Cyclohexyl diethylenetriaminopentaacetate, CHX-DTPA is an acyclic chelator that provides superior kinetic and thermodynamic properties for the complexation of various metals, particularly yttrium-90 and bismth-213. This chelator was developed in the laboratory of the National Institute of Health and is being investigated in several systems for use in radiopharmaceutical products. Compared to DOTA, CHX-DTPA forms complexes much faster and still provides the stability required of complexes for radiopharmaceuticals.
Cyclohexyl diethylenetriaminopentaacetate, CHX-DTPA is an acyclic chelator that provides superior kinetic and thermodynamic properties for the complexation of various metals, particularly yttrium-90 and bismth-213. This chelator was developed in the laboratory of the National Institute of Health and is being investigated in several systems for use in radiopharmaceutical products. Compared to DOTA, CHX-DTPA forms complexes much faster and provides the stability required of complexes for radiopharmaceutical applications.
An ideal chelator for radiopharmaceutical applications must have a number of key attributes. Chelator production has not been straightforward and scale-up, reproducible quality, and cost all remain challenges. The most widely used chelators are prepared as region- and stereo-isomeric mixtures requiring difficult separations. Simpler preparations must be developed. Complexation kinetics and thermodynamic stability are perhaps the most critical challenges. These properties must be further optimized for most systems.
Appropriate chelator functionalization for stability and good bioconjugation chemistry is difficult as best. Most of the current bifunctional chelators target amino groups as conjugation sites on the biomolecules. More creative chemistry may be required to provide chelators that can be easily stored and still provide the desired reactivity toward a range of target sites. One of several approaches to specifically address thermodynamic stability and complexation kinetics is outlined in the abstract below. Other issues are also under consideration and project objectives will be developed for these shortly.
Structural inversion is a major contributor to complex dissociation in most systems. The improved thermodynamic stability for CHX-DTPA is due to the introduction of the cyclohexyl substituent directly into the DTPA backbone, which imparts increased rigidity to the structure, making complexes of this ligand more stable. Macrocyclics produces chelators such as CHX-DTPA as well as the closely related, MX-DTPA, which is currently being employed in the only FDA-approved, commercial radiopharmaceutical product of this kind.
CHX-DTPA provides bioconjugation via an isothiocyanto functional group. Reaction of this chelator with amino groups on the biomolecule results in a stable thiourea bond. The kinetics of this reaction is also very favorable, providing an ideal bioconjugation target. One of the major challenges with chelators for bioconjugation is the conflicting criteria of high reactivity for bioconjugation and stability for storage. These two properties must be compromised against each other in order to obtain a product that is practical and useful.