PSMA-Targeted Peptide-Urea Derivatives for Imaging and Therapy
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Solution Overview
Problem
Existing peptide-urea derivatives for prostate cancer diagnosis and treatment lack structural diversity, leading to unsatisfactory pharmacokinetics, prolonged retention in non-target organs like the kidney, and insufficient retention on target tumor cells.
Innovation Solution
A novel peptide-urea derivative with specific ring structures and chelating agents is developed, enhancing uptake and retention on target cells while reducing accumulation in non-target organs, enabling both diagnostic imaging and therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If existing peptide-urea derivatives are used for prostate cancer imaging and treatment, then PSMA targeting capability is achieved, but the retention time in non-target organs like kidney is prolonged causing potential harm
Solution Approach 1:
The patent introduces different ring structures (L1 and L2 moieties) with specific properties at different positions of the peptide-urea derivative molecule. L1 is a 5-12 membered carbon heterocyclic ring or heteroaromatic ring, while L2 is a 5-12 membered carbocyclic ring, heteroaromatic ring, or heterocyclic ring. These local structural variations optimize the molecule's interaction with PSMA in target tissues while reducing non-specific binding in non-target organs like kidneys, thereby improving local quality of the radiopharmaceutical's biodistribution.
Solution Approach 2:
The patent systematically varies multiple parameters including ring size (5-12 members), ring type (carbocyclic, heterocyclic, aromatic), substitution patterns (R1-1, R1-2, R2-1, R2-2, R2-3, R2-4 groups), and linker configurations (L3-L5). These parameter changes create a library of derivatives with optimized pharmacokinetic properties, achieving faster clearance from non-target organs while maintaining target retention.
2Duration of action of moving object
If existing peptide-urea derivatives are used, then diagnostic imaging capability is provided, but the retention time on target tumor cells is insufficient
Solution Approach 1:
The patent creates composite molecular structures combining peptide-urea core with specific ring systems (L1 and L2) and chelating agents. This composite approach integrates multiple functional elements: the peptide-urea provides PSMA binding affinity, the ring structures optimize pharmacokinetics and stability, and the chelating agents enable radiometal incorporation. The synergistic combination achieves both high target retention for prolonged imaging and high measurement precision through optimized radiotracer properties.
3Reliability
If structural diversity is increased in peptide-urea derivatives, then pharmacokinetics are improved, but device complexity increases
Solution Approach 1:
The patent divides the radiopharmaceutical molecule into distinct functional segments: the peptide-urea core (providing PSMA targeting), L1 ring structure (optimizing one aspect of pharmacokinetics), L2 ring structure (optimizing another aspect), L3-L5 linkers (providing flexibility and spacing), and chelating agents (enabling radiometal binding). This segmentation allows independent optimization of each module while maintaining overall molecular reliability and desired pharmacokinetic profile.
Solution Approach 2:
The patent explores structural diversity not by increasing complexity within a single dimension but by transitioning to another dimension of molecular design - incorporating spatially distinct ring systems at specific positions (L1 at N-terminal, L2 at C-terminal) rather than increasing chain length or adding random substituents. This dimensional approach to structural variation achieves improved pharmacokinetics through controlled three-dimensional architecture rather than simple complexity increase.
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 derivative achieves improved targeting and retention on PSMA-positive prostate cancer cells, reducing non-target organ uptake and extending residence time, integrating diagnosis and treatment effectively.
Implementation Method 1
PSMA is a type II transmembrane glycoprotein, also known as glutamic acid carboxypeptidase, which is a specific molecular marker of prostate cancer. It is expressed in a very small amount in kidney, small intestine, and brain tissue, and the expression level in tumor tissue is much higher than the expression in normal tissues. A representative ligand of PSMA is a peptide derivative such as Glu-urea-Lys (GUL) or Glu-urea-Cys (GUC).
Implementation Method 2
The radiopharmaceuticals currently used for prostate cancer-specific imaging use PSMA specific ligands as targeting vectors... These diagnostic imaging methods have recently been widely used due to the dramatic improvement in image quality via the development of SPECT-CT/MRI and PET-CT/MRI that combine CT and MRI with SPECT or PET. The radioisotopes used for labeling peptides are mainly α-ray-emitting radionuclides, β-ray-emitting radionuclides, γ-ray-emitting radionuclides, and positron beam-emitting radionuclides. Among the radioisotopes, α-ray-emitting radionuclides and β-ray-emitting radionuclides are used for therapy, and γ-ray-emitting radionuclides and positron beam-emitting radionuclides are used for diagnosis by nuclear imaging.
Implementation Method 3
The radioisotopes used for labeling peptides are mainly α-ray-emitting radionuclides, β-ray-emitting radionuclides, γ-ray-emitting radionuclides, and positron beam-emitting radionuclides. Among the radioisotopes, α-ray-emitting radionuclides and β-ray-emitting radionuclides are used for therapy, and γ-ray-emitting radionuclides and positron beam-emitting radionuclides are used for diagnosis by nuclear imaging.
Implementation Method 4
The radioisotopes used for labeling peptides are mainly α-ray-emitting radionuclides, β-ray-emitting radionuclides, γ-ray-emitting radionuclides, and positron beam-emitting radionuclides. Among the radioisotopes, α-ray-emitting radionuclides and β-ray-emitting radionuclides are used for therapy...
Implementation Method 5
The radioisotopes used for labeling peptides are mainly α-ray-emitting radionuclides, β-ray-emitting radionuclides, γ-ray-emitting radionuclides, and positron beam-emitting radionuclides. Among the radioisotopes, α-ray-emitting radionuclides and β-ray-emitting radionuclides are used for therapy...
Implementation Method 6
There are generally two methods for radioactive isotope labeling of ligands: the method of directly attaching the ligand to the radioisotope, or the method of chelating the radioisotope by the ligand through bifunctional chelating agents (BFCA) such as DTPA, DOTA, TETA, HYNIC, N2S2, and MAG3. The method using a bifunctional chelating agent (BFCA) is mainly used for the labeling of various metal radioisotopes...
Data Source
AI summary
A peptide-urea derivative, a pharmaceutical composition containing same and an application thereof are provided, the derivative being as shown in formula I. The derivative can be used for preoperative imaging diagnosis and grading of PSMA-positive prostate cancer, and can also be used for the treatment of various types and stages of prostate cancer, achieving the integration of diagnosis and treatment, and having broad application prospects.