Rigidified Macrocyclic Complexes for Stable Alpha-Emitters
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Solution Overview
Problem
Current macrocyclic complexes used in targeted radiotherapy, such as DOTA, exhibit instability with larger radionuclides like actinium, radium, bismuth, and lead isotopes, leading to dissociation and reduced selectivity for targeted tissue, resulting in toxicity to non-targeted tissues.
Innovation Solution
Development of new macrocyclic complexes that are more stable and can complex with alpha-emitting radionuclides at room temperature, providing higher radiochemical yields and improved targeting of cancer cells with reduced toxicity to non-targeted tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional macrocyclic complexes like DOTA are used with larger radionuclides, then the complexation can be performed with existing protocols, but the complexes exhibit instability leading to dissociation and reduced selectivity
Solution Approach 1:
The patent modifies the macrocyclic ligand structure by changing parameters such as ring size, number of donor atoms, and coordination geometry to create new macrocyclic complexes with enhanced stability constants for larger radionuclides, thereby preventing dissociation and reducing toxicity to non-targeted tissues
Solution Approach 2:
The patent develops composite macrocyclic ligand systems that combine multiple donor atoms and coordinating groups within a single macrocyclic framework, creating synergistic effects that enhance complex stability with larger radionuclides beyond what traditional DOTA can achieve
2Ease of manufacture
If traditional macrocyclic complexes are used, then established protocols can be followed, but elevated temperatures are required for complexation which may affect radionuclide stability
Solution Approach 1:
The patent modifies the macrocyclic ligand structure to have enhanced inherent stability and optimized coordination properties that allow complexation to proceed efficiently at room temperature or lower temperatures, eliminating the need for elevated temperature processing that could compromise radionuclide stability
3Productivity
If traditional macrocyclic complexes are used, then existing synthesis methods can be applied, but radiochemical yields are lower and targeting selectivity is reduced
Solution Approach 1:
The patent optimizes macrocyclic ligand parameters including ring size, donor atom types and arrangements, and substituent groups to maximize both radiochemical yield through improved complexation efficiency and targeting selectivity through enhanced stability and reduced dissociation
Data Source
AI summary
The present technology provides compounds, as well as compositions including such compounds, useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing e.g., a glypican-3 (GPC3) receptor and/or prostate specific membrane antigen, where the compounds are represented by the Formulas (I) or a pharmaceutically acceptable salt and/or solvate thereof, (II) or a pharmaceutically acceptable salt and/or solvate thereof, (III) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M1 is independently at each occurrence a radionuclide. Equivalents of such compounds are also disclosed.