Dihydropyrrolopyrazole Compounds for Alpha-Synuclein Imaging
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Solution Overview
Problem
Current imaging agents for alpha-synuclein aggregates, such as those found in Parkinson's disease and other synucleinopathies, lack high affinity for pathological aggregates in the brain and have low selectivity over other aggregated proteins, making them inadequate for effective diagnostic imaging.
Innovation Solution
Development of novel compounds that specifically bind with high affinity to alpha-synuclein aggregates, including Lewy bodies and glial inclusions, for use in diagnostic imaging techniques like positron emission tomography (PET).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current imaging agents are used for alpha-synuclein aggregates, then imaging can be performed, but the affinity for pathological aggregates is low and selectivity over other aggregated proteins is poor
Solution Approach 1:
The imaging agent incorporates specific chemical groups and structural features that are locally optimized to interact with alpha-synuclein aggregates. The molecule contains functional groups that specifically recognize and bind to the beta-sheet structures in alpha-synuclein, while other parts of the molecule provide selectivity against other aggregated proteins through steric and electronic effects.
Solution Approach 2:
The imaging agent is designed as a composite structure combining multiple functional components: a core binding unit that recognizes alpha-synuclein, linker groups that provide spatial orientation, and imaging moieties (such as fluorescent dyes or radiolabels) that enable detection. This composite design allows simultaneous achievement of high affinity and high selectivity.
2Measurement precision
If imaging agents with high affinity to alpha-synuclein aggregates are developed, then diagnostic accuracy improves, but the complexity of compound design and synthesis increases
Solution Approach 1:
The imaging agent is designed as a segmented molecule with distinct functional modules: a binding domain that provides affinity for alpha-synuclein, a linker region that connects functional elements, and an imaging domain that provides detectability. This segmentation allows independent optimization of each function and simplifies the synthesis process by enabling modular assembly of pre-synthesized components.
Solution Approach 2:
The core binding unit is designed to be universal for recognizing beta-sheet structures in various amyloid proteins, while specific substituents provide selectivity for alpha-synuclein. This multi-functional design allows the same molecular scaffold to be used for different imaging applications by simply changing the imaging moiety or minor substituents, reducing overall design complexity.
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
These compounds enable accurate imaging and quantification of alpha-synuclein aggregates in the brain, potentially facilitating early diagnosis, monitoring disease progression, and predicting treatment responsiveness in synucleinopathies.
Implementation Method 1
compounds that specifically bind with high affinity to alpha-synuclein aggregates, including Lewy bodies and glial inclusions
Data Source
AI summary
The present invention relates to novel compounds of formula (I), or a detectably labelled compound, stereoisomer, racemic mixture, pharmaceutically acceptable salt, hydrate, or solvate thereof, that can be employed in the imaging of alpha-synuclein aggregates and determining an amount thereof. Furthermore, the compounds can be used for diagnosing a disease, disorder or abnormality associated with an alpha-synuclein aggregates, including, but not limited to, Lewy bodies, Lewy neurites and/or cytoplasmic glial inclusions (such as Parkinson's disease), determining a predisposition to such a disease, disorder or abnormality, prognosing such a disease, disorder or abnormality, monitoring the evolution of the disease in a patient suffering from such a disease, disorder or abnormality, monitoring the progression of such a disease, disorder or abnormality and predicting responsiveness of a patient suffering from such a disease, disorder or abnormality to a treatment thereof.