SSTR2 Antagonists for Selective Tumor Imaging
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Solution Overview
Problem
There is a need for somatostatin peptide antagonists that strongly bind to SSTR2 while minimizing binding to other somatostatin receptors, as existing agonists may be internalized and cause unwanted side effects, and current diagnostic and therapeutic agents lack specificity for SSTR2.
Innovation Solution
Development of novel somatostatin antagonists, such as DOTA-Cpa-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2, which selectively bind to SSTR2, are not significantly internalized, and when radiolabeled, can be used for targeted cancer imaging and treatment by preferentially accumulating in tumors relative to other tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If somatostatin agonists are used to bind to SSTR2, then binding affinity is improved, but receptor internalization occurs causing unwanted side effects
Solution Approach 1:
The patent inverts the conventional agonist approach by designing antagonists that bind to SSTR2 without activating internalization. Instead of using agonists like octreotide that trigger receptor internalization and subsequent side effects, the invention employs competitive antagonists (e.g., compounds with DOTA chelators and specific peptide sequences) that occupy the binding site and prevent agonist-induced internalization, thereby maintaining binding affinity while eliminating the harmful internalization effect
Solution Approach 2:
The patent modifies molecular parameters by changing the chemical structure from agonist to antagonist configurations. Specific structural modifications include incorporating DOTA chelators, altering amino acid sequences (e.g., using Cpa, DAph(Cbm), DTyr residues), and adjusting the peptide backbone to create compounds that bind with high affinity to SSTR2 but do not trigger the conformational changes required for internalization
2Reliability
If somatostatin antagonists are designed to bind strongly to SSTR2, then selectivity is improved, but binding affinity to other SSTR subtypes may increase
Solution Approach 1:
The patent applies local quality by designing antagonists with specific structural features that target SSTR2's unique binding pocket characteristics. The antagonists incorporate specific amino acid residues (e.g., DAph(Cbm) at position 7, DTyr at position 13) and DOTA chelator configurations that form selective interactions with SSTR2's extracellular domain, ensuring high selectivity while maintaining strong binding affinity only for the target subtype
3Measurement precision
If radiolabeled agonists are used for diagnostic imaging, then tumor detection is improved, but non-specific uptake in normal tissues occurs
Solution Approach 1:
The patent inverts the diagnostic approach by using radiolabeled antagonists instead of agonists. The antagonists (e.g., 68Ga-DOTA-Cpa-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) bind to SSTR2 on tumor cells without triggering internalization, allowing sustained extracellular binding and high tumor-to-background ratios. This prevents the non-specific uptake in normal tissues that occurs with agonists, as the antagonists remain bound to the cell surface and do not internalize in non-tumor tissues
Data Source
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AI summary
Described herein are somatostatin analogs that are preceptor antagonists oft the somatostatin preceptor, including SSTR2-selective antagonists. Related compounds, kits and methods, including antagonists complexed with or conjugated to radioactive nuclides and uses thereof. The antagonists of the invention are useful in diagnosing and treating neoplastic and non-neoplastic mammalian diseases.