Radiolabeled Risedronic Acid Chelates for Bone Lesion Imaging
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Solution Overview
Problem
Current imaging agents for bone metastasis, such as 99mTc-MDP, have low localization and display of lesions, while first-generation bisphosphonates like HEDP lack potency compared to second- and third-generation nitrogen-containing bisphosphonates, necessitating the development of compounds with better imaging quality and therapeutic effects for treating bone tumors.
Innovation Solution
A radiolabeled risedronic acid derivative, represented by Formula II, is synthesized by labeling a precursor compound (Formula I) with radionuclides like 68Ga, 111In, 89Zr, 177Lu, 225Ac, or 64Cu, using chelating agents NOTA or DOTA, to create compounds with high imaging and therapeutic potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If first-generation bisphosphonates like HEDP are used for bone imaging, then the imaging agent can be prepared, but the imaging quality and lesion localization are insufficient
Solution Approach 1:
The patent modifies the chemical structure of bisphosphonate by introducing nitrogen-containing groups (R1 and R2 substituents) and conjugating with chelating agents (NOTA, DOTA) to coordinate radionuclides. This parameter change in molecular structure enhances both the bone affinity and imaging quality, resolving the contradiction between lesion localization accuracy and imaging quality
Solution Approach 2:
The invention creates a composite radiolabeled compound combining risedronic acid derivative (for bone targeting), chelating agent (for radionuclide coordination), and radionuclide (for imaging). This composite structure integrates multiple functions: bone specificity from bisphosphonate, stable radionuclide binding from chelator, and high-quality imaging from radionuclide, simultaneously improving both lesion localization and imaging quality
2Reliability
If second- and third-generation nitrogen-containing bisphosphonates are used, then therapeutic potency is improved, but the need for additional imaging capability is created
Solution Approach 1:
The radiolabeled risedronic acid derivative serves multiple functions simultaneously: the risedronic acid core provides bone targeting and therapeutic potency through nitrogen-containing groups, while the chelating agent enables radionuclide coordination for imaging. This multi-functional design resolves the contradiction by making a single compound both therapeutically potent and imaged-capable
Solution Approach 2:
The patent merges the therapeutic function (nitrogen-containing bisphosphonate for bone tumor treatment) with the imaging function (radionuclide-chelator complex for detection) into a single integrated radiolabeled compound. This combination allows simultaneous therapeutic potency and imaging capability, eliminating the need for separate agents
3Reliability
If existing radionuclide therapy drugs are used, then bone pain relief is achieved, but the imaging quality and lesion display are insufficient
Solution Approach 1:
The patent changes the chemical parameters of existing radionuclide therapy drugs by incorporating risedronic acid derivative structure with nitrogen-containing groups and specific chelating agents. This modification maintains the bone-targeting and pain-relief efficacy while significantly improving lesion display quality through enhanced imaging characteristics of the radiolabeled compound
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 radiolabeled compounds exhibit high water solubility, in-vitro stability, and prolonged bone uptake, offering excellent performance as both imaging agents and therapeutic radiopharmaceuticals for metastatic bone tumors, with a high lesion-to-non-target ratio and improved uptake compared to existing agents.
Implementation Method 1
using chelating agents NOTA or DOTA, to create compounds with high imaging and therapeutic potential
Implementation Method 2
Second- and third-generation bisphosphonates, represented by nitrogen-containing bisphosphonates, work by competing with adenosine triphosphate (ATP) for binding to hydroxyapatite
Data Source
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AI summary
Disclosed in the present invention are a radiolabeled compound of a risedronic acid derivative, and a precursor compound thereof, and a preparation method therefor and the use, which belong to the technical field of nuclear medicine. Provided in the present invention are a precursor compound of a radiolabeled compound of a risedronic acid derivative as shown in formula (I) or a pharmaceutically acceptable salt thereof, and a radiolabeled compound of a risedronic acid derivative as shown in formula (II) or a pharmaceutically acceptable salt thereof. In the present invention, risedronic acid is creatively combined with a chelating agent to obtain NOTA-risedronic acid and DOTA-risedronic acid, and then a radionuclide is used for labelling. The radiolabeled product of the present invention has a relatively high water solubility, good in-vitro stability at room temperature, and a high plasma protein binding rate, and exhibits a relatively high and prolonged bone uptake in terms of imaging and in vivo distribution in mice; and compared to 68Ga-DOTA-ibandronic acid, the uptake of the compound of the present invention at the lesion site is twice as high.