Related Experiment Video
Updated: Mar 22, 2026
Quantifying the Binding Interactions Between CuII and Peptide Residues in the Presence and Absence of Chromophores
Published on: April 5, 2022
The influence of different metal-chelate conjugates of pentixafor on the CXCR4 affinity
Andreas Poschenrieder1, Margret Schottelius2, Markus Schwaiger3
1Pharmaceutical Radiochemistry, Technical University Munich, Walther-Meißner-Str.3, 85748, Garching, Germany. a.poschenrieder@tum.de.
Background:
The overexpression of the chemokine receptor 4 (CXCR4) in different epithelial, mesenchymal, and hematopoietic cancers makes CXCR4 an attractive diagnostic and therapeutic target. However, targeting the CXCR4 receptor with small cyclic pentapeptide-based radiopharmaceuticals remains challenging because minor structural modifications within the ligand-linker-chelate structure often significantly affect the receptor affinity. Based on the excellent in vivo properties of CXCR4-directed pentapeptide [(68)Ga]pentixafor (cyclo(-D-Tyr-N-Me-D-Orn(AMB-DOTA)-L-Arg-L-2-Nal-Gly-)), this study aims to broaden the spectrum of applicable (radio)metal-labeled pentixafor analogs.
Methods:
Cyclic pentapeptides, based on the pentixafor scaffold, were synthesized by a combined solid- and solution-phase peptide synthesis. The CXCR4 receptor affinities of the cold reference compounds were determined in competitive binding assays using CXCR4-expressing Jurkat T - cell leukemia cells and [(125)I]FC131 as the radioligand.
Results:
Metalated pentixafor derivatives with cyclic and acyclic chelators were synthesized by solid-phase peptide synthesis and evaluated in vitro. The resulting CXCR4 affinities (IC50) were highly dependent on the chelator and metal used. Two pentapeptides, Ga-NOTA and Bi-DOTA conjugates, offer an improved affinity compared to [(68)Ga]pentixafor.
Conclusions:
Based on the pentapeptide [(68)Ga]pentixafor, a broad range of metal-labeled analogs were investigated. The affinities of the new compounds were found to be strongly dependent on both the chelator and the metal used. Bi-labeled pentixafor showed high receptor affinity and seems to be a promising ligand for further preclinical evaluation and future α-emitter-based endoradiotherapy.
Insights
Researchers explored new metal-labeled analogs of the CXCR4-targeting drug pentixafor. Bismuth-labeled pentixafor showed high receptor affinity, indicating potential for future cancer therapies.
Area of Science:
- Oncology
- Radiopharmaceutical Chemistry
- Molecular Imaging
Background:
- Chemokine receptor 4 (CXCR4) is overexpressed in many cancers, making it a key diagnostic and therapeutic target.
- Developing CXCR4-targeting radiopharmaceuticals is challenging due to ligand-linker-chelate structure sensitivity.
- Pentixafor is a known CXCR4-targeting pentapeptide with favorable in vivo properties.
Purpose of the Study:
- To synthesize and evaluate novel (radio)metal-labeled pentixafor analogs.
- To investigate the impact of different chelators and metals on CXCR4 affinity.
- To identify promising candidates for preclinical development and endoradiotherapy.
Main Methods:
- Synthesis of cyclic pentapeptides based on the pentixafor scaffold using combined solid- and solution-phase peptide synthesis.
- Determination of CXCR4 receptor affinities via competitive binding assays using Jurkat T-cell leukemia cells and [(125)I]FC131.
- In vitro evaluation of metalated pentixafor derivatives with various cyclic and acyclic chelators.
Main Results:
- Synthesized and evaluated metalated pentixafor derivatives with diverse chelators.
- CXCR4 affinities (IC50) were significantly influenced by the chelator and metal used.
- Ga-NOTA and Bi-DOTA conjugates demonstrated improved affinity over [(68)Ga]pentixafor.
Conclusions:
- A wide array of metal-labeled pentixafor analogs were successfully investigated.
- Receptor affinity is highly dependent on the specific chelator and metal combination.
- Bismuth-labeled pentixafor exhibits high receptor affinity, showing promise for preclinical studies and alpha-emitter-based endoradiotherapy.
More Related Videos
14:44Structure and Coordination Determination of Peptide-metal Complexes Using 1D and 2D 1H NMR
Published on: December 16, 2013
06:56A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
Published on: March 10, 2018
Related Concept Videos
01:19Complexation Equilibria: The Chelate Effect
01:22EDTA: Chemistry and Properties
00:56Extraction: Advanced Methods
02:51Metal-Ligand Bonds
In these complexes, transition metals form coordinate covalent bonds, a kind of Lewis acid-base interaction in which both of the electrons in the bond are contributed by a donor (Lewis base) to an electron acceptor (Lewis acid). The Lewis acid in...
00:43Complexometric Titration: Ligands
02:46Crystal Field Theory - Tetrahedral and Square Planar Complexes
Crystal field theory (CFT) is applicable to molecules in geometries other than octahedral. In octahedral complexes, the lobes of the dx2−y2 and dz2 orbitals point directly at the ligands. For tetrahedral complexes, the d orbitals remain in place, but with only four ligands located between the axes. None of the orbitals points directly at the tetrahedral ligands. However, the dx2−y2 and dz2 orbitals (along the Cartesian axes) overlap with the ligands less than the dxy,...