DREADD Agonist Compounds for Brain-Penetrant Receptor Imaging
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Solution Overview
Problem
Existing DREADD compositions and methods lack improved compounds for treating diseases or disorders, with limitations in affinity for hM3Dq and hM4Di receptors, brain penetrance, and suitability for DREAMM and theranostic applications, and issues with fluorescent reporter proteins.
Innovation Solution
Development of compounds of formula (I) with high affinity for hM3Dq and hM4Di receptors, enhanced brain penetrance, suitable for DREAMM and theranostic methods, and labeled with radioactive isotopes for imaging, eliminating the need for fluorescent reporter proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CNO or clozapine analogs are used to activate DREADD receptors, then receptor activation is achieved, but affinity for hM3Dq and hM4Di receptors is insufficient
Solution Approach 1:
The patent modifies the chemical structure of clozapine by introducing specific substituents at defined positions to create compounds with optimized pharmacological properties. This structural parameter change increases affinity for hM3Dq and hM4Di receptors while maintaining selective activation capability, directly resolving the insufficient affinity issue of conventional CNO or clozapine analogs
2Difficulty of detecting and measuring
If fluorescent reporter proteins are used to visualize DREADD location, then receptor placement can be detected post-mortem, but issues with receptor internalization, toxicity, and immune responses occur
Solution Approach 1:
The patent eliminates the need for fluorescent reporter proteins by using radioligand binding assays that directly measure receptor presence and location through radioactive ligand binding. This extraction of the fluorescent protein component removes the associated toxicity and immune response issues while maintaining the ability to detect and quantify receptor expression and placement in both live and post-mortem subjects
3Measurement precision
If compounds with short half-life like carbon-11 are used for imaging, then imaging can be performed, but theranostic methods and adjusted treatment regimens cannot be implemented
Solution Approach 1:
The patent employs radioligands with longer half-lives that allow preliminary imaging to confirm receptor expression and placement before treatment initiation. This preliminary action enables verification of accurate DREADD placement and appropriate receptor location, allowing clinicians to adjust treatment regimens based on confirmed receptor distribution before administering therapeutic compounds
4Productivity
If existing DREADD compounds are used for DREAMM, then metabolic mapping can be performed, but significant impact on brain metabolic activity occurs even without behavior effects
Solution Approach 1:
The patent develops compounds with optimized pharmacological properties that enable metabolic mapping through DREADD activation while minimizing off-target effects and impact on overall brain metabolic activity. The localized and selective activation of DREADD-expressing cells allows metabolic mapping of specific neural circuits without causing significant disruption to global brain metabolism, enabling productive research with reduced harmful effects
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
Compounds of formula (I) provide superior receptor affinity and brain penetrance, enabling reliable DREAMM and theranostic methods, and non-invasive imaging through MRI and MRS, improving treatment efficacy and reliability across species.
Implementation Method 1
compounds of formula (I) have a high affinity for hM3Dq and hM4Di receptors... It was also surprisingly discovered that compounds of formula (I) exhibit superior brain penetrance... compounds of formula (I) can be used in DREADD-assisted metabolic mapping (DREAMM)
Implementation Method 2
the compounds of formula (I) can be labeled with radioactive isotopes with sufficient half-lives that allow for successful in vivo and ex-vivo imaging... The increased half-life allows for theranostic methods... labeling of the compound of formula (I) with radioactive isotopes (and then using PET)
Implementation Method 3
enabling reliable DREAMM and theranostic methods, and non-invasive imaging through MRI and MRS
Data Source
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AI summary
Disclosed is a compound of formula (I) in which R1, R2, and R3 are as described herein. Also provided are pharmaceutical compositions comprising the compound of formula (I) and methods of using the compound of formula (I), including a method of treating a disease or disorder and a method for effectuating a G-protein coupled receptor (GPCR)-mediated response in a subject.