Functionalized Bisaminothiol Chelators for Stable 99mTc PSMA Complexes
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Solution Overview
Problem
Existing 99mTc-labeled PSMA-ligands for SPECT imaging suffer from slow distribution, high liver uptake, and slow clearance, leading to adverse effects due to radiotoxicity and inferior diagnostic performance compared to PET-nuclides, with HYNIC chelating moieties causing instability and undesired side products.
Innovation Solution
Development of functionalized bisaminothiol derivatives that form stable complexes with metals like technetium and rhenium, incorporating a urea-based pharmacophore and amino acid sequences as ligands for prostate-specific membrane antigen (PSMA), allowing for improved pharmacokinetics and diagnostic/therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If HYNIC chelating moieties are used in 99mTc-labeled PSMA-ligands, then the complexes can be formed, but the complexes exhibit instability and form undesired side products
Solution Approach 1:
The patent changes the chemical parameters of the chelating moiety by replacing HYNIC with a bisaminothiol derivative featuring a specific six-membered ring structure containing two nitrogen and two sulfur atoms. This structural parameter change results in improved complex stability with technetium and reduced formation of undesired side products while maintaining PSMA binding activity.
Solution Approach 2:
The invention uses a composite chelating structure combining amino acid residues (such as cysteine, methionine, histidine) with a six-membered ring containing nitrogen and sulfur atoms. This composite molecular design creates a synergistic effect that enhances complex stability and reduces harmful side reactions compared to simple chelators like HYNIC.
2Loss of time
If early 99mTc-labeled PSMA-ligands are used, then SPECT imaging can be performed, but the compounds exhibit slow distribution and high liver uptake
Solution Approach 1:
The patent introduces local structural modifications at the chelating site and linker regions of the PSMA-ligand molecules. Specific amino acid sequences and the six-membered ring chelator structure create localized chemical properties that optimize pharmacokinetic behavior, resulting in faster distribution and reduced liver uptake compared to early generation compounds.
3Productivity
If 99mTc-labeled PSMA-ligands are used for therapeutic application, then treatment can be administered, but the compounds exhibit slow clearance and high uptake in off-target organs
Solution Approach 1:
The invention modifies the pharmacokinetic parameters of the PSMA-ligand by changing the chelator structure to a bisaminothiol derivative with a six-membered ring. This parameter change accelerates clearance rates and reduces accumulation in off-target organs, thereby decreasing radiotoxicity while maintaining therapeutic efficacy.
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 bisaminothiol derivatives exhibit faster pharmacokinetic properties with high tumor uptake and low non-target organ uptake, enabling early imaging and therapeutic applications with reduced radiotoxicity, comparable to PET tracers like 68Ga-PSMA-11.
Implementation Method 1
functionalized bisaminothiol derivatives that form stable complexes with metals like technetium and rhenium
Implementation Method 2
incorporating a urea-based pharmacophore and amino acid sequences as ligands for prostate-specific membrane antigen (PSMA)
Data Source
AI summary
A compound of general formula Iwhere A is a chelator selected from the group ofk is independently at each occurrence 0, 1, or 2;m is independently at each occurrence 1, 2, 3, 4 or 5;n is independently at each occurrence 0, 1, 2 or 3;p is independently at each occurrence 1, 2 or 3;q is independently at each occurrence 1, 2 or 3;u is independently at each occurrence 0 or 1;X and Y are substituted or unsubstituted amino acids;L is a bifunctional linker selected from group ofwhere v, x, and y are independently of each other 0, 1, 2, or 3 and z is 0, 1, 2, 3, 4 or 5; and R is H, methyl or ethyl.