Anthranilic Acid Derivatives for P-gp PET Imaging
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Solution Overview
Problem
Current radiotracers for PET imaging and targeted radionuclide therapy are limited in their ability to effectively detect and quantify P-glycoprotein (P-gp) expression, leading to inadequate assessment of multidrug resistance (MDR) in cancer patients, as they exhibit low uptake and selectivity, and are hindered by the presence of radio metabolites, making them unsuitable for precise monitoring of P-gp functionality and drug resistance mechanisms.
Innovation Solution
Development of novel anthranilic acid derivatives that can act as substrates and radiotracers for ABC transporters like P-gp, MRP1, and BCRP, enabling PET imaging and targeted radionuclide therapy, and allowing for the detection of MDR pathology and assignment of P-gp as the cause of drug resistance in cancer patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current radiotracers are used for PET imaging, then imaging can be performed, but sensitivity and specificity for detecting P-gp expression are low
Solution Approach 1:
The patent modifies molecular parameters of radiotracers by changing chemical structure (using anthranilic acid derivatives with specific substituents), optimizing lipophilicity (logP values between 2-5), and adjusting molecular weight to improve P-gp substrate recognition and transport efficiency, thereby enhancing detection sensitivity and specificity
Solution Approach 2:
The patent introduces specific functional groups and substituents at particular positions on the anthranilic acid core structure (e.g., substituents at positions 2, 4, and 6 of the benzene ring) to create localized interactions with P-gp binding sites, improving both sensitivity and reliability of P-gp expression detection
2Quantity of substance
If current radiotracers are administered, then PET imaging is possible, but uptake in target tissue is low
Solution Approach 1:
The patent optimizes physical-chemical parameters including lipophilicity (logP 2-5), hydrogen bonding capacity, and molecular size to enhance passive diffusion and active transport of radiotracers into target tissues, significantly increasing radiotracer uptake and quantification accuracy
Solution Approach 2:
The patent designs radiotracers with dynamic molecular characteristics that allow conformational changes to adapt to P-gp binding sites, facilitating efficient transport across cell membranes and improving tissue uptake while maintaining accurate quantification
3Measurement precision
If current radiotracers are used, then imaging can proceed, but selectivity for P-gp is insufficient
Solution Approach 1:
The patent introduces specific substituents with distinct spatial and electronic properties (e.g., halogen atoms, alkoxy groups, alkyl chains at specific positions) that create unique local interaction patterns with P-gp binding sites, enhancing selectivity while reducing non-specific binding and metabolite interference
Solution Approach 2:
The patent stabilizes radiotracer molecules through optimized chemical structure to resist metabolic degradation, or converts potential metabolites into inactive forms that do not interfere with imaging, thereby improving P-gp detection selectivity and reducing harmful interference
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 novel anthranilic acid derivatives provide enhanced sensitivity and specificity for imaging P-gp expression, enabling non-invasive detection of MDR and guiding therapeutic strategies to improve treatment outcomes and patient quality of life by accurately identifying drug resistance mechanisms.
Implementation Method 1
These techniques rely on the use of imaging instruments that can detect radiation emitted from radiotracers administered to living subjects
Implementation Method 2
A positron-emitting radionuclide is introduced, usually by injection, and accumulates in the target tissue. As it decays it emits a positron, which promptly combines with a nearby electron resulting in the simultaneous emission of two identifiable gamma rays in opposite directions
Data Source
AI summary
The present invention is directed to a novel compound of Formula 1 wherein the radiolabeled compound of Formula 1 is capable of being used as a radiotracer in PET imaging of a targeted localized tissue and targeted radionuclide therapy of one or more conditions that may be regulated or normalized via inhibition of transporter such as Pgp, BCRP or MRP I. The novel compounds of Formula 1 can also be used as substrates for binding with one or more ABC transporters. In particular, the present invention aids in diagnosis and therapeutic treatment of MDR disorders in all forms of cancers and neurological disorders of the central nervous system. The present invention further provides methods of preparation of compounds of Formula 1 and novel intermediates used in the preparation of compounds of Formula 1.