Radiolabeled Cholesterol Derivatives With Improved Metabolic Stability
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Solution Overview
Problem
The rapid metabolization of cholesterol limits its therapeutic use, and existing cholesterol derivatives lack superior stability and effective pharmacokinetic/pharmacodynamic properties for treating infections and diseases associated with decreased cholesterol levels.
Innovation Solution
Development of deuterated and radiolabeled cholesterol derivatives with specific chemical modifications, including stealth polymers like PEG, and incorporation of isotopes such as 18F, 131I, and 124I, to enhance stability and enable detection via PET/CT, providing improved pharmacokinetic and pharmacodynamic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cholesterol is used for therapeutic purposes, then it can counteract infections by altering cellular properties, but its rapid metabolization limits its therapeutic use
Solution Approach 1:
The patent applies parameter changes by deuterating specific positions of the cholesterol molecule (replacing hydrogen with deuterium at positions 24, 25, 26, and 27). This isotopic substitution alters the metabolic stability parameter of cholesterol, slowing down its metabolization rate while preserving its therapeutic ability to counteract bacterial virulence factors like pneumolysin.
Solution Approach 2:
The invention creates composite structures by combining deuterated cholesterol with stealth polymers such as PEG (polyethylene glycol). This composite approach enhances the stability and pharmacokinetic properties of the cholesterol derivative, protecting it from rapid metabolization while maintaining its biological activity.
2Duration of action of stationary object
If cholesterol derivatives are developed to improve stability, then they gain superior pharmacokinetic properties, but existing derivatives lack effective pharmacokinetic and pharmacodynamic properties for treating infections
Solution Approach 1:
The patent applies local quality by selectively deuterating only specific positions (24, 25, 26, 27) of the cholesterol molecule rather than the entire structure. This localized modification optimizes metabolic stability at critical positions while preserving the essential pharmacodynamic properties needed for anti-infective activity.
Solution Approach 2:
The invention changes physical and chemical parameters of cholesterol derivatives through deuterium substitution and PEGylation, optimizing both stability and pharmacodynamic effectiveness. The deuterated positions and polymer attachments are carefully selected to enhance half-life and reduce metabolization without compromising the molecule's ability to interact with bacterial virulence factors.
3Measurement precision
If radiolabels are incorporated into cholesterol derivatives, then detection via PET/CT is enabled, but the compounds require complex synthesis and labeling procedures
Solution Approach 1:
The patent applies preliminary action by pre-installing labeling groups (such as hydroxyl or carboxyl groups at specific positions) during the deuterated cholesterol synthesis. These pre-positioned functional groups are optimized for subsequent radiolabeling with isotopes like 18F, 131I, or 124I, streamlining the overall process and reducing synthesis complexity.
Solution Approach 2:
The invention uses stealth polymers like PEG as intermediaries that can incorporate radiolabels. The PEG chain serves as a flexible linker that connects the deuterated cholesterol core to radiometal chelators or radioactive isotopes, enabling detection while maintaining the stability and pharmacokinetic advantages of the deuterated structure.
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 modified cholesterol derivatives exhibit enhanced stability and effectiveness in treating infections and diseases, allowing for personalized therapy and drug monitoring, and serve as additives for nanomedicines.
Implementation Method 1
deuterated substituted cholesterol derivatives according to the invention have essentially better pharmacokinetic and/or pharmacodynamic properties than the undeuterated and/or unlabeled radio active compounds
Implementation Method 2
The isotopes are radio labeled and/or labelled isotopes, namely 18F, 131I and 124I... their radiolabels allow detection via positron emission tomography (PET) combined with computed tomography (CT)
Implementation Method 3
Development of deuterated and radiolabeled cholesterol derivatives with specific chemical modifications, including stealth polymers like PEG
Data Source
AI summary
The invention concerns synthesis of isotope labeled cholesterol derivatives as diagnostic agents. The isotopes are radio labeled and/or labelled isotopes, namely 18F, and/or 131I, and/or 124I , and/or deuterium. In addition, the invention concerns the use of radiolabeled cholesterol derivatives as well as their physiologically tolerated salts for the preparation of pharmaceutical drugs for the treatment of infectious diseases, particularly pneumonia or septic cardiomyopathy, but also other diseases associated with decreased cholesterol levels (hypercholesterinemia), e.g. Smith-Lemli-Opitz syndrome. In a further addition, the invention discloses pharmaceutical formulation containing radiolabeled cholesterol derivatives as well as their physiologically tolerated salts for the treatment of infectious diseases, particularly pneumonia or septic cardiomyopathy, but also other diseases associated with decreased cholesterol levels (hypercholesterinemia), e.g. Smith-Lemli-Opitz syndrome.