BBB-Permeable PET Probes for GSK-3 Imaging

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Solution Overview

Problem

There is an unmet need for a noninvasive, selective, and blood brain barrier (BBB) permeable positron emission tomography (PET) imaging probe to study glycogen synthase kinase-3 (GSK-3) in neurodegenerative diseases, as existing attempts have resulted in compounds that are either not or minimally permeable to the BBB or have significant off-target binding.

Innovation Solution

Development of compounds of specific formulas, where R1, R2, R3, and R4 are selected from various alkyl, haloalkyl, hydroxyalkyl, and phenyl groups, with at least one atom replaced with a positron emitter like 18F, which are designed to be BBB permeable and selective PET probes for GSK-3.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing PET probe compounds are used, then GSK-3 binding affinity is achieved, but blood brain barrier permeability is insufficient

Engineering Contradiction:

ImproveGSK-3 binding affinityVSAvoidblood brain barrier permeability

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies molecular parameters of PET probes by introducing specific substituents (R1-R6 groups including alkyl, haloalkyl, hydroxyalkyl, phenyl, etc.) and adjusting physical properties such as lipophilicity and molecular size to enhance blood brain barrier permeability while maintaining GSK-3 binding affinity through optimized binding moieties

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates composite molecular structures combining multiple functional elements: GSK-3 binding moieties, BBB-permeable structural features (such as specific aromatic rings and alkyl chains), and positron emitter labels (18F, 11C, 13N, 15O), achieving simultaneous optimization of binding affinity, permeability, and detectability

Inventive Principle:

Principle #40Composite materials

2Reliability

If existing PET probe compounds are used, then GSK-3 targeting is achieved, but off-target binding occurs

Engineering Contradiction:

ImproveGSK-3 targetingVSAvoidoff-target binding

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent introduces selective binding moieties with specific molecular features (such as particular aromatic ring arrangements, amino acid-mimicking structures, or kinase-specific interaction sites) that provide high affinity for GSK-3 while avoiding interaction with other proteins, achieving local optimization of binding specificity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs molecular mimics that replicate key binding interactions of endogenous GSK-3 substrates or inhibitors, creating probes that copy the binding mode of known GSK-3 ligands to ensure selective targeting while avoiding off-target effects

Inventive Principle:

Principle #26Copying

3Ease of operation

If noninvasive imaging is implemented, then GSK-3 study in neurodegenerative diseases is enabled, but selective and BBB permeable probes are absent

Engineering Contradiction:

Improvenoninvasive imaging capabilityVSAvoidprobe selectivity and BBB permeability

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent designs multi-functional PET probes that simultaneously achieve: (1) high GSK-3 binding affinity through specific binding moieties, (2) blood brain barrier permeability through optimized molecular structure (lipophilicity, size, charge), and (3) detectability through positron emitters, enabling noninvasive imaging of GSK-3 in neurodegenerative diseases

Inventive Principle:

Principle #6Universality (Multi-functionality)

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 developed PET probes demonstrate high nanomolar affinity towards GSK-3α and GSK-3β with minimal binding to competing proteins, and show significant brain uptake in preclinical studies, indicating their potential for noninvasive imaging and understanding GSK-3's role in neurodegenerative diseases.

Implementation Method 1

The developed PET probes demonstrate high nanomolar affinity towards GSK-3α and GSK-3β with minimal binding to competing proteins

Methodology Applied

Scientific EffectBinding affinity:

Implementation Method 2

at least one atom in R1 is replaced with a positron emitter. In one embodiment, the positron emitter is 18F

Methodology Applied

Scientific EffectPositron emission: Radioactive Decay

Data Source

PatentUS20250025581A1Medical Imaging of Glycogen Synthase Kinase-3 with a PET Probe

Publication Date: 2025.01.23 MAYO FOUNDATION FOR MEDICAL EDUCATION & RESEARCH

AI summary

Disclosed are compounds of formula (1), formula (2), formula (75), formula (80) and formula (90): wherein R1, R2, R3, R4, and R5 can be selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted haloalkyl, substituted haloalkyl, unsubstituted hydroxyalkyl, substituted hydroxyalkyl, benzyl, phenyl, substituted phenyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted cycloalkyl, substituted cycloalkyl, hydroxy, unsubstituted alkoxy, substituted alkoxy, unsubstituted haloalkoxy, substituted haloalkoxy, unsubstituted phenoxy, substituted phenoxy, unsubstituted sulfonyloxy, substituted sulfonyloxy, carbonyl, carboxy, unsubstituted amino, substituted amino, unsubstituted amido, and substituted amido, and wherein at least one atom in R1 is replaced with a positron emitter. Also disclosed are methods for in vivo imaging of a subject using the compound of formula (1) or formula (2) or formula (75) or formula (80) or formula (90).