PSMA Ligand-SIFA-Chelator Imaging Agents for Lower Hydrophobicity

Solution Overview

Problem

Existing 18F-labelled silicon fluoride acceptor (SIFA) radiopharmaceuticals face significant hydrophobicity issues, leading to unsuitable in vivo biodistribution and high unspecific binding in non-target tissues, which have not been adequately addressed in prior art.

Innovation Solution

A ligand-SIFA-chelator conjugate is developed, where a silicon-fluoride acceptor is combined with a hydrophilic chelating group, such as DOTAGA or DOTA, to reduce the hydrophobicity of the molecule, ensuring favorable in-vivo properties and targeted binding to prostate-specific membrane antigen (PSMA).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If 18F-labelled silicon fluoride acceptor radiopharmaceuticals are used for diagnostic imaging, then high affinity binding to PSMA is achieved, but high hydrophobicity causes unsuitable in vivo biodistribution and high unspecific binding in non-target tissues

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The radiopharmaceutical molecule is segmented into distinct functional modules: a hydrophilic chelator unit (DOTA or DOTAGA) and a silicon fluoride acceptor unit. This segmentation allows each module to perform its specific function independently - the chelator provides hydrophilicity and stable metal ion coordination, while the SIFA unit provides high affinity PSMA binding through fluorine-18 labeling.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates a composite radiopharmaceutical by combining two chemically distinct units: a hydrophilic chelating agent (containing DOTA or DOTAGA) and a silicon fluoride acceptor moiety. This composite structure integrates the beneficial properties of both components - the hydrophilicity and stability of the chelator with the high binding affinity of the SIFA unit - thereby resolving the contradiction between binding reliability and hydrophobicity.

Inventive Principle:

Principle #40Composite materials

2Reliability

If hydrophobic 18F-labelled SIFA radiopharmaceuticals are used, then targeted binding capability is improved, but in vivo biodistribution becomes unsuitable due to high unspecific binding in non-target tissues

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

Different regions of the radiopharmaceutical molecule are assigned different chemical properties: the chelator portion is designed to be highly hydrophilic to ensure favorable biodistribution and rapid renal clearance, while the SIFA portion maintains its hydrophobic character necessary for high affinity PSMA binding. This local differentiation of chemical properties allows the molecule to exhibit both targeted binding capability and suitable in vivo behavior.

Inventive Principle:

Principle #3Local quality

3Reliability

If silicon fluoride acceptor moiety is incorporated into the radiopharmaceutical, then high affinity PSMA binding is achieved, but kidney accumulation increases due to hydrophobicity

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The hydrophilic chelator (DOTA or DOTAGA) acts as an intermediary component that mediates between the hydrophobic SIFA unit and the aqueous biological environment. This intermediary structure reduces the overall hydrophobicity of the radiopharmaceutical, thereby decreasing unspecific binding in non-target tissues and reducing kidney accumulation while preserving the high affinity binding capability of the SIFA-PSMA interaction.

Inventive Principle:

Principle #24Intermediary (Mediator)

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 conjugate achieves reduced kidney accumulation and improved in-vivo distribution, making it suitable for diagnostic imaging and potential therapeutic applications, particularly for prostate cancer.

Implementation Method 1

one or more ligands which are capable of binding to PSMA

Methodology Applied

Scientific EffectLigand-receptor binding:

Implementation Method 2

one or more chelating groups, containing a chelated nonradioactive cation

Methodology Applied

Scientific EffectChelation:

Data Source

PatentUS12377176B2Cancer diagnostic imaging agents

Publication Date: 2025.08.05

AI summary

The present invention relates to a ligand-SIFA-chelator conjugate, comprising, within a single molecule three separate moieties: (a) one or more ligands which are capable of binding to PSMA, (b) a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon atom and a fluorine atom, and (c) one or more chelating groups, containing a chelated nonradioactive cation.