Minigastrin Derivatives for CCK-2 Receptor Targeting
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Solution Overview
Problem
Radiolabelled peptides targeting the CCK-2 receptor for cancer therapy face challenges due to high kidney uptake and rapid methionine oxidation, leading to decreased receptor affinity and production issues, limiting their clinical application for medullary thyroid carcinomas and other CCK-2 receptor-positive tumors.
Innovation Solution
Development of minigastrin derivatives with six D-glutamic acids or glutamines, replacing methionine with non-oxidizable norleucine and incorporating 1,4-disubstituted or 1,5-disubstituted 1,2,3-triazole modifications in the peptide sequence, along with chelators like DOTA for radiolabelling, to enhance receptor affinity, specificity, and metabolic stability, thereby reducing kidney accumulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radiolabelled gastrin analogues with six negatively charged glutamic acids are used for targeting CCK-2 receptor positive tumours, then tumour targeting capability is improved, but kidney uptake increases leading to nephrotoxicity
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of gastrin analogues - specifically replacing L-glutamic acid with D-glutamic acid or glutamine residues. This stereochemical and compositional change alters the peptide's interaction with renal tubules, significantly reducing kidney uptake while preserving CCK-2 receptor binding affinity. The structural modification transforms the harmful nephrotoxicity parameter without compromising tumour targeting capability.
2Reliability
If methionine is present in the gastrin analogue sequence, then receptor affinity is maintained, but the methionine can be oxidised easily leading to decreased receptor affinity and production issues
Solution Approach 1:
The patent extracts the problematic methionine residue from the gastrin analogue sequence and replaces it with norleucine, an oxidation-resistant amino acid with similar structural properties. This substitution removes the oxidation vulnerability while preserving the peptide's ability to bind CCK-2 receptors, solving both the stability and affinity requirements simultaneously.
3Ease of manufacture
If conventional gastrin analogues are used for radiolabelling, then production is straightforward, but the combination of high kidney uptake and methionine oxidation hampered GMP production dramatically
Solution Approach 1:
The patent applies preliminary action by pre-modifying the gastrin analogue structure during synthesis to incorporate D-glutamic acid/glutamine and norleucine residues before radiolabelling. This upfront structural optimization prevents oxidation issues and reduces kidney uptake during subsequent production and clinical use, thereby streamlining GMP manufacturing processes and improving overall production efficiency.
Data Source
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AI summary
It is therefore the objective of the present invention to provide minigastrin derivates which further improve the accumulation in CCK-2 receptor positive tumours by simultaneously very low accumulation in other organs, e.g. the kidneys. This objective is achieved according to the present invention by a minigastrin derivate having the formula: X-Z-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (Y), wherein at least one of the connecting or terminal amide bonds between, before or after the amino acids of the sequence Z, Ala, Tyr, Gly, Trp, Met, Asp, Phe and NH2 or Y (C-terminal) is replaced by a 1,4-disubstituted or a 1,5-disubstituted 1,2,3-triazole, while X stands for a chemical group attached to the peptide for the purpose of diagnostic and/or therapeutic intervention at CCK-2 receptor relevant diseases, Y stands for C-terminal modifications of the peptide, such as amide, primary and secondary amides, free carboxylic acids and carboxylic ester derivatives including but not limited to amides and esters derived from linear or branched alkyl-,alkenyl-, alkynyl- aromatic-, and heterocyclic alcohols, and Z stands for a linker or DGlu* wherein DGlu* stands for a chain of DGlu having 1 to 6 repetitions (-DGlu-to -DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-). These minigastrin derivates have a high specific internalization, excellent IC50 values and sufficient plasma stability.