)-NRbRc, -C(O)-C(Ra)2-NRbRc, and -C(O)-NRb-(CH2)n-C(O)- O-Ra, wherein Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted aryl group and a group L and n is an integer from 1 to 10; R3 is selected from the group consisting of oxygen, sulfur, =NRd, and =CHRd, wherein Rd is selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted aryl group, -O-Re, -C(O)-O-Re, -C(O)-NRfRg, and a group L, Re is hydrogen or a substituted or unsubstituted C1-C6 alkyl group, and Rf and Rg each independently are hydrogen or a substituted or unsubstituted C1-C6 alkyl group; and R4 is selected from the group consisting of -ORh, -SRh, -NHRh and -CH2Rh, wherein Rh is selected from the group consisting of hydrogen, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 alkenyl group, a substituted or unsubstituted C1-C6 alkynyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted aryl group, -C(O)-(CH2)m-Rk, -C(O)- (CH2)m-NRmRn, a group -A-L and a group L, Rk is selected from the group consisting of a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 heteroalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted carboxy group, Rm and Rn each independently are hydrogen or a substituted or unsubstituted C1-C6 alkyl group, and m is 0 or an integer from 1 to 10; R5 and R6 independently are selected from the group consisting of hydrogen, chloro, bromo, iodo, and O-Ro, wherein Ro is a substituted or unsubstituted C1-C6 alkyl group; A is a linker group and L is an amino acid residue or a peptide.