Multimeric Gd(III) PSMA Inhibitors for Sensitive Imaging and Radiotherapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current MR imaging technologies face limitations in sensitivity for molecular imaging due to the low concentration of Gd(III)-based contrast agents, requiring high local concentrations of biological targets, and existing radiotherapy methods using radiolabeled antibodies face challenges such as prolonged circulation times and unpredictable biological effects.
Innovation Solution
Development of low molecular weight, high-affinity metal/radiometal-labeled PSMA inhibitors that combine a PSMA targeting moiety with multimeric Gd(III) agents for enhanced MR imaging and radiotherapy, utilizing compounds of Formula (I) with varying numbers of Gd-chelates to optimize relaxometric behavior and binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If Gd(III)-based contrast agents are used for MR imaging, then T1-weighted positive contrast is provided, but sensitivity remains a limiting factor and high local concentrations of biological targets are required
Solution Approach 1:
The patent combines multiple Gd(III) chelate units into a single multimeric contrast agent molecule, merging several contrast-generating units to amplify the MR signal per molecule and reduce the required concentration of biological targets
Solution Approach 2:
The patent modifies the relaxivity parameter of Gd(III) contrast agents by creating multimeric structures with multiple Gd-chelates, thereby changing the signal generation capacity and improving detection sensitivity
2Reliability
If radiolabeled antibodies are used for radiotherapy, then PSMA-targeted treatment is achieved, but prolonged circulation times and unpredictable biological effects occur
Solution Approach 1:
The patent segments the large antibody molecule into smaller peptide or small molecule fragments that retain PSMA-targeting capability, resulting in faster clearance and reduced circulation time while maintaining treatment efficacy
Solution Approach 2:
The patent extracts only the essential PSMA-binding domain from the full antibody, removing the Fc region and other non-essential portions that contribute to prolonged circulation, thereby achieving faster clearance while preserving target specificity
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 approach provides improved MR sensitivity and specificity for PSMA-expressing tumors, allowing for effective imaging and radiotherapy with rapid clearance from the body, reducing side effects and enhancing treatment efficacy.
Implementation Method 1
Gd(III)-based contrast agents are widely accepted by clinicians because they are easy to administer and provide T1-weighted, positive contrast
Implementation Method 2
utilizing compounds of Formula (I) with varying numbers of Gd-chelates to optimize relaxometric behavior and binding affinity
Implementation Method 3
Metal/radiometal-labeled PSMA inhibitors for PSMA-targeted imaging and radiotherapy
Data Source
AI summary
Low-molecular weight gadolinium (Gd)-based MR contrast agents for PSMA-specific T1-weighted MR imaging are disclosed. The (Gd)-based MR contrast agents exhibit high binding affinity for PSMA and exhibit specific T1 contrast enhancement at PSMA+ cells. The PSMA-targeted Gd-based MR contrast agents can be used for PSMA-targeted imaging in vivo. 86Y-labeled PSMA-binding ureas also are provided, wherein the PSMA-binding ureas also are suitable for use with other radiotherapeutics.